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hort of the US population, 1971–1993. Diabetes
Care 21:1138–1145, 1998
36. Kawaguchi M, Techigawara M, Ishihata
T, Asakura T, Saito F, Maehara K, Maruyama Y:
A comparison of ultrastructural changes on en-
domyocardial biopsy specimens obtained from
patients with diabetes mellitus with and without
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37. Pop-Busui R, Kirkwood I, Schmid H, Ma-
rinescu V, Schroeder J, Larkin D, Yamada E,
Raffel DM, Stevens MJ: Sympathetic dysfunc-
tion in type 1 diabetes: association with impaired
myocardial blood flow reserve and diastolic dys-
function. J Am Coll Cardiol 44:2368–2374, 2004
38. 4. Solomon H, Man JW, Wierzbicki AS,
Jackson G. Relation of erectile dysfunction to an-
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Matthews R, Mayeda G, Burstein S,
40. Peled H, Pollick C, Choudhary R, Rosen
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41. 6. Montorsi F, Briganti A, Salonia A, Rigat-
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THE TRIAD STORY OF T2D - GLYCEMIC VARIABILITY,
HYPOGLYCAEMIA AND CLINICAL OUTCOMES

Dr.R.Arulprakash. MD.,MRCP(UK)., FRCP(London)
Indra Diabetes Centre, Tuticorin

Abstract: liver, pancreas, and brain to ensure stable fast-
ing BG levels and transient postprandial glucose
Glycemic control, glycemic variability (GV), and fluctuations. In other words, BG fluctuations in
risk for hypoglycemia are closely related, and it type 1 diabetes result from the activity of a com-
is now evident that GV is important in both the plex metabolic system perturbed by behavioral
physiology and pathophysiology of diabetes. challenges. The frequency and extent of these
However, its quantitative assessment is complex challenges and the ability of the person’s sys-
because blood glucose (BG) fluctuations are tem to absorb them determine the stability of
characterized by both amplitude and timing. The glycemic control. The degree of system desta-
GV estimation tools pose additional complexity bilization depends on each individual’s physio-
in assessment. In this Perspective, we focus on logical parameters of glucose–insulin kinetics,
the acute manifestations of GV, particularly on including glucose appearance from food, insulin
hypoglycemia, and review measures assessing secretion, insulin sensitivity, and counterregula-
the amplitude of GV from routine self-monitored tory response. A major source of GV is the rapid
BG data, as well as its timing from continuous onset of hyperglycemia due to the consumption
glucose monitoring (CGM) data. With availability of “high–glycemic index” foods. Moreover, sus-
of CGM, the latter is not only possible but also tained hyperglycemia engendered by foods with
can now assess rapid glucose fluctuations in real simple carbohydrates and high fat (classically
time and relate their speed and magnitude to clini- pizza) may challenge therapy. Such foods often
cally relevant outcomes. Our primary message is have hedonic qualities (e.g., comfort foods) lead-
that diabetes control is all about optimization and ing to repeated challenges to glycemic stability.
balance between two key factors, frequency of There is strong evidence that feeding behaviour
hypoglycemia and HbA1c reflecting average BG is abnormal in both uncontrolled diabetes and
and primarily driven by the extent of hyperglyce- hypoglycemia and that feeding signals within
mia. GV is a primary barrier to this optimization, the brain and hormones affecting feeding, such
including to automated technologies such as the as leptin and ghrelin, are implicated in diabetes.
“artificial pancreas.” Thus, it is time to standard- Insulin secretion and action vary with the type
ize GV measurement and thereby streamline the and duration of diabetes. In type 1 diabetes, in-
assessment of its two most important compo- sulin secretion is virtually absent, which destroys
nents amplitude and timing. Although reducing the natural insulin–glucagon feedback loop and
hyperglycemia and targeting HbA1c values of thereby diminishes the dampening effect of glu-
7% or less result in decreased risk of micro- and cagon on hypoglycemia. In addition, insulin is
macrovascular complications , the risk for hy- typically administered subcutaneously, which
poglycaemia increases with tightening glycemic adds delays to insulin action and thereby am-
control. Consequently, hypoglycaemia has been plifies the amplitude of glucose fluctuations. In
implicated as the primary barrier to tight control. type 2 diabetes, increased insulin resistance and
progressive loss of b-cell function result in higher
Cause Of Glycemic variability and prolonged postprandial glucose excursions.
Although observed in type 2 diabetes, impaired
In health, glucose metabolism is tightly con- hypoglycemia counterregulation and increased
trolled by a hormonal network including the gut,

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GV in the hypoglycemic range are particularly Measuring the amplitude of GV.
relevant to type 1diabetes: It has been shown
that glucagon response is impaired, and epi- Large number of different methods are currently
nephrine response is typically attenuated as used to assess GV. Currently, a clear consen-
well. Antecedent hypoglycemia shifts down BG sus on the gold-standard method for measuring
thresholds for autonomic and cognitive respons- GV in clinical practice and research is lacking,
es, thereby further impairing both the hormonal al¬though numerous indicators have been pro-
defences and the detection of hypoglycemia . posed. On the contrary, an excessive amount of
Studies have established relationships between variability indices could lead to an increase of
intensive therapy, hypoglycaemia unawareness, the existing confusion surrounding this im¬port-
and impaired counterregulation and concluded ant issue.The traditional statistical calculation of
that recurrent hypoglycemia spirals into a “vi- BG includes standard deviation (SD), coefficient
cious cycle” known as hypoglycaemia associat- of variation (CV), or other metrics, such as the
ed autonomic failure (HAAF) . M-value introduced in 1965 , the mean ampli-
Studies showed that increased GV and the ex- tude of glucose excursions (MAGE) introduced
tent and frequency of low BG are major contrib- in 1970, the glycemic lability index , or the mean
utors to hypoglycaemia and that such changes absolute glucose (MAG) change. As recently
are detectable by frequent BG measurement . In shown, the multitude of GV metrics introduced
addition, a study involving 34 subjects with type1 over the years can be reduced to fewer repre-
diabetes found that higher insulin sensitivity and sentative indices.
lower epinephrine response during hypoglyce-
mia measured in a hospital setting were relat- The risk Analysis include low BG index (LBGI),
ed to increased GV and risk for hypoglycaemia high BG index (HBGI), and average daily risk
measured in the field, irrespective of HbA1c and range (ADRR) are based on a transformation of
other patient characteristics. the BG measurement scale f(x) in the formulas
which aims to correct the substantial asymme-
The benefits of CGM in children and younger try of the BG measurement scale. Numerically,
adults with T1DM are beyond doubt with a num- the hypoglycemic range (BG ,70 mg/dL) is much
ber of studies showing improvement in glycemic narrower than that in the hyperglycemic range
control and reduction in hypoglycemia. The land- (BG .180 mg/dL). SD, CV, MAGE, and MAG
mark Juvenile Diabetes Research Foundation are inherently biased toward hyperglycemia and
(JDRF) trials, using the three main CGM devic- have a relatively weak association with hypogly-
es (DexCom, Medtronic, and FreeStyle Navi- cemia, the LBGI and ADRR account well for the
gator) have shown that CGM improves HbA1c risk of hypoglycemic excursions. On the basis of
by 0.5%–0.8% without an increase in hypogly- this transformation, theory has been developed
cemia in 322 individuals with T1DM and starting for risk analysis of BG data, defining a computa-
HbA1c >7.0%. A secondary study evaluated 129 tional risk space that proved to be very suitable
T1DM patients with HbA1c <7.0% and demon- for quantifying the extent and frequency of glu-
strated reduction in hypoglycemia by 30%–50% cose excursions. Most recently, corrections were
using real-time CGM, indicating a benefit even in introduced that allowed the LBGI and HBGI to
those who are labelled as having good glucose be computed from CGM data with results directly
control. A meta-analysis of 10 studies comparing comparable to SMBG.
real-time CGM with SMBG in T1DM showed a
0.26% reduction in HbA1c without an increase in Besides glucose traces and histograms showing
hypoglycemia further supporting the use of CGM the spread of BG data, there are very few graphs
in this population. specifically aimed to visualize the amplitude of
GV. One such plot is the variability grid analy-
sis (VGA), a method visually presenting GV at
a population level. The VGA is a minimum/max

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Cardio Diabetes Medicine 2018 101

imum plot of the BG readings for a subject tak- does play a role in any estimation of glycemic
en over a certain observation period (e.g., 72 h). variability, including the GVP metric proposed in
The minimum BG (the lower 2.5th percentile) is this study.
plotted on the x-axis, which is inverse coded from
110 mg/dL to ,50 mg/dL. The maximum BG (the HYPOGLYCEMIA:
upper 2.5th percentile) is plotted on the y-axis.
Hypoglycemia is increasingly seen in diabetes
Measuring the timing of GV. given the ever tighter glycemic targets and this
complication of therapy can have detrimental ef-
Although apparently useful, considering time as fects through a number of mechanisms, includ-
an additional component of GV adds an addition- ing cardiac dysrhythmias, increased production
al layer of complexity, which so far has preclud- of vascular inflammatory molecules, and an en-
ed widespread clinical use of time dependent GV hanced thrombotic environment (reviewed in Fri-
metrics. The mean of daily differences (MOD- er et al and King and Ajjan). Therefore, it is not
D),which is designed to assess interday glyce- surprising that a number of studies have shown
mic variation and therefore circadian periodicity. associations between hypoglycemia and high
A generalization of this approach to a finer-res- mortality in patients with both T1DM and T2DM
olution measurement of GV was presented by . Furthermore, accumulating evidence suggests
the continuous overlapping net glycemic action that hypoglycemia is more frequent than initial-
(CONGA) metric that calculates the difference ly envisaged even in those classified as having
between a current BG reading and a reading “preserved hypoglycemic awareness”; therefore,
taken (n) hours earlier and then takes the SD of the size of problem may be even bigger than pre-
these differences. If the BG readings are more viously projected. HbA1c fails to address hypo-
frequent than (n) hours, CONGA will take into its glycemia and therefore frequent SMBG, which
calculation overlapping time windows. Such a is impractical, or CGM, which can be costly, is
representation becomes possible with the avail- required to accurately identify periods of hypo-
ability of CGM time series data, a sequence of glycemia. The advent of new glucose monitor-
frequent, equally spaced in time BG determina- ing devices that are affordable, convenient, and
tions that capture a high resolution picture of the accurate will help to further address the role of
dynamics of BG fluctuations. The duration over hypoglycemia in adverse clinical outcomes. De-
which glycemic variability can be calculated with vote 2 study clearly demonstrates that higher
this method would be calculated the same for dif- day-to-day fasting glycaemic variability is asso-
ferent intervals such as days, weeks, or months. ciated with a higher risk of both severe hypogly-
The calculations of GVP (Glycemic variability per- caemia and all-cause mortality. This result was
centage) from the CGM data were performed in consistent even following adjustments for vari-
Excel using a simple macro or script to automate ous baseline characteristics, including baseline
the data analysis procedure. A sample script is HbA1c and the most recent HbA1c measure-
available upon request from the corresponding ment throughout the trial. A similar result was re-
author. The script was applied to data obtained ported by an analysis of the Predictable Results
from Dexcom CGM devices with five-minute and Experience in Diabetes through Intensifica-
data records. Kohnert et al. evaluated the MAG tion and Control to Target: An International Vari-
change metric in subjects with type 1 and type ability Evaluation (PREDICTIVE) study that used
2 diabetes and found good results when used FPG values as a measure of variability, whereby
with CGM at high sampling rates (once every fasting glycaemic variability was significantly as-
5 min), but expressed concern that it could be sociated with nocturnal hypoglycaemia following
misleading with low sampling rates (once every adjustments for change in HbA1c measurements
60 min).30 As expected, the sampling frequency .Clamp studies have shown that fluctuations in

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blood glucose induce higher levels of oxidative contrast to a study involving just 100 patients
stress and endothelial dysfunction, factors that over 4 weeks , that there was no evidence that
are implicated in the development of cardiovas- glycemic variability contributed to neuropathy
cular disease in individuals with type 2 diabetes, development either. A further analysis extended
compared with stable, constant high blood glu- the follow-up into year 4 of the continuation study
cose concentrations . However, it is possible that to the DCCT, the Epidemiology of Diabetes Inter-
glycaemic variability may indirectly increase the ventions and Complications (EDIC) study. Again,
risk of cardiovascular events due to an increase there was no signal of a contribution of glucose
in severe hypoglycaemia. fluctuations toward small vessel complications.
There is also a complete paucity of data relat-
CLINICAL OUTCOMES: ing degrees of PPG to the development of di-
abetes microvascular complications. Indeed, in
Basic science evidence: type 2 diabetes as a whole there are few stud-
ies to test the hypothesis that glucose variability
While there are many studies that show that gly- contributes to complications. However, in the UK
cemic variability can contribute to an increase Prospective Diabetes Study (UKPDS) the fact
in the production of free radicals, there are also that insulin treatment (where patients are liable
many others that do not. In contrast to the study to greater glycemic instability) did not seem to
by Monnier et al. that showed a close relation- confer a higher risk of microvascular disease
ship between glucose variability in free-living than oral hypoglycemic agents makes a positive
type 2 diabetic patients and their 24-h urinary association in type 2 diabetes less likely. In com-
excretion of the oxidative stress marker 8-isoP- parison with this short-term glucose variability, it
GF2a, DeVries and colleagues have shown no has proven far less difficult to show an associ-
such association in either type 2 or type 1 dia- ation between HbA1c variability and microvas-
betes. This was despite using a similar study cular risk (9). Of course, the timescale of glyce-
design but with more participants and a wider mic changes that fluctuations in HbA1c reflect is
range of glucose variability and using a more orders of magnitude greater than the within-day
specific method to measure the urinary isopros- fluctuations usually described in relation to glu-
tanes. Adding to these concerns, it is now also cose variability, and this has given rise to sev-
clear that there are potential confounders in us- eral proposed mechanisms for the observation
ing markers such as 8-iso PGF2a to represent that are unconnected to glucose variability per
free radical damage. For instance, Monnier et al. se. For example, it may be that patients with the
found that insulin treatment, but not oral agents, largest fluctuations in HbA1c are also those with
can lead to a marked reduction in the production the most haphazard overall diabetes care. How-
of this urinary isoprostane; yet, evidence from ever, if long-term glycemic variability were truly
studies such as the UKPDS would suggest that to be implicated then a possible mechanism may
oral agents and insulin are equally successful in relate to the observation that acute improve-
reducing microvascular risk. ments in HbA1c can lead to a short-term “early”
In looking to identify a link between glucose vari- worsening in retinopathy before subsequently
ability and microvascular complication risk, the resulting in a net long-term improvement. If a pa-
DCCT provides a large dataset on which to test tient therefore has cycles of HbA1c improvement
this hypothesis, as it collected seven point lab- followed by worsening, it is possible that there is
oratory-measured glucose day profiles every 3 insufficient time for them to acquire the long-term
months throughout the study in its 1,441 partici- complication benefits before they have another
pants over an average of 6.5 years. It has been cycle of this fluctuant glycaemia. Evidence from
found that glucose variability, defined statistically DEVOTE supports associations between higher
in numerous ways, did not add to mean glucose day-to-day fasting glycaemic variability and in-
in predicting the development or progression of creased risks of severe hypoglycaemia and all-
retinopathy or nephropathy. It also showed, in

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Cardio Diabetes Medicine 2018 103

cause mortality. docrinology 2004;145:4575–4582

Highlights: 7. German JP, Wisse BE, Thaler JP, et al. Leptin-
deficiency causes insulin resistance induced by
•Glycemic variability and hypoglycaemia are uncontrolled diabetes. Diabetes 2010;59:1626–
closely related phenomenon. 1634
•The association of hypoglycaemia and micro or 8.Dagogo-Jack SE, Craft S, Cryer PE. Hypogly-
macrovascular complications are being studied cemia-associated autonomic failure in insulinde-
but no conclusions are arrived yet. pendent diabetes mellitus. Recent antecedent
•It is worth measuring glycemic variability which hypoglycemia reduces autonomic responses
will predict hypoglycemic episodes and hyper- to,symptoms of, and defense against subsequent
glycemic excursions which will improve optimis- hypoglycemia.J Clin Invest 1993;91:819–828
ation of blood glucose control. 9.Cox DJ, Gonder-Frederick L, Ritterband L,-
•Continuous glucose monitoring has become Clarke W, Kovatchev BP. Prediction of severe hy-
affordable and accessible to the patients, which poglycemia. Diabetes Care 2007;30:1370–1373
will certainly will be helpful to monitor GV. 10. Rodbard D. New and improved methods to
•Apart form HBA1c and SMBG, the role of CGM characterize glycemic variability using continu-
and metrics of GV has to be standardised. ous glucose monitoring. Diabetes Technol Ther
2009;11:551–565
References 11.Rodbard D. The challenges of measuring
glycemic variability. J Diabetes Sci Technol
1.UK Prospective Diabetes Study (UKPDS) 2012;6:712–715
Group. Intensive blood-glucose control with sul- 12.Kovatchev BP, Clarke WL, Breton M,Brayman
phonylureas or insulin compared with conven- K, McCall A. Quantifying temporal glucose vari-
tional treatment and risk of complications in pa- ability in diabetes via continuous glucose moni-
tients with type 2 diabetes (UKPDS 33). Lancet toring: mathematical methods and clinical appli-
1998;352:837–853 cation. Diabetes Technol Ther 2005;7:849–862

2.The Diabetes Control and Complications Trial
Research Group. Hypoglycemia in the Diabe-
tes Control and Complications Trial. Diabetes
1997;46:271–286

3.Cryer PE. Hypoglycaemia: the limiting factor in 13.Kovatchev BP, Shields D, Breton M. Graphi-
the glycaemic management of type I and type II cal and numerical evaluation of continuous glu-
diabetes. Diabetologia 2002;45:937–948 cose sensing time lag. Diabetes Technol Ther
4.Hirsch IB. Glycemic variability and diabetes 2009;11:139–143
complications: does it matter? Of course it does! 14.Glucose Variability and Risk Analysis of
Diabetes Care 2015;38:1610–1614 Diabetes Diabetes Care Volume 39, April
5.Bergenstal RM. Glycemic variability and di- 2016;39:502–510 | DOI: 10.2337/dc15-2035.
abetes complications: does it matter? Simply 15.Zinman B, Marso SP, Poulter NR, Emer-
put, there are better glycemic markers! Diabetes son SS, Pieber TR, Pratley RE, Lange M,
Care 2015;38:1615–1621 Brown-Frandsen K, Moses A, Ocampo Fran-
6. Gelling RW, Overduin J, Morrison CD, et al.Ef- cisco AM, Barner Lekdorf J, Kvist K, Buse JB;
fect of uncontrolled diabetes on plasma ghrelin Day-to-day fasting glycaemic variability in DE-
concentrations and ghrelin-induced feeding.En- VOTE: associations with severe hypoglycaemia
and cardiovascular outcomes (DEVOTE 2).Dia-

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betologia. 2018 Jan;61(1):48-57. doi: 10.1007/
s00125-017-4423-z. Epub 2017 Sep 15.
16.Lüddeke HJ1, Sreenan S, Aczel S, Maxeiner
S, Yenigun M, Kozlovski P, Gydesen H, Dorn-
horst A; PREDICTIVE Study GroupPredictive
study Diabetes Obes Metab. 2007 May;9(3):428-
34..
17.Saisho Y et al.Glycemic variability and oxida-
tive stress: a link between diabetes and cardio-
vascular disease? Int J Mol Sci. (2014)36. Magni
L et al. Evaluating the efficacy of closed-loop glu-
cose regulation via control-variability grid analy-
sis. J Diabetes Sci Technol. (2008)
18.Muñoz OM, Gómez AM, Maira GJ, Fabián
Mauricio LV, Ruiz-Morales ÁJ.The different
methods of assessing glycemic variability, qual-
ity of glycemic control and glycemic risk cannot
be interpreted as equivalent in clinical practice.
Diabetes Metab Syndr. 2018 Jul;12(4):555-561.
doi: 10.1016/j.dsx.2018.03.028. Epub 2018 Mar
28.

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Cardio Diabetes Medicine 2018 105
MICROALBUMUNURIA- A CVD RISK MARKER

Dr.Mritunjay Kr Singh
Consultant Physician & Nephrologist

Aims, Gaya

“One can obtain considerable information concerning
the general health by examining the urine” – Hippocrates

ABSTRACT

Coronary artery disease (CAD) is a major cause The albumin-to-creatinine ratio (ACR) is consis-
of mortality and morbidity in both developed & tent with the 24-hour timed collection (the gold
now in developing countries. Atherosclerosis is standard) and is the recommended method of
responsible for almost all cases of CAD. CAD assessing albuminuria
is a multifactorial disorder with several classical
risk factors -namely blood pressure, smoking, MAU is defined as persistent increased urinary
cholesterol, diabetes, and obesity. Subsequent albumin excretion (UAE) in the range of 20-200
studies and meta-analyses have identified other µg/min or 30 -300 mg/24 hours. Persistent MAU
factors to better identify patients potentially at is defined as the presence of MAU in two or
Risk of CAD, including inflammatory markers, three consecutively collected samples prefera-
haemostatic factors, left ventricular hypertro- bly within a period of six months.
phy, metabolic syndrome and markers of kidney
dysfunctions like decreased GFR and microal- MAU can also be defined in terms of the uri-
bumunuria. Microalbuminuria (MA) is gaining nary albumin to creatinine ratio. A ratio great-
recognition as a simple marker of an athergenic er than 30 mg/gm in the first voided, clear and
mileu, owing to its association with several ath- midstream morning urine sample is considered
erosclerotic risk factors and early systemic vas- abnormal.
cular (endothelial) damage. MA is also a marker
of subclinical organ damage and cost effective LINK BETWEEN ALBUMUNURIA AND
and useful tool for screening of high risk per- CAD (2)
sons and helps in modifying and optimizing the
treatment strategy. The endothelium, once considered a simple, in-
ert semipermeable barrier between the blood-
MICROALBUMUNURIA: MEASUR- stream and the outer vascular wall, is now
MENT AND DEFINITION(1) recognized to mediate vasoactivity, maintains
blood fluidity, and contributes to the local bal-
A 24-hour timed urine sample has long been the ance between pro and anti-inflammatory activity
gold standard for measuring albuminuria, but as well as pro and anticoagulant activity.
the collection is cumbersome and time-consum-
ing, and the test is prone to laboratory error. Thus endothelial dysfunctions are considered to
be the first stage of athersclerosis and precede
Dipstick measurements are more convenient structural disorder, plaque buildup and clinical
but they have low sensitivity and high interob- events like CAD. (fig1)
server variation.
It was shown that imaging technique for encular

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Microalbumunuria- a cvd risk marker 106

Fig1 Schematic representation of the cardiovascular continuum from normal phys-
iologic condition (left) to the presence of cardiovascular risk factors, subclinical or-
gan damage, and eventually cardiovascular, cerebrovascular, and renal events (right)

dothelial dysfunction(ED) such as flow-medi- alence of microalbuminuria in an aselect sam-

ated vasodilation, was impaired in individuals ple (n=40,856) of the mostly Caucasian popu-

with diabetes mellitus as compared with those lation of 28-75 years in the city of Groningen

without and also was impaired in individuals is 7.2% (n=2918). Of the 2,918 subjects, that

with microalbumunuria as compared with those were found to be microalbuminuric (defined as

without, regardless of whether they had diabe- a morning urinary albumin concentration of 20-

tes or not. 200 mg/L) only 6.2% was known to be diabetic

and 18.9% was known to be hypertensive.

In view of these considerations, endothelial

dysfunction with an impaired nitric oxide (NO) A clear positive relationship was observed be-

balance, activation of local mediators and in- tween urinary albumin excretion (UAE) and all-

creased activity of the RAAS system possibly cause, cardiovascular, and noncardiovascular

explain the association between microalbumin- death. The hazard ratio for cardiovascular mor-

uria and CVD. tality shows a splay as shown in figure 2, with-

PREVEND: to assess the impact of out a specific cut-off value above which the risk
microalbumunuria in general (3) is increased. For every doubling of UAE the risk
of cardiovascular death is increased by almost

The Prevention of Renal and Vascular End- 30%. The results provide compelling evidence
stage Disease (PREVEND) study aims to that microalbuminuria is a strong predictor of
study the natural course of an elevated urinary cardiovascular mortality, independent of other
cardiovascular risk factors .
albumin loss in general population. The prev-
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Cardio Diabetes Medicine 2018 107

Fig3 Composite end point stratified by time-varying
albuminuria.The numbers in parentheses are the num-
bers of at-risk patients in each range of UACR at base-
line, year 2, and year 4.

Fig2 HOPE (Heart Outcomes Prevention
Evaluation): to assess the impact of
The LIFE Study: to assess the impact microalbumunuria in high risk pa-
of Albuminuria in Hypertensive Pa-
tients 5)

In a Heart Outcomes Prevention Evaluation

tients with Left Ventricular Hypertro- (HOPE) substudy, UAE predicted mortality in
phy (4) patients who were at high cardiovascular risk
(55 yr of age with CVD or diabetes plus at least

The Losartan Intervention for Endpoint reduc- one other cardiovascular risk factor). A linear re-
tion in hypertension (LIFE) study aims to deter- lationship was also observed between the level
mine the albuminuria level at which cardiovas- of microalbumunuria and cardiovascular events,
cular morbidity and mortality are increased in a even extending below the traditional microalbu-
large group (n=8106) of hypertensive patients minuria threshold.

with left ventricular hypertrophy. CV RISK STRATIFICATION (6)

A clear positive relationship was observed be- (CV) risk assessment in the clinical practice is
tween UACR and primary composite end point mostly based on risk charts, such as Framing-
(CV death, fatal and non-fatal MI, fatal and ham risk score and Systemic Coronary Risk Es-
non-fatal stroke). (fig3) Moreover it has been timation (SCORE). Based on these individuals
shown that MAU is independently associated are classified at low risk (<1% of cvd death at
with CV mortality with such a relationship main- 10yrs with SCORE), intermediate risk (1-5% in
tained even within normal range of UACR. In- SCORE), or high risk (>5% with SCORE).These
vestigators also suggested that detecting micro- scoring systems guides the appropriate clinical
albuminuria would help clinicians decide when management
to initiate antihypertensive therapy, since it rep-

resents target organ damage. Sehestedt et al Investigated, whether inclsion

of marker of subclinical organ damage like MA

and LVH could improve the CV risk prediction

beyond SCORE. Based on their findings the au-

thors concluded that the most efficient approach

would be only to measure MA in subjects with
Cardio Diabetes Medicine

Microalbumunuria- a cvd risk marker 108

duc-SCORE between 1 and 5% rather than in <70 mg/dl is patients with diabetes and CVD
subjects with SCORE <1%. In fact, these pa- HDL levels
tients in the presence of MAU would become Consider screening in patients with diabetes
at high CV risk by having CV death odds more
than three-fold higher compared to those pa- Smoking cessation
tients without MAU. Dietary limitation of salt (3 g/d) and saturated fat

GUIDELINES ON SCREENING Regular exercise and weight control

KDIGO - People with diabetes, hypertension, Antiplatelet therapy

cardiovascular disease, family history of CKD, Highlights:
obesity, hyperlipidemia, metabolic syndrome,
smoking, treatment with potentially nephrotox- • MAU is a risk marker of both renal and
ic drugs, some chronic infectious diseases and cardiovascular disease.
cancers, age > 60.
• MAU and CVD linked by a common
ADA- Patients with type 1 diabetes with a du- pathophysiological process (generalized endo-
thelial dysfunction).
ration ≥ 5 years and in all patients with type 2
diabetes at the time of diagnosis.

NICE- People at risk—eg, those with diabetes, • MAU is most effective tool to measure
target organ damage in hypertensive patients
hypertension, cardiovascular disease, structural .
renal tract disease, renal calculi, prostatic hy- • Risk of adverse clinical outcomes start
pertrophy, multisystem diseases such as SLE, below the traditional MAU threshold.
a family history of stage 5 CKD or hereditary
kidney disease, or opportunistic detection of he- • It is a treatable marker, and blood pres-
maturia. sure control is most effective means to reduce
MAU.
Not recommended: routine screening in
References:
the general population who are asymptomatic
or are considered at low risk. 1. Richard J. jhonson, John Feehally, Jur-
gen Floege Comprehensive clinical nephrology,
Summary of recommendations for pa- 5th Edition ELSEVIER SAUNDERS
tients with microalbumunuria (7)
2. DANIELE VERSARI, MD ELENA
Reno protection with ACE inhibitors or an- DAGHINI, MD AGOSTINO VIRDIS, MD LO-
RENZO GHIADONI, MD, PHD STEFANO TAD-
giotensin receptor blockers for patients with di- DEI, MD Endothelial Dysfunction as a Target
abetes for Prevention of Cardiovascular Disease DIA-
BETES CARE, VOLUME 32, SUPPLEMENT 2,
BP control NOVEMBER 2009

< 140/90 mmHg for the general population 3. Hillege HL, Fidler V, Diercks GF, et al.
< 130/80 mmHg for patients with diabetes Urinary albumin excretion predicts cardiovas-
cular and noncardiovascular mortality in gener-
Glycemic control: hemoglobin A1c 7% al population. Circulation. 2002;106:1777-8

LDL cholesterol goal

<100 mg/dl for patients with advanced renal dis-
ease or diabetes

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4. Ibsen H, Olsen MH, Wachtell K, et al.
Reduction in albuminuria translates to reduc-
tion in cardiovascular events in hypertensive
patients: losartan intervention for endpoint
reduction in hypertension study. Hypertension
2005; 45:198-202.
5. Gersstein HC, Mann JF, Pogue J, et all.
Prevalence and determinants of microalbumin-
uria in high risk diabetesdeterminants of micro-
albuminuria in high risk diabetes and non-dia-
betic patients in the heart outcomes prevention
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6. Sehestedt T, Jeppesen J, Hansen TW,
Wachtell K, Ibsen H, Torp-Pedersen C, Hildeb-
randt P et al. Risk prediction is improved by
adding markers of subclinical organ damage to
SCORE. Eur Heart J 2010; 31:883-891
7. Matthew R. Weir. Microalbuminuria
and Cardiovascular Disease. Clin J Am Soc
Nephrol 2: 581-590, 2007

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Gestational Diabetes Mellitus: Mother of NCDs

Dr Rajiv Kovil, MBBS, D.Dia, Mumbai
Dr Kovil Diabetes Care Centre Mumbai

Abstract: characterized by elevated blood glucose levels,

The realization that diabetes in pregnancy is a impaired insulin secretion, and/ or peripheral

significant contributor to the growing epidemic resistance to insulin action. There are now an

of type 2 diabetes mellitus (T2DM) can help us estimated 382 million people with diabetes,

focus our attention on the pregnant woman as a of which 184 million are women. In addition,

critical target for diabetes prevention strategies. about 316 million people have impaired glucose

Diabetes in pregnancy has serious consequences tolerance.3 Most of these cases were distributed

for the mother as well as the baby. The clinical throughout the developing countries, such as

issues that follow GDM in pregnancy are well China and India.

appreciated. In fact, GDM is believed to be a

stage in the evolution of type 2 DM. GDM is also Not only does diabetes mellitus cause many

a known risk factor for T2DM besides its known complications for patients, but also poses a

adverse impact on pregnancy outcome. The higher risk of malformations in their offspring.

pregnant diabetic mother provides a critical link Furthermore, maternal diabetes mellitus can

for transgenerational transmission. Epigenetic affect the offspring’s health by increasing the

changes in various genes may increase the risk for some non-communicable disorders in

lifelong metabolic disease susceptibility and, adulthood. Infants of diabetic mothers are more

thus, the likelihood for a new generation of susceptible to diseases, such as obesity, type 2

mothers with GDM and/or obesity thus feeding diabetes, cardiovascular complications, and even

the vicious cycle of diabetes which sets off a cancer. A three- to fivefold higher incidence of

self-perpetuating cycle of rising diabetes in pregnancy complications is seen even in women

the community. Thus, pregnancy offers a huge with pre-existing insulin dependent diabetes

window of opportunity to not only improve mellitus, well controlled on insulin. Intra-uterine

pregnancy outcomes in GDM but also to address exposures and gestational programming are

intergenerational prevention of NCDs, such as emerging as potential causative factors in this

diabetes and cardiovascular disease. globally emerging epidemic of diabetes mellitus.

Offspring of diabetic mothers are susceptible

Introduction: to the onset of metabolic syndromes, such as

Pregnancy is no longer limited to obstetric type 2 diabetes and obesity at adulthood, and

complications like haemorrhage and eclampsia. this trend can be inherited between generations.

A number of other medical conditions, such as The risk for non-communicable diseases may

non-communicable diseases affect pregnancy be caused by epigenetic variations but genetics

and result in adverse outcomes for both the explains only a small proportion of the effects.

mother and offspring, contributing to death and This phenomenon may be explained well by

poor health. the ‘‘Barker hypothesis,’’ which states that

Over the last twenty years, the prevalence of undernutrition before birth induces persisting

Gestational diabetes, defined as ‘any degree of changes in a range of metabolic, physiological,

glucose intolerance with onset or first recognition and structural parameters.6 It is now well known

during pregnancy’ has increased, reflecting the that risk exposure to NCDs begins as early as

increasing frequency of type 2 diabetes in the intrauterine life and gradually accumulates over

underlying population. the coming years. The question we are now

Diabetes mellitus is a chronic disease posed with is- Does pregnancy and early life offer
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Gestational DCiabrdeitoeDsiaMbeeltleitsuMs:eMdiocitnhee2r0o1f8NCDs 111

a window of opportunity for intervening? Can we Haemorrhage, hypertensive disorders,

leverage the synergies between maternal health obstructed labour, and infection/sepsis are

and NCD prevention to the advantage of both? among the leading global causes of maternal

mortality. High blood pressure and gestational

Gestational Diabetes Mellitus hyperglycaemia are linked directly or indirectly

to all of them. According to WHO’s report on
Epidemiology Across the world, one in ten Women and Health, high blood pressure and

pregnancies may be associated with diabetes, high blood glucose are two leading risk factors for

90% of which are gestational diabetes (GDM). death from chronic conditions in women above

Up to 30% of pregnancies may involve diabetes 20 years of age, yet women are not routinely

in high risk groups. The rate of GDM in India, screened for hyperglycaemia during pregnancy

one of the most populous country in the world is and the diagnosis of gestational diabetes is

14.3%.1,4 often missed; maternal mortality and morbidity

In 2013, 16.8% of live births (21.4 of 127 million) attributable to diabetes in women may therefore

were associated with hyperglycemia in pregnancy actually be considerably higher than current

and 16% of these were dude to overt diabetes in estimates.

pregnancy.3An estimated 22 million women with

diabetes were in the reproductive age group of Thereareseveralfetalandmaternalcomplications

20–39 years; in 2010, an additional 54 million in associated with GDM. As a general rule, women

this age group had impaired glucose tolerance or with diabetes have a poor outcome compared

pre diabetes with potential to develop gestational with those without diabetes. It is observed that the

diabetes if they become pregnant. Thus over rate of congenital malformations, preeclampsia,

76 million women are at risk of their pregnancy premature delivery, perinatal mortality, and risk

being complicated with pre-existing diabetes or of delivering a macrosomic baby are increased.

gestational diabetes. Globally, the perinatal mortality rate rises by

The prevalence of hyperglycemia is highest nearly fourfold and the congenital malformation

among women over 45 years of age. (47.7%) rate rises twofold in women with diabetes. Poor

signalling that increasing age is associated glycemic control in early pregnancy may be

with a higher prevalence of hyperglycemia in related to the risk of such adverse outcomes. A

pregnancy. meta-analysis has shown a reduction in the risk

Identifying women with high risk of GDM of major congenital malformations with improved

The following markers have been described to pre-pregnancy care which targets optimal

clinically identify women with high risk of GDM3,4 gylcemic control.5 Women with pre-existing

· Race/Ethnicity or pre-gestational DM are at increased risk for

· BMI pre-eclampsia and Caesarian delivery while
their infants tend to experience higher rates of
· History of T2DM in first-degree relatives macrosomia and shoulder dystocia.
Overall, women with GDM have an increased
· History of GDM, macrosomia, unexplained risk of developing T2DM [RR 7.43]. The relative
stillbirth and spontaneous abortion in previous risk is 4.69 within five years of index pregnancy,
pregnancies

· Excessive weight gain, Presence of polycystic which more than doubles to 9.34, five years post-

ovarian syndrome, metablic syndrome, partum. The prevalence of metabolic syndrome

polyhydramnios, and suspected macrosomia and risk of cardiovascular disease (CVD) are

during current pregnancy. also increased in women with a history of GDM.

Universal screening for hyperglycemia must Risks associated with hyperglycemia in

be the standard practice since more than half pregnancy

the women with GDM are not being identified

currently.

Complications for the mother and child

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Cardio Diabetes Medicine 2018 112

GDM and the risk of NCDs : What is the obesity in the youth can be attributed to maternal;
link? GDM and obesity. GDM creates a vicious cycle

Role of Epigenetics in which diabetes begets diabetes.

Epigenetics provides a link between genes and

the environment, and epigenetic alterations Possible mechanisms

can be inherited by the next generation. Early

environmental exposure to maternal diabetes There are some likely biological mechanisms

may be a key reason for the offspring’s impaired through which GDM increases the risk of an

health in adulthood. This can be explained by the offspring to have obesity or DM. In the early

evidence that developmental anomalies induced phase of intrauterine development of the fetus in

by maternal diabetes mellitus are also found in women with GDM, there is increased vulnerability

the embryo and fetus and maternal diabetes of having a defect in organogenesis and

mellitus injures ovarian function and oogenesis. physiologic function development when exposed

Many studies have confirmed that epigenetics to increased levels of metabolic substrates,

may be crucial for the detrimental effects such as amino acids, glucose and fatty acids,

on offspring exposed to the hyperglycemic Moreover IUGR in a female fetus can also result

environment. Although the adverse effects on in women having GDM as adults

epigenetics in offspring of diabetic mothers may

be the result of the poor intrauterine environment,

epigenetic modifications in oocytes of diabetic .

mothers are also affected. However, the Conclusion

detailed mechanism(s) causing the alteration of GDM can have serious immediate as well as long

epigenetics are still not completely understood. term implications for the health of the mother as

Epigenetic modifications are generally assumed well as the offspring. Having saved a mother

to mediate gene-environment interactions, with GDM from dying of obstructed labour and

leading to persistent changes of gene regulation her macrosomic baby, what can be done to

and metabolic pathways However, how the ensure their future good health and to prevent or

alterations of epigenetics in offspring of maternal significantly delay the onset of T2DM?

diabetes are transmitted to the next generations Preventive strategies such as life style

by oocytes is poorly understood.6 Role of fetal modifications such a healthy diet, losing weight,

environment quit smoking and healthy physical activity will

reduce the rate of obesity and hypertension which

in turn will go a long way in decreasing the rising

Fetal environment contributes significantly to incidence of Type 2 Diabetes Mellitus. Since GDM

higher risk for diabetes than can be explained by is the mother of all NCDs, taking adequate care

genetic inheritance alone. Offsprings of mothers of the girl child before she becomes a mother,

with GDM are 4-8 times more likely to develop is a step forward in addressing the challenge

diabetes compared to a non-GDM pregnancy. of improving maternal health and prevention of

Children born to obese or diabetic mothers are NCDs

at higher risk of obesity and/or insulin resistance

and T2DM during childhood, adolescence, and

early adulthood. Almost half of diabetes and

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Cardio Diabetes Medicine 2018 113

Highlights:

Across the world, one in ten pregnancies may
be associated with diabetes, 90% of which are
gestational diabetes (GDM).

Universal screening for hyperglycemia must
be the standard practice since more than half
the women with GDM are not being identified
currently. .

There are several fetal and maternal
complications associated with GDM.

Early environmental exposure to maternal
diabetes may be a key reason for the offspring’s
impaired health in adulthood.

Fetal environment contributes significantly to
higher risk for diabetes than can be explained by
genetic inheritance alone.

Pregnancy offers a huge window of opportunity
to not only improve pregnancy outcomes in GDM
but also to address intergenerational prevention
of NCDs, such as diabetes and cardiovascular
disease.

References

1. Hussein J. Non-communicable diseases during
pregnancy in low and middle income countries.
Obstetric Medicine 2017. 10(1): 26-29.

2. Dain K. Gestational diabetes: a serious
maternal and invisible health issue. Diabetes
Voice 2011. 56(1): 22-25.

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Cardio Diabetes Medicine 2018 114

REVISITING DIABETES IN INFERTILITY

Dr. Archana Ambujan Ms(OG), DRM (Germany)
Consultant Gynogolagist

Sundram Arulrhaj Hospital Tuticorin

Diabetes is an epidemic today. The incidence of Menarche & Menstrual Cycle Distur-
diabetes mellitus is rising rapidly Worldwide, with bances in Type 1 Diabetes :
an estimated 366 million people living with the
disease by 2030 (WHO, 2002). The overall na- Before the first introduction of insulin in clinical
tion wide prevalence of diabetes in India is now care of Type 1 diabetes in 1922, menarche rarely
9%. Currently 61.3 million people in India are occurred in girls with diabetes during childhood,
suffering from diabetes and homes the second and when it did occur, menses usually ceased.
largest number globally. The number is expect- Successful pregnancy was achieved in only
ed to reach 101.2 million in 2030. Approximately 2% of Type 1 diabetic women. Initiation of insu-
half of the population are women. Diabetes is a lin treatment caused menstruation to appear in
chronic disorder contributing to many complica- most female diabetic patients, but did not abolish
tions affecting various systems such as arterio menstrual irregularities. Earlier studies showed
sclerosis, microangiopathy, nephropathy and delayed menarche among women with the on-
neuropathy. Although most problems due to di- set of diabetes before menarche. Although con-
abetes have been widely studied, the reproduc- trolled for their diabetes mellitus together with
tive system affections are still little understood. persistent menstrual disorders remained in the
third and forth decade in 30% of these women.
Female Diabetes and Infertility : The prevalence of these disorders, mainly sec-
ondary amenorrhea and oligomenorrhea, was
Diabetes affects women in many ways, here our shown to be three-times more frequent com-
focus will be – the association between diabetes pared to nondiabetic women.
mellitus and infertility In a study by Strotmeyer et al study, Type 1 dia-
betes was independently associated with longer
Infertility risk factors related to DM: cycle length (>31 days), long menstruation (≥6
days), heavy menstruation, and more reports of
any menstrual problem at the younger age rang-
es (<29 years). As women moved closer to the
end of their reproductive years, the differences
found by diabetes status were no longer signif-
icant.
The above described observations may reflect
a general dysfunction of the hypothalamic–pitu-
itary–ovarian (HPO) axis
The effect of Type 1 diabetes on the reproduc-
tive endocrine axis can be conceptualized as
anorexia-like hypothalamic anovulation. Diabet-
ic women with low BMI are more likely to have
menstrual irregularities. There are katabolic
processes in young diabetic girls and nutrition-

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Cardio Diabetes Medicine 2018 115

al restriction leading to intracellular starvation, obesity is increasing, thus raising the incidence
especially before the diagnosis and initiating in- of Type 2 diabetes during the reproductive years.
sulin treatment. This may subsequently cause There is an association between Type 2 diabe-
disruption in hypothalamic pulsatile secretion of tes and fertility, alterations in the length of the
gonadotrophin-releasing hormone (GnRH), with menstrual cycle, and the age of onset of meno-
a resultant decrease in gonadotropins secretion pause. This association may be explained by
in turn leading to menstrual irregularities. linking this disease to PCOS, the most common
Neuroendocrine control must also be consid- hormonal disorder among women of reproduc-
ered when interpreting disturbances in the HPO tive age, and a leading cause of infertility. Insulin
axis. It has been reported that Type 1 diabetic resistance, obesity and diabetes mellitus strong-
women had lower basal prolactin levels, unrelat- ly correlate with PCOS. Both PCOS and Type
ed to the presence of menstrual disorders. How- 2 diabetes have the same risk factors, such as
ever, only diabetic amenorrheic patients have hypertension, obesity, dyslipidemia and hyperin-
a decreased prolactin response to dopamine sulinemia. Hyperinsulinemia results from insulin
antagonists. These results suggest that diabetic resistance, which through alterations in the level
patients with menstrual disorders may have in- of IGFBP, IGF1 and SHBG stimulates increased
creased central dopaminergic activity, which in androgen secretion at the adrenal gland and the
turn inhibits GnRH secretion. Endogenous opi- ovary, subsequently causing anovulation. PCOS
um-like peptides – endorphins – also have an women are at significantly increased risk for im-
inhibitory effect on GnRH release. It is believed paired glucose tolerance and Type 2 diabetes
that gonadotrophin secretion is regulated by mellitus at all weights and at a young age.
an interaction between dopamine and endoge-
nous opioids. Finally, an association between Obesity is common in both PCOS and Type 2
Type 1 diabetes and polycystic ovary syndrome diabetic women. Studies show that obese wom-
(PCOS) has also been reported. These authors en seeking pregnancy experience longer times
found that vigorous treatment with insulin, fre- to conception, unrelated to age and to cyclic
quently applied in Type 1 diabetes in order to regularity, which is suggestive of alterations in
prevent diabetic complications, may lead to su- ovarian function during the periconceptual pe-
praphysiolgical doses of insulin, subsequently riod. Oocytes from women with increased BMI
initiating hyperandrogenism and PCOS. In ad- give rise to blastocyts of poorer quality. There is
dition to exogenous hyperinsulinism, insulin re- elevated intrafollicular insulin and triglycerides,
sistance is also possible in women with Type 1 and increased expression of lipoprotein recep-
diabetes, owing to decreased glucose uptake by tors in overweight and obese women. There is
the muscle. That also contributes to the devel- an increase in free androgen profile within the
opment of androgen excess in women with Type ovarian follicles of obese women, as well as an
1 diabetes. This is especially prominent among increased level of C-reactive protein, and all
women with the onset of Type 1 diabetes before these put together are associated with the poor-
menarche. PCOS prevalence of 31 and 40% er reproductive outcomes typically observed in
were reported using the Androgen excess soci- these patients.
ety criteria and Rotterdam criteria, respectively
Finally, systematic review on pregnancy and fer-
Correlation between Type 2 Diabetes tility following bariatric surgery showed that some
& Fertility : normalization of sex hormones and menstrual ir-
regularities, as well as improvement in PCOS,
Most of the Type 2 diabetes female patients are has occurred. However, the influence on fertility
postmenopausal women, but with changing di- still needs to be further studied.
etary and lifestyle patterns, the prevalence of

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Cardio Diabetes Medicine 2018 116

Association of Modern Management of diabetic women. In particular, patients with early
Diabetes Mellitus Type 1 with Decrease menopause were younger at Type 1 diabetic on-
in Infertility : set (8.6 vs 12.6 years of age; p = 0.10). Multivar-
iate analysis confirmed that Type 1 diabetes was
The relationship between menstrual dysfunction an independent determinant of early menopause
and diabetic control was considered controver- (HR: 1.98; p = 0.056). In the same study, the age
sial. Kajer et al. showed an association between of menarche was found to be significantly older
low BMI, high concentrations of HbA1C and the for Type 1 diabetic women compared with non-
presence of menstrual irregularities. Yeshaya et diabetic women; taken together with premature
al. found that patients with diabetic complica- menopause, this therefore reduces the repro-
tions had a higher incidence of menstrual dis- ductive period in Type 1 diabetic women by 6
orders compared with diabetic patients without years.
complications. Schroeder et al. examined the
correlation between the degree of glycemic con- Premature menopause in Type 1 diabetic women
trol in Type 1 diabetic adolescents and menstrual may also be related to the autoimmunity aspects
regulation. of Type 1 diabetes. Studies have found higher
Limited conclusions could be made regarding the prevalence of thyroid peroxidase autoantibodies
influence of diabetes on fertility, since the studies in patients with premature ovarian failure com-
described above are based on a small number of pared with healthy controls.
patients. They also addressed menstrual prob- Regarding women with Type 2 diabetes, few
lems alone, without long-term follow-up on fertil- studies have so far been conducted. The only
ity rates among patients with Type 1 diabetes in study that was found did not show increased risk
relationship to their gycemic control.The stricter for premature menopause. López-López R et al.
metabolic control exercised in the past 20 years, compared 409 women without diabetes and 404
together with better control of blood pressure women with Type 2 diabetes and found no differ-
and more frequent use of drugs active in block- ence for age at menopause between these two
ing the renin–angiotensin system, has also been groups.
successful with regard to preserving fertility.
Autoimmunity :
Menopause :
Autoimmune diseases, including oophoritis, or-
It has been known that patients with diabetes chitis and hypothyroidism, are well-known caus-
mellitus experience changes of cell senescence es of infertility. Autoimmune oophoritis may oc-
earlier than the general population. This could cur as part of type I and type II syndromes of
indicate that one such sign of aging in women, polyglandular autoimmune failure, which are
menopause, may occur earlier compared with associated with autoantibodies to multiple en-
nondiabetic women. docrine and other organs. Young women with
spontaneous premature ovarian failure are at in-
Studies in Caucasian women with Type 1 dia- creased risk of autoimmune hypothyroidism and
betes compared the age at menopause of with should be screened for this condition.
Type 1 diabetes, to their nondiabetic sisters and Type 1 diabetes and autoimmune thyroid diseas-
unrelated nondiabetic controls. They found that es frequently occur together within families and in
the mean age was significantly younger for Type the same individual. Therefore, we can assume
1 diabetic women. Women with Type 1 diabetes that patients with Type 1 diabetes who have
were approximately twice as likely to have ex- overt or concealed hypothyroidism may also be
perienced menopause earlier than similar non- at risk for premature ovarian failure. In general,

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Cardio Diabetes Medicine 2018 117

evaluation of premature ovarian failure should Management of Infertility in Diabetic
include serum concentration of follicle-stimulat- Women :
ing hormone and estradiol and screening for as-
ymptomatic autoimmune adrenal insufficiency, The major association in patients with Type 2 di-
since it is more common in women with autoim- abetes & also Type 1 diabetes and fertility is the
mune ovarian failure. In addition, testing should linkage of this disease to PCOS. According to
include thyroid-stimulating hormone, free T4, an- the ESHRE 2018 PCOS Consensus regardless
tithyroid-peroxidase, antithyroglobulin antibodies of age, gestational diabetes, impaired glucose
and karyotype. tolerance and type 2 diabetes are increased in
Menstrual cycle changes observed in patients PCOS, with risk independent of, yet exacerbated
with Hashimoto’s thyroiditis include menorrha- by obesity.
gia, more frequent and longer periods, and dys- Glycemic status should be assessed at baseline
menorrhea. Prevalence of thyroid autoimmuni- in all with PCOS and thereafter, every one to
ty is significantly higher among infertile women three years, based on presence of other diabe-
than among fertile women, especially among tes risk factors.
those whose infertility is caused by endometrio- In high risk women with PCOS (BMI > 25 kg/
sis or ovarian dysfunction. m2 or in Asian > 23kg/ m2, history of abnormal
Further studies on the presence of organ-spe- glucose tolerance or family history of diabetes,
cific autoantibodies and other endocrine auto- hypertension or high risk ethnicity) an OGTT is
immune disorders in girls with Type 1 diabetes, recommended otherwise a fasting glucose or
have found ovarian autoantibodies in 67.9% of HbA1c should be performed. An OGTT should
Type 1 diabetic girls compared to 4.8% of healthy be offered in all with PCOS when planning
controls (p < 0.01). Autoantibodies directed to pregnancy or seeking fertility treatment, given
ovarian steroid-producing cells were frequent in increased hyperglycemia and comorbidities in
diabetic girls with both irregular and normal men- pregnancy. If not performed pre-conception, an
strual cycles. OGTT should be offered at <20 weeks gestation
The role of thyroid involvement in diabetes Type and all women with PCOS should be tested at
1 patients and its effect on menstruation cycle 24-28 weeks gestation.
and fertility has been well observed. More stud- The first line non-pharmacological management
ies, however, are needed to explore the correla- of infertility in these patients is lifestyle interven-
tion between Type 1 diabetic women and the tions which includes diet and exercise along with
presence of antiovarian autoantibodies among strict diabetic control. General healthy eating
these women, with relationship to infertility. principles should be followed for all women with
PCOS across the life course. To achieve weight
Sexual Dysfunction & Diabetes : loss in those with excess weight, an energy defi-
cit of 30% or 500 to 750 kcal/day (1200-1500
The effect of diabetes on female sexual function, kcal) could be prescribed. Regarding exercise
includes impaired sexual arousal and inadequate for prevention of weight gain and maintenance
lubrication in approximately 14–45% of diabetic of health, In adults from 18-64 yrs, a minimum
women, significantly higher than in healthy wom- of 150 min/week of moderate intensity physical
en. In a subsequent controlled study that they activity or 75 min/week of vigorous intensity ex-
conducted in 2002, Enzlin et al. found that more ercise on 2 non-consecutive days/week. In ado-
women with diabetes than control subjects re- lescents, at least 60 minutes of moderate to vig-
ported sexual dysfunction (27 vs 15%; p = 0.04). orous intensity physical activity per day should
Female sexual dysfunction may have a second- be followed.
ary effect on fertility by decreasing sexual desire The first line pharmacological management for
and limiting sexual activity, especially around the infertility includes ovulation induction with Letro-
time of ovulation.

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Cardio Diabetes Medicine 2018 118

zole. Alternatively clomiphare citrate, metformin without diabetes. In addition, secondary infer-
alone or in combination with clomiphare citrate tility is higher than primary infertility. About half
can be tried. If these drugs fail to achieve ovu- of the infertile men with diabetes are overweight
lation, the second line pharmacological man- and 30% of them are obese. The smoking habit
agement of infertility, Gonadotrophins (FSH or is more common in infertile men (45%). Statis-
HMG) can be used for Ovulation induction and tical analysis has confirmed that age, smoking
is preferably combined with an IUI (Intrautrine habits are the significant major contributors for
insemination) to obtain higher pregnancy rates, infertility in man with diabetes. Obesity is the
or alternatively laparoscopic ovarian surgery can leading contributor for infertility. Other co-morbid
be considered to reduce the polycystic ovaries factors associated with infertility is men with di-
mechanically. But it should be remembered that abetes are hypertension, erectile dysfunction &
Laparoscopic ovarian surgery can destroy the varicocoele. A recent review showed that when
normal ovarian follicles thus reducing the ovari- anti diabetic treatment was given to infertile male
an reserve and hence should be performed cau- partner with diabetes, other than reduced sperm
tiously in selected patients. The third line of man- motility, the men had normal semen. No differ-
agement when other methods fails to achieve ence in fertilization rate or embryo quality was
pregnancy is to move ahead with IVF/ICSI ac- found whereas pregnancy rate following natural
cording to the male semen parameters and tight as well as assisted methods of conception es-
blood sugar control. pecially fresh embryo transfer was significantly
In women with type 1 diabetes and hypothyroid- lower and increased miscarriage rates were not-
ism who may present with premature ovarian fail- ed. The success rate for frozen embryo transfer
ure Donor oocyte programmes may be offered. was similar to general population because these
embryos had survived the freeze thaw process-
Male Diabetes and Infertility : es and the embryos were self selected for those
that were inherently stronger or of better equal-
The prevalence of DM in male partners of infer- ity. Approximately three times more couples with
tile couples is approximately 1-2%. Although diabetic men sought fertility treatment than ex-
diabetes mellitus (DM) is known to cause many pected mostly as “unexplained infertility.” Clinical
systemic complications, male infertility, based studies have shown that diabetic men particu-
on erectile dysfunction, retrograde ejaculation larly type 1 DM have altered sperm parameters
and hypogonadism is not widely recognized to such as low semen volume, sperm motility and
be one of them. It has been estimated that ap- sperm morphology, whereas survival fructose
proximately 35-75% of men with diabetes will and glucose were significantly higher. The alter-
experience at least some degree of erectile dys- nations in sperm parameters depended on the
function during their lifetime. They tend to devel- duration of DM, the glycemic control, presence
op erectile dysfunction 10-15yrs earlier than men of complications and the type of treatment giv-
without diabetes. Because of paucity of studies en. In addition, DM causes histologic damage of
and inconsistencies regarding the impact of DM the epidiymis, with a negative impact on sperm
on semen quality, this disease is seldom looked transit.
for in the infertile patient. Recently, this view has
been challenged by findings showing that DM in- Various mechanisms may explain the
duces subtle molecular changes that are import- sperm damage observed in patients with DM.
ant for sperm quality and function. These include endocrine disorders, neuropathy
and increased oxidative stress. Many authors
The prevalence of primary (16%) and sec- suggest that DM decreases serum testosterome
ondary (19%) infertility is significantly higher in levels and increases gonadotropin levels. These
patients with diabetes compared with patients changes are associated with a steroidogenetic
defect in leydig cells. Some of these alterations

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Cardio Diabetes Medicine 2018 119

are not seen in insulin treated diabetics, show- males to assess the degree of DNA Damage. In
ing that an adequate treatment of DM can im- patients with DFI > 30% treatment with anti ox-
prove endocrine disorders. In addition, diabetic idant therapy and life style modifications for 2-3
neuropathy seems to cause atonia of seminal months has been recommended. Retesting later
vesicles, bladder and urethra resulting in retro- after 2-3 months and if DFI has reduced we can
grade ejaculation. Infertile patients with diabetes plan natural or IUI conception. If DFI remains
and neuropathy have seminal vesicle ultrasound persistently high the better option for the infertile
features suggestive of functional atony and the couple would be to go ahead with ICSI with tes-
duration of the disease is associated with worse ticular sperm retrieval (TESE) to overcome the
ultrasound findings. effects of sperm DNA damage and improve the
clinical pregnancy rates and reduce the miscar-
Furthermore DM is associated riage rates.
with an increased oxidative stress which dam-
ages sperm nuclear and mitochondrial DNA. Finally, spermatogenesis derangement and
The mechanism by which this diabetes related germ cell apoptosis in type 1 DM may relate to
sperm DNA damage occurs remains unknown. a local autoimmune damage, whereas insulin
The presence of increased levels of the most resistances, obesity and other related comor-
prominent member Carboxymethyllysine (CML) bidites may impair sperm parameters and de-
of the advanced glycation end products (AGE) crease testosterone serum levels in patients with
and their receptors (RAGE) in the reproductive type 2 DM.
tract of patients with diabetes has provided a new
avenue for research. CML was observed in the References:
testis, epidodymis and spermatozoa. Sperma-
tozoa from diabetic men strongly showed CML 1.International evidence – based guideline for
immunolocalization in the acrosomal cap, equa- the assessment and management of PCOS
torial region & cystoplasmic droplets. The identi- 2018 ESHRE 2018, Barcelona, Spain
fication of high levels of AGEs and their PAGEs
throughout the male reproductive tract coupled 2.Rzepka I, Prochorow M, Tolwiska Z: Menstru-
with changes in testicular metabolite levels and ation in diabetic girls. Ginekol. Pol. 48(2), 157–
spermatogenic gene expression suggest that 162 (1976).
glycation may play an integral role in oxidative
stress in which in turn damages sperm DNA in 3.Yeshaya A, Orvieto R, Dicker D, Karp M,
diabetic infertile men. Hence treatment with an- Ben-Rafael Z: Menstrual characteristics of wom-
tioxidant agents such as vitamins E and C, & en suffering from insulin-dependent diabetes
lipoic acid and pioglitazone and glimepride re- mellitus. Int. J. Ferti. Menopausal. Stud. 40(5),
duces germ cell apoptosis, decrease sperm ab- 269–273 (1995).
normalities, particularly morphologic alternations
including effects of oxidative stress and improve 4.Kjaer K, Hagen C, Sand SH, Eshqj O: Epide-
conventional sperm parameters. Studies of IUI, miology of menarche and menstrual disturbanc-
IVF and ICSI outcomes have found a major dif- es in an unselected group of women with insu-
ference is the percentage of DNA fragmentation lin dependent diabetes mellitus compared with
in spermatozoa between those who successfully controls. J. Clin. Endocrinol. Metab. 75, 524–529
conceived and those who did not. Sperm DNA in- (1992).
tegrity has also been associated with decreased
embryo quality and an increase in miscarriage 5.Codner E, Escobar-Morreale HF: Clinical re-
mates. Hence it is essential to perform the DNA view: Hyperandrogenism and polycstic ovary
fragmentation Index (DFI) in all diabetic infertile syndrome in women with Type 1 diabetes mel-

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litus. J. Clin. Endocrinol. Metab. 92, 1209–1216
(2007).
6.Schroeder B, Hertweck SP, Sanfilippo JS, Fos-
ter MB: Correlation between glycemic control
and menstruation in diabetic adolescents. J. Re-
prod. Med. 45(1), 1–5 (2000).
7.Enzlin P, Mathieu C, Van den Bruel A et al.:
Sexual dysfunction in women with Type 1 dia-
betes: a controlled study. Diabetes Care 25(4),
672–677 (2002).
8.James Mulholland, Can Mallidis, Ishola Ag-
bage, Neil McClure: Male diabetes mellitus and
assisted reproduction treatment outcome; a ret-
rospective study. University of Munster, Germa-
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9 . h t t p s : / / o n l i n e l i b r a r y. w i l e s y. c o m / d o i l / f u l l /
ID.2164/jandrol.111.013193

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INTERPLAY OF DIABETES, HYPERTENSION AND OBESITY IN
MATERNAL HEALTH

Dr.Chandrika N Wijeyaratne

Professor in Reproductive Medicine
Faculty of Medicine, University of Colombo
Honorary Physician and Endocrinologist,

De Soysa Hospital for Women, Colombo
Sri Lanka

The temporal trends of obesity and the risk fac- The clinical outcomes of the metabolic syndrome
tor constellation of the metabolic syndrome have are primarily due to vascular disease. It is im-
over the past few decades shown a troublesome portant to explore the pathophysiological basis
trajectory in reaching epidemic proportions; glob- of macrovascular and microvascular dysfunction
ally and particularly in South Asia. The women caused by excess of white adipose tissue. It is
of reproductive age have not been spared, and noteworthy that the normal healthy function of
have shown an even greater risk for obesity and perivascular adipose tissue as an anti-contrac-
the metabolic syndrome than adult males. Preg- tile mediator in the microvasculature is deranged
nancy is the key player in the transgeneration- in obesity. Obesity results in inflammation and
al effect of maternal obesity and the metabolic recruitment of pro-inflammatory macrophages to
syndrome. It is well established that pregnancy the perivascular adipose tissue that is mirrored
complications of maternal metabolic risks have by the depletion of vasorelaxant signaling mole-
a direct impact on the future health of the fetus cules within blood vessels. In terms of the main-
through the phenomenon of fetal programming. tenance of vascular health, the closely apposed
vascular endothelial cells of a normal individual
This presentation will address the basis of the key has many vasculo-protective systems in opera-
intergenerational effects. These will include the tion; which themselves play direct roles in com-
identification of key players of the metabolic syn- bating inflammation, by acting as key co-factors
drome affecting vascular health, the interplay of in anti-inflammatory and anticoagulant protective
maternal obesity – hypertension – and diabetes mechanisms. Phosphorylated endothelial nitric
with pregnancy outcomes, the interplay of ma- oxide synthase (eNOS-P) induces the release
ternal obesity – hypertension – and diabetes with of nitric oxide (NO), a potent vasodilator: with
long-term cardiovascular (CVD) risks/outcomes the co-factors suppressing coagulation, inflam-
and vascular dysfunction; the role of the pla- mation and platelet activation. All these mecha-
centa (structurally and functionally) that thereby nisms help promote endothelial cell health and
link maternal hyperglycemia in pregnancy (HIP), vascular integrity. Vascular aging is accelerated
hypertensive disorders of pregnancy (HDP) and by the metabolic syndrome. Among the numer-
obesity; thus underpinning the basis for future ous changes that occur with vascular ageing,
CVD risks across generations. This discussion vascular permeability increases and the endo-
highlights the importance of achieving optimal thelial cells become dysfunctional. Reactive ox-
maternal metabolic health to ensure a healthy ygen species (ROS) promote oxidative changes
metabolic and cardiovascular disease-free fu- with reduction of existing protective mechanisms
ture for both mother and offspring alike. A true and of bioavailable NO. Circulating levels of the
inter-generational impact on health-related out- procoagulant factors and fibrinolysis become
comes. evident. Platelet dysfunction augments these
changes and reduce the microcirculation.

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Ill effects of the metabolic syndrome on the vas- ly in Asians, with a two-fold risk for developing
cular systems in pregnant women directly impact HDP. Obese pregnant women demonstrate en-
on the placental vascular bed that in turn affects dothelial dysfunction in the first trimester (51%
fetal growth; thereby augmenting the risks for fu- decrease in endothelium-dependent vasodila-
ture metabolic disease of the offspring. Mater- tion compared to lean pregnant women). The
nal obesity is a major contributing factor to the obese gravida exhibits significant microvascular
two most common medical risks (cardiovascular endothelial dysfunction with increased fasting in-
and metabolic) during pregnancy: hypertension sulin, circulating inflammatory markers IL-6 and
and diabetes mellitus. Obesity in pregnancy is C-reactive protein and higher blood pressure.
characterized by significant vascular, metabolic
and inflammatory dysregulation. Animal studies The incidence of gestational hypertension and
have demonstrated that offspring of obese moth- preeclampsia are increased in women with di-
ers had significantly higher body weight with ev- abetes in pregnancy (DIP – previously termed
idence of endothelial dysfunction and hyperten- pregestational diabetes). The co-existence of
sion - indicating cardiovascular and metabolic gestational hypertension and hyperglycaemia
abnormalities. Maternal obesity is also linked to are related to the underlying vascular dysfunction
complicated delivery, Caesarean sections, pre- and pre-gestational hypertension. It is notewor-
maturity, fetal macrosomia and fetal growth re- thy that maternal obesity and excess gestational
tardation. weight gain were independent risk factors for ad-
verse pregnancy outcomes (including cesarean
Hypertensive disorders of pregnancy (HDP) con- delivery) beyond the risks conferred by pre-ges-
stitutes of two categories as a continuum of the tational and gestational diabetes. Chronic dia-
underlying pathology – from life-threatening pre- betes among non-pregnant women has been
eclampsia (PE) to gestational hypertension (GH). recognized as a strong risk factor for developing
While PE is recognized as de novo hypertension HDP. Chronic hypertension prior to pregnancy
[SBP] ≥140 and/or [DBP] ≥90 mm Hg at ≥20 also confers a substantial risk of superimposed
weeks POA with end-organ dysfunction (protein- PE and a three-fold risk for adverse outcomes of
uria). PE manifests as a multi-system affection pregnancy. The co-existence of these two high
characterized by abnormal vascular response risk pregnancy complications reflect their com-
to placentation with the pathogenesis involving mon pathophysiological mechanisms through
vasoactive hormones and endothelial dysfunc- the metabolic syndrome.
tion in the multiple organs and body systems
that have potential to become severely affected. Ageing populations and epidemiological/risk fac-
Such outcome risks are reversed with the deliv- tor transitions suggest more women with chronic
ery of the placenta with the risks remaining on a hypertension and/or diabetes mellitus are likely
declining trend for the post-partum period when to become pregnant. This co-existence is reflect-
the physiological changes of pregnancy become ed in the numerous large-scale data sets world-
reversed. GH (pregnancy-induced hypertension) wide that link hyperglycaemia in pregnancy (HIP)
that is defined as de novo hypertension [SBP] and hypertensive disorders of pregnancy (HDP).
≥140 and/or [DBP] ≥90 mm Hg at ≥20 weeks Population based data from the USA showed
POA in the absence of end-organ dysfunction is that following adjustments for maternal BMI, age
more often a reflection of chronic hypertension, and ethnicity an increased risk occurred among
the metabolic syndrome and maternal obesity. It women with HIP for severe preeclampsia - odds
is noteworthy that obesity contributes the most ratio 1.5, 95% (CI: 1.1, 2.1), mild preeclampsia
(greater than a two-fold risk), where the heaviest (OR = 1.5, 95% CI: 1.3, 1.8), and gestational hy-
maternal weight had the greatest risk of PE/GH pertension (OR = 1.4, 95% CI: 1.2, 1.6).
complications. Excess gestational weight gain is A Swedish cohort exceeding 10,000 women
identified as an important predictor, particular- reported a significantly increased risk for pre-

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Cardio Diabetes Medicine 2018 123

eclampsia among mothers with HIP (OR = 3.16, with no difference whether it is type 1 or type 2
95 percent CI: 1.65, 6.03). A Latin American diabetes mellitus. It is noteworthy that analysis
population exceeding 890,000 demonstrated an of a large cohort of women with Type 1 diabe-
association between gestational diabetes and tes has shown a prevalence of 8% for PE and
preeclampsia (relative risk = 1.93, 95 percent 9% for GH, with a cumulative prevalence of 17%
CI: 1.66, 2.25). The causative association – of for HDP. Therefore, it is recommended to com-
a maternal hyperglycaemia induced vascular mence low dose aspirin 150mg at night from 10
dysfunction and pregnancy hypertension - was weeks of gestation in all women with established
suggested through compelling data that showed diabetes mellitus, well in advance of the second
gestational diabetes is associated with a lower wave of placentation, in order to achieve the op-
risk of HDP among those who received a more timal pregnancy/fetal outcomes. Additionally,
intense prenatal care. tight control of diastolic blood pressure in early
pregnancy has been shown to reduce PE, as an
Maternal diabetes and excess gestational weight independent risk predictor among well controlled
can adversely affect birth outcomes, through type 1 diabetics. Recognized risk factors for PE
two different causal pathways. One pathway is among women with type 1 diabetes include: long
through the contribution of maternal hypergly- duration of diabetes, nulliparity, maternal obesi-
caemia and its effects on placentation that leads ty, diabetic kidney involvement (nephropathy or
in turn to the development of preeclampsia. Life microalbuminuria), elevated BP before pregnan-
threatening PE can trigger the preterm delivery cy, retinopathy and poor glycemic control.
of a low birth weight baby, often by cesarean de-
livery (LSCS). The second pathway is through What are the long-term effects of maternal obe-
the increased risk of a macrosomic infant via the sity, HDP and HIP?
mechanism of fetal hyperglycaemia induced fetal
hyperinsulinaemia and increased fetal adiposity Obesity of the expectant mother affects her off-
based on the Pederson hypothesis, that increas- spring’s health throughout the life span, which
es the risk for shoulder dystocia and birth inju- includes an increased risk for diabetes, hyper-
ry/asphyxia, which in turn leads to an elevated tension and obesity as well as adverse neurode-
cesarean delivery rate. It is noteworthy that an velopment. Additionally, maternal obesity is as-
interplay of these risk factors may operate differ- sociated with increased peripartum risks such as
ently within differing racial/ethnic groups. South venous thrombo-embolism, decreased breast-
Asians have been reported to have a greater feeding initiation rates, delayed onset of full milk
risk of adverse pregnancy outcomes of mater- production – that can affect both the inherent
nal obesity / preeclampsia-GH / DIP-HIP leading post- partum maternal weight loss and crucial
to difficult delivery, Primary LSCS, preterm birth, nutrition in the first weeks of life of the offspring.
fetal growth retardation and placental abrup- The global prevalence of maternal hypergly-
tion; along with neonatal hypoglycaemia and caemia in pregnancy is 16%, while the global
increased perinatal risks. It is noteworthy that prevalence of gestational hypertension is ap-
chronic diabetes (pre-gestational) and HIP have proximately 8% of pregnant women, which also
been demonstrated to have a significant impact demonstrate an increasing trend, largely due to
on pregnancy outcomes; and identified as inde- the obesity epidemic and of the increasing ma-
pendent risk factors for a primary cesarean deliv- ternal age. HIP is a well-established predictor
ery and for pre- term birth in all the racial/ethnic for progression to type 2 diabetes and carries up
groups studied so far. to a 70% lifetime risk.

In depth analysis of the effect of maternal dia- Women with HIP are more likely to have markers
betes on HDP has led to the conclusion that 20- for insulin resistance and beta cell dysfunction,
40% of women with diabetes have a risk for HDP,

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particularly if overweight. Women with HIP and non-communicable diseases (NCDs).
HDP have an even higher risk of type 2 diabetes
mellitus, hypertension and CVD in the long-term. The Helsinki Birth Cohort study by Kajantie et
Hence, timely detection through quality pre-con- al. 2009 has reported that the offspring of pre-
ception and ante-natal care along with long-term eclamptic pregnancies had a 1.9-fold higher risk
inter-pregnancy healthy lifestyle and behaviours of stroke mortality as adults. A systematic review
must be encouraged in all health systems among and meta-analysis in 2011 on the offspring of
high risk ethnic groups, such as in South Asians, mothers with PE was associated with 2.39 mm
in order to protect these women from premature Hg higher SBP and 1.35 mm Hg higher DBP
atherosclerosis. during childhood and young adulthood.
Large population-based data quantified a signifi-
HDP promotes the release of vasculotoxic fac- cantly increased long-term risk of CVD in women
tors into the maternal circulation, which subse- with previous HIP. These include Canadian retro-
quently traverse the placenta to adversely impact spective study over 12 years (8,191 women with
fetal development by causing impaired vascular HIP and age-matched 81,262 controls), a French
function and chronic inflammation that may per- study of hospital records over 7 years (1.5 mil-
sist throughout the offspring’s life course. When lion women who delivered infants - 62,958 wom-
the estimated fetal weight in utero is below the en with HIP), North American Nurses’ Health
10th centile on ultrasound, these babies are born Study II over 26 years (5,992 nurses who self-re-
small-for-gestational age. Although healthy these ported GDM from a total cohort of 89,479), a UK
babies are yet constitutively small, and must be primary care database of a retrospective cohort
distinguished from those with pathological fetal study ranging from 3 to 26 years (9,118 women
growth retardation. Fetuses that are <10th per- diagnosed with HIP).
centile by placental insufficiency and growth re-
striction have significant risk for perinatal adverse In conclusion - Women with HIP need our special
events, idiopathic respiratory distress syndrome, attention – from universal screening to life-circle
intraventricular hemorrhage, lengthy NICU stay approach to behavioural change modification
and increased perinatal mortality. They are also that would help towards risk factor reduction and
at risk for long-term CVD risks. achieve secondary prevention of complications.
Women with HDP also need long term surveil-
It is important to appreciate that fetal growth re- lance. There is no doubt that the combination of
striction mediated through placental insufficiency HIP and HDP escalates the risk although there
can be due to a multitude of aetiologies – such is no data on the long-term impact of mater-
as maternal obesity and the metabolic syndrome nal obesity and excess gestational weight gain
with cardiovascular risks, maternal hypothyroid- alone. The impact of the maternal metabolic
ism, thrombophilia and even nutritional anaemia. syndrome on the next generation through com-
The common pathological pathway through the plicated pregnancies requires due attention and
placenta can prove life-threatening, particularly appropriate action in achieving metabolic health
by developing preeclampsia. among girls and women.
Therefore, today’s pragmatic clinical recommen-
dations in maternal and child health systems is References:
the need for a sustained effort to ensure long-
term surveillance and management of CVD risk 1. Rosenberg T J, Garbers S, Lipkind H, Chi-
factors in women with these pregnancy-related asson M. Maternal Obesity and Diabetes as
complications. This reflects a true amalgamation Risk Factors for Adverse Pregnancy Out-
of initiatives to promote maternal and child health comes: Differences Among 4 Racial / Ethnic
(MCH) with prevention and control of chronic Groups. Am J Public Health. 2005;95: 1544–

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1551. doi:10.2105/AJPH.2005.065680
2. Kanguru L, McCaw-Binns A, Bell J,

Yonger-Coleman N, Wilks R, Hussein J. The
burden of obesity in women of reproductive
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3. McLaughlin K, Audette MC, Parker JD,
Kingdom JC, Mechanisms and Clinical
Significance of Endothelial Dysfunction In
High-Risk Pregnancies, Canadian Jour-
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cjca.2018.01.006.
4. Branham K et al., Chronic hypertension and
pregnancy outcomes: systematic review and
meta-analysis. BMJ 2014; 348: g2301 doi:
10.1136/bmj.g2301
5. Brown MC, Best KDE, Pearce MS et al.
Cardiovascular disease risk in women with
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6. Nørgaard SK, Jenlev Vestgaard M, Linde-
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diabetes, Diabetes Research and Clinical
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diabres.2018.02.014
7. Schwarzenberg SJ, Georgieff MK, AAP
COMMITTEE ON NUTRITION.Advocacy for
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8. Daly B, Toulis KA, Thomas N, Gokhale K,
Martin J, Webber J, et al. (2018) Increased
risk of ischemic heart disease, hyperten-
sion, and type 2 diabetes in women with
previous gestational diabetes mellitus, a tar-
get group in general practice for preventive
interventions: A population-based cohort
study. PLoS Med 15(1): e1002488. https://
doi.org/10.1371/journal.pmed.1002488

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RENOVASCULAR HYPERTENSION 126

RENOVASCULAR HYPERTENSION

Dr .Virendra Kumar Goyal
Prof & Head-Internal Medicine
American International Institute Of Medical Sciences

Udaipur-Rajasthan-India

Co-Author-Dr Jitesh Aggarwal
Assistant Professor,Department Of Medicine

ABSTRACT

Renovascular hypertension is caused mainly Renovasography represents the gold standard
by renal artery stenosis. Its prevalence in pop- for the diagnosis of renovascular hypertension.
ulations of hypertensive patients is 1-8%, and
in populations of patients with acute severe or KEY WORDS:Renovascular hypertension
resistant hypertension, it is up to 20%. The two
main causes of stenosis are atherosclerosis and (RVH), Atherosclerotic renal artery steno-
fibromuscular dysplasia of the renal artery.RVH sis (ARAS), Fibromuscular dysplasia (FMD),
is precipitated by a hemodynamically significant ACE inhibitors, Angiotensin Receptor Blockers
stenosis of a renal artery or arteries (that is, a (ARBs), Angioplasty, Stenting.
stenosis greater than 75% of the vessel lumen
or 50% with post- stenotic dilation). The main INTRODUCTION
clinical consequences of renal artery stenosis
include renovascular hypertension, ischemic Renovascular hypertension is defined as hyper-
nephropathy and “flash” acute pulmonary oe- tension mainly caused by renal artery stenosis
dema . Renovascular etiology of hypertension (RAS). In the hypertensive patient populations
should be questioned in patients with resistant (blood pressure >140/90 mmHg), renovascular
hypertension, hypertension with a murmur iden- hypertension prevalence is 1-8%. In the pop-
tified upon auscultation of the renal arteries, ulation of patients with resistant hypertension
and a noticeable side-to-side difference in kid- (defined as increased blood pressure despite
ney size. RVH is a potentially curable cause of the use of three or more antihypertensive drugs
hypertension and major advances in vascular at the optimal dosage, including a diuretic), the
imaging has lead to early and easy non invasive prevalence of renovascular hypertension is
identification of vascular lesions. Effective and higher, (2.5-20% 1, 2, 3)
well tolerated antihypertensive drug therapy
has lead to satisfactory medical management of WHEN TO SUSPECT FOR RENOVAS-
RVH. Selected patients may need angioplasty, CULAR HYPERTENSION
stenting or both. Non-invasive diagnostic tests
include the determination of concentrations of The clinical clues which suggest the presence
peripheral vein plasma renin activity, the capto- of renal arterial disease as the cause of hyper-
pril test, captopril scintigraphy, colour Doppler tension and CKD include:-
ultrasonography,computed tomography angiog- • Age at onset of hypertension <30 years or
raphy, and nuclear resonance angiography. >55years
• Abrupt onset of hypertension
• Acceleration of previously well controlled hy-
pertension

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Cardio Diabetes Medicine 2018 127

• Refractory hypertension which has been shown by pathognomonic angi-
• Accelerated hypertensive retinopathy ography to cause slight stenosis along a vessel
• Malignant hypertension with intervening areas of dilatation (small aneu-
• Systolic diastolic abdominal bruit rysms) creating a “string of beads” appearance.
• Flash pulmonary edema It occurs most often in women 15-50 years of
• Evidence of generalised atherosclerosis oblit- age. Clinical appearance often involves reno-
erans vascular hypertension and irreversible kidney
• Asymmetry in kidney size on imaging studies damage, such as ischemic nephropathy.
• Acute kidney failure on treatment with an ACE
inhibitor or ARB. Pathogenesis of the development of
Because of the potential risks of invasive pro- renovascular hypertension and Pick-
cedures, only those patients who have a high ering syndrome
likelihood of getting benefit from the procedure
should be tested for RAS which include severe Pathogenesis of renovascular hyper-
hypertension with progressive renal insuffi- tension:
ciency, refractory hypertension, accelerated or
malignant hypertension, unexplained recurrent Unilateral stenosis (stenosis of one renal ar-
flash pulmonary oedema, hypertension with tery) induces increased renin release and ac-
ACEI or ARB induced acute renal failure and se- tivation of the renin-angiotensin aldosterone
vere hypertension with asymmetry of renal size. system (RAAS). As the condition progresses,
angiotensin II is increasingly produced and re-
Aetiopathogenesis of renovascular leased, causing the development of angioten-
hypertension sin II-dependent hypertension. Perfusion of the
other, unaffected, kidney is increased due to
The etiology of renal artery stenosis: increased renal perfusion pressure, and this re-
sults in RAAS inhibition and increased excretion
Renal artery stenosis may manifest as either uni- of sodium (natriuresis is dependent on pres-
lateral or bilateral. The two most common caus- sure). In patients with bilateral stenosis (steno-
es of renal artery stenosis are atherosclerosis sis of both renal arteries), or in patients with only
and fibromuscular dysplasia. Atherosclerosis of one active kidney that is effected by stenosis,
the renal artery (ARAS) is the cause of stenosis renal perfusion pressure is decreased, causing
in 90% of cases, and it usually involves the os- increased renin release, increased RAAS activ-
tium and proximal third of the renal artery trunk. ity, increased production of angiotensin II and
It usually affects patients over 65 years of age aldosterone, and reduced excretion of sodium
with known cardiovascular risk factors (obesity, and water. Due to retention of sodium and water,
hypertension, hyperlipidaemia, hyperglycae- blood volume in arterial circulation is increased,
mia) and ranges from 30% among patients with leading to the development of volume-depen-
coronary artery disease to 50% among the el- dent hypertension.
derly and those with diffuse atherosclerotic vas-
cular diseases. Clinical features of renal artery Pathogenesis of ischemic nephropa-
stenosis include renovascular hypertension, thy:
ischemic nephropathy, and recurrent flash pul-
monary oedema (bilateral atherosclerotic renal Renal artery stenosis causes kidney tissue hy-
artery disease). Fibromuscular dysplasia (FMD) poxia, increased local production of renin and
is a non-atherosclerotic,non-inflammatory dis- angiotensin II, increased production of free
ease, most commonly affecting the renal and in- oxygen radicals, platelet-derived growth fac-
ternal carotid arteries. It implicates renal artery tor-(PDGF) and transforming growth factor
stenosis in 5-10% of cases and affects the distal (TGF). These mediators cause glomeruloscle-
part of the renal artery. The most common form rosis and tubulointerstitial injury, which results
is fibromuscular dysplasia of the media (fibro- in a decrease of glomerular filtration rate (GFR)
plasia of the media occurs in 70-95% of cases), and the development of chronic kidney disease
(ischemic nephropathy)

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RENOVASCULAR HYPERTENSION 128

Pathogenesis of sudden acute pulmo- Diagnosis of renovascular hyperten-
nary oedema (flash pulmonary oede- sion
ma)
The diagnosis of renovascular hypertension is
Flash pulmonary oedema (FPO) or Pickering performed by detecting and demonstrating the
syndrome is defined as an unexpected and sud- haemodynamic significance of RAS. Tests for
den form of acute heart failure (acute pulmonary the diagnosis of renovascular hypertension can
oedema) in patients with bilateral renal artery be divided into three groups.
stenosis . The first group includes functional tests, proof
and assessment of the haemodynamic signifi-
Clinical features of renovascular hy- cance of stenosis, and assessment of renin-an-
pertension giotensin system activation. The functional tests
include direct measurement of plasma rennin
Renovascular hypertension should be suspect- concentration and plasma renin activity (PRA)
ed in patients with moderate (diastolic blood from a peripheral vein, the captopril test (mea-
pressure _> 105 mmHg) or severe hypertension surement of plasma renin activity from a periph-
(diastolic blood pressure _>120mmHg), eral vein after administration of captopril), and
Resistant hypertension (increased BP despite measuring the concentration of renin from a
the use of three antihypertensive drugs includ- renal vein sample and determining the side-by-
ing a diuretic), a murmur found by renal artery side ratio of plasma renin activity (lateralization
auscultation, when the difference in the longitu- estimation). For assessment of individual renal
dinal diameter between the right and left kidney function, radio isotopic techniques are used
is > 1.5 - 2.0 cm, and an increase in serum cre- (scintigraphy and captopril renal scintigraphy).
atinine after administration of angiotensin con-
verting enzyme inhibitors (ACEI) or angiotensin The second group consists of tests that assess
receptor II blockers (ARB). the morphology of the renal artery.Non-invasive

Probability CLINICAL FEATURES

Low (RAS: < 1.0%) Borderline or moderate hypertension (diastolic blood pressure ≥ 105
mmHg), without clinical signs

Moderate (RAS: 15-30%) Severe hypertension (diastolic blood pressure ≥ 120 mmHg Re-
sistant hypertension (use of ≥ 3 antihypertensive drugs) e sudden
appearance of hypertension in people younger than 30 years
(fi -bromuscular dysplasia) or persons over 50 years old (atheroscle-
rosis). Hypertension with the finding of a murmur at auscultation of
the renal arteries Moderate hypertension (diastolic blood pressure ≥
105 mmHg) in patients with atherosclerotic disease (CAD, PAD).

High (RAS: 30-40%) Severe hypertension (diastolic blood pressure ≥ 120 mmHg) with
progressive renal impairment Accelerating hypertension (an increase
of SAP > 15 mmHg for six months) or malignant hypertension (ret-
inopathy grade III and IV) Hypertension with an increase in serum
creatinine concentration after administration of ACE I or ARB [↑ se-
rum creatinine 0.5-1.0 mg/dL (44.2-88.4 µ mol/L)] Moderate (diastolic
blood pressure ≥ 105 mmHg) or severe hypertension (diastolic blood
pressure ≥ 120 mmHg) with difference in the longitudinal diameter of
the right and left kidney >1.5-2.0 cm

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Cardio Diabetes Medicine 2018 129

versions of these tests include: colour doppler control after revascularization of RAS

of the renal arteries, computed tomography

angiography (CTA), and nuclear magnetic res- Colour Doppler of renal arteries:
onance angiography (NMRA), while invasive Colour Doppler ultrasonography of the renal ar-

tests include angiography with contrast medi- teries should be performed in all patients with

um, or renovasography. a moderate to high probability for renovascular

hypertension in which the PRA is 1.6 ng/mL/h

A third group of tests judge the benefit of RAS The direct criteria for renovascular hypertension

revascularization (using colour Doppler ultraso- include peak systolic blood flow velocity (PSV)

nography and lateralization tests). > 180 cm/s, end-diastolic flow velocity (EDFV)

> 50 cm/s, reno-aortic ratio (RAR) > 3.5 and re-

Peripheral blood plasma-renin activity no-renal ratio (RRR) > 4.0, (Figure 2) . In re-
nal transplant patient groups, the presence of
measurements RAS is indicated by a PSV >200 cm/s, intrare-
nal artery blood flow curve AT > 100 ms, and
Peripheral blood plasma-renin activity (PRA) a PSV ratio between the renal artery and kid-
measurement and the captopril test play an im- ney transplant external iliac artery of > 1.84. In
portant role in the diagnosis of renovascular hy- cases where colour Doppler ultrasonography is
pertension. High plasma renin activity (consid- not feasible or its findings are incomplete, either
ered to be PRA 3.2 ng/ mL/h) strongly suggests a CTA or NMRA is indicated. These two diag-
existence of renovascular hypertension and re- nostic methods require contrast mediums (such
quires direct renovasography. as the ionic contrast agent, gadolinium) and
The captopril test is the most sensitive test for are not indicated in the group of patients with
the detection of RAS. Before the test is admin- a reduced glomerular filtration rate (less than
istered, adequate preparation of patients is re- 30 mL/ min/1.73 m2), due to hazard of contrast
quired. Patients must have a normal salt intake. nephropathy (CN) and nephrogenic systemic
Additionally, three weeks prior to the test the fibrosis (NSF) ). The gold standard in RAS di-
use of several classes of drugs must be dis- agnostics remains a conventional intra-arterial
continued (i.e., drugs that affect the PRA such digital subtraction angiograph (DSA).
as angiotensin converting enzyme inhibitors,
angiotensin receptor II blockers, beta blockers,

and direct renin blockers). Thirty minutes prior to

the blood sampling, the patient should take rest Differential diagnosis:
and be relaxed. To determine the initial PRA, a Renovascular hypertension should be distin-
blood sample is taken at 20, 25 and 30 minutes guished from primary aldosteronism and pheo-
before the test. After that, a 25 mg captopril tab- chromocytoma (resistant hypertension) 5.Pri-
let is given to the patient and blood pressure is mary aldosteronism is the most common form
recorded after 15, 30, 45 and 60 minutes. After of secondary hypertension. The main causes
60 minutes, a blood sample is taken for determi- of primary aldosteronism are adrenal adenoma
nation of stimulated PRA. The test is positive if that produces aldosterone and idiopathic bilat-
PRA measures at 12 ng/mL/h, or if the absolute eral adrenal hyperplasia. Screening for primary
aldosteronism should be performed in patients
increase of PRA is 10 ng/mL/h
with resistant hypertension, moderate or severe

hypertension and hypertension associated with

Renal vein plasma renin activity: hypokalaemia and in patients younger than 40
years with cerebrovascular events due to hyper-
A good response after revascularization is in- tension.

dicated if the PRA ratio of the renal vein sam-

ple taken from a kidney affected by RAS to one

without RAS is > 1.5.

Lateralization of plasma renin activity indicates

haemodynamically significant stenosis. Gener-

ally, the higher the degree of lateralization, the

greater the likelihood of optimal blood pressure

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RENOVASCULAR HYPERTENSION 130

in the treatment of RVH. If blood pressure con- CONCLUSION:
trol and renal function can be maintained with
optimal medical therapy, little more is gained by Renovascular hypertension is the most im-
elaborate diagnostic procedures. On the con- portant cause of secondary hypertension. It is
trary, failure of medical therapy points to a po- generally due to renal artery stenosis caused
tential benefit of improvement with intervention- by atherosclerotic arterial disease or fibro mus-
al procedures. Indications for invasive treatment cular dysplasia. It could be unilateral or bilater-
of ARAS are controversial. Intervention should al. The evaluation should be restricted to high
be done based on patient’s clinical symptoms risk patients.Duplex Doppler ultrasound (US) is
and for hemodynamically useful as a noninvasive screening test as it is
a relatively inexpensive,that does not require
significant stenosis defined as 1) Greater than contrast, and can be used in patients with any
50% diameter stenosis or greater than 75% re- level of renal function, though it is operator de-
duction in cross sectional area and 2) Systolic pendent. The newer non-invasive imaging mo-
pressure gradient greater than 10% of systolic dalities like CT or MR angiogram have made
pressure or a pressure gradient of 20 mmHg. the evaluation easy though more expensive.
While stenting is superior to percutaneous renal Medical treatment remains the standard of care,
artery transluminal angioplasty (PRTA) in ARAS, which includes optimization of antihypertensive
PRTA is the preferred treatment in FMD. therapy along with CV risk reduction including
lipid lowering and anti platelet therapy. Selected
MANAGEMENT OF RENOVASCULAR patients may need angioplasty, stenting or both.
HYPERTENSION Surgical procedures are reserved for patients
who have complex anatomical lesions of renal
1. Antihypertensive Drug Therapy artery, for patients who require nephrectomy
Blockade of the Renin-Angiotensin System us- and those requiring surgery of aorta. As early
ing ACEIs, ARBs recognition and treatment may result in reversal
Direct Renin Inhibitors (Aliskiren) of the disease and control of blood pressure, a
Calcium Channel Blocking Agents high index of suspicion is needed.
Diuretics
Mineralocorticoid Receptor Blockade REFERENCES:
Additional Classes: Beta-Blockade, alpha-re-
ceptor blockade, sympatholytic agents, vasodi- 1. Rimoldi SF, Scherrer U, Masserli FH. Second-
lators ary arterial hypertension: when, who, and how
to screen? Eur Heart J 2014; 35(19): 1245-54.
2. Cardiovascular Risk Reduction
Removal of tobacco use 2. Fagard RH. Resistant Hypertension. Heart
Treatment of dyslipidemia 2012; 98(3): 254-61.
Treatment of obesity: obstructive sleep apnea
Management of glucose intolerance / diabetes 3. Petrovic D. Resistant Hypertension: etio-
pathogenesis, diagnosis, and treatment. In:
3. Renal Revascularization: Selected Cases Acute kidney injury in clinical practice. Petrovic
D. Ed. Kragujevac: Interprint 2012: 349-52.
Endovascular revascularization
4. Chen W, Kayler LK, Zand MS, Muttana R,
• PTRA: primarily fibromuscular dysplasia Chernyak V, DeBoccardo GO. Transplant renal
• PTRA with stenting: Atherosclerotic disease artery stenosis: clinical manifestations, diagno-
sis and therapy. Clin Kidney J 2015; 8(1): 71-8.

5. Romero CA, Orias M, and Weir M. Novel
RAAS agonists and antagonists: clinical appli-
cations and controversies. Nat Rev Endocrinol
2015; 11: 242-52.

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Cardio Diabetes Medicine 2018 131

ISCHEMIC STROKE AND DIABETES - THE “BAD ASSOCIATES”

Dr Avais Pathan, M.B.B.S; Dip Diabetology; PGCC (Diabetes); PGP (Diabetes)

Consultant Diabetologist and Metabolic Physician, Mumbai

Abstract hibiting the nitric oxide (NO), which mediates
the vasodilation, and the decreased availability
Objective: of NO can cause endothelial dysfunction and
To know the relation between Ischemic stroke trigger atherosclerosis.

and Diabetes and its prevention.

Introduction: Management:

Ischemic stroke is a medical condition which is Hyperglycemia is a common phenomenon pre-
the sudden loss of blood circulation to an area sented in the early acute stroke phase. Hyper-
of the brain, leading to dysfunction of brain tis- glycemia is associated with poor outcomes,
sue in the affected area. Acute ischemic stroke proper management of post-stroke hypergly-
is caused by thrombotic or embolic occlusion cemia is critical for improving outcomes. The
of a cerebral artery and is more common than American Heart Association (AHA)/American
hemorrhagic stroke.1 Uncontrolled high blood Stroke Association guidelines for the early
pressure, diabetes, coronary artery disease management of patients with acute ischemic
and high blood cholesterol are all risk factors stroke recommends “to achieve serum glucose
for stroke. concentrations in the range of 140–180 mg/
dL (7.8–10 mmol/L) during the first 24 hours
Diabetes is a chronic disease, which occurs after acute ischemic stroke in all hospitalized
when the pancreas does not produce enough patients.” Hypertension which usually coexists
insulin, or when the body cannot effectively use with diabetes is also one of the major risk factor
the insulin it produces. This leads to an in- for stroke. Controlling the blood pressure (BP)
creased concentration of glucose in the blood. has been proven to be effective in preventing
Incidence: Diabetes is a growing challenge in stroke in individuals with diabetes. National
India with estimated 8.7% diabetic population High Blood Pressure Education Program rec-
in the age group of 20 and 70 years.3The ommended “patients with diabetes and chron-
greater Cincinnati/Northern Kentucky Stroke ic kidney disease, BP goal should be < 130/80
Study showed that diabetes increases isch- mm Hg.”
emic stroke incidence at all ages, but this risk
is most prominent before age 55 in African Conclusion:
Americans and before age 65 in whites.4In the
United States, diabetes is the seventh leading Ischemic stroke is one of the major cause
cause of death and 65% of these deaths are disability in adult population. With the great-
attributable to CVD or stroke or to both. er incidence of Ischemic stroke in diabetic
patients it is very necessary to control dia-
Pathophysiology: betes in order to prevent Ischemic stroke.
Intensive blood glucose control by oral hy-
Some of the mechanisms which leads to stroke poglycemics or insulins or life style modifica-
in diabetes affected are: vascular endothelial tions plays a very vital role in maintaining
dysfunction, increased early-age arterial stiff- blood glucose which will help in reducing the
ness, systemic inflammation and thickening of incidents of diabetes causing the Ischemic
the capillary basal membrane.Vascular endo- stroke.
thelium dysfunction is one of major reasons for
stroke in diabetes patients. Diabetes impairs
the vasodilation of vascular endothelium by in-

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Cardio Diabetes Medicine 2018 132

Objective: diabetes is twice those without diabetes, even
after adjustment for risk factors.
To know the relation between Ischemic
stroke and Diabetes and its prevention. Epidemiology:

Introduction: An estimated 285 million individuals worldwide
suffered diabetes during 2010, and the number
Ischemic stroke is a medical condition which is projected to increase to 439 million worldwide
is the sudden loss of blood circulation to by 20305. Diabetes is a growing challenge in
an area of the brain, leading to dysfunction India with estimated 8.7% diabetic population
of brain tissue in the affected area. Acute in the age group of 20 and 70 years.
ischemic stroke is caused by thrombotic or
embolic occlusion of a cerebral artery and Stroke is one of the leading causes of death and
is more common than hemorrhagic stroke. disability in India. The estimated adjusted prev-
Classification of stroke into hemorrhagic alence rate of stroke range, 84-262/100,000 in
and infarctive stroke subtypes was based on rural and 334-424/100,000 in urban areas.11In
Brain CT or MRI. Uncontrolled high blood one of the recent studies carried out among
pressure, diabetes, coronary artery disease stroke patient in India, the incidence of differ-
and high blood cholesterol are all risk factors ent risk factors were as follows: hypertension
for stroke.2 Diabetes mellitus (DM) is a com- (56.9%), diabetes (34.8%), Hyperlipidemia
mon problem whose prevalence is increas- (23.7%) smoking (38.9%) a n d C A D (18%).
ing due to population aging and also due to A Prospective Study of the Middle-aged
growing incidence of obesity.Diabetes and Finnish Population which comprises of 8077
ischemic stroke are common diseases that men and 8572 women has shown that di-
frequently occurring together. abetes was the strongest risk factor for
death from stroke among both men and
There is a synergy between DM and stroke with women. Men with diabetes at baseline ap-
DM being an established risk factor for stroke. peared to be at a six-fold increased risk
DM is the 7th leading cause of death and 65% of death from stroke, while relative risk for
of these deaths are attributable to stroke. DM men who developed diabetes during the fol-
patients have 1.5 to 3 times high risk of stroke low-up was 1.7. In women, those who were
especially cerebral infarction as compared diabetic at baseline were at higher risk of
to non-diabetic patients. According to several stroke than women who developed diabe-
studies, strict control of blood sugar has not tes later (relative risks, 8.2 and 3.7, respec-
been shown to reduce the overall incidence of tively). Of stroke deaths, 16% in men and
stroke in DM patients, therefore management 33% in women were attributed to diabe-
of the risk factors particularly, like dyslipidemia tes. The prevalence of diabetes increases
and hypertension are important for the preven- with age in all race/ethnicity groups. With-
tion of stroke in DM patient. in each age-group, prevalence is higher in
African-American and Hispanic populations
Risk Factors: as compared with whites. Exploration of the
race/ethnicity-specific differences in stroke
Diabetes is an important risk factor for isch- risk conferred by diabetes is necessary
emic stroke and is associated with an increase for optimal prevention and management of
in overall stroke mortality. Some of the major stroke in these groups.14 Even prediabetes
risk factors which play a key role to promote the has been linked to a greater risk of stroke.
development of ischemic stroke are hypergly-
cemia, hypertension and dyslipidemia. Along Pathophysiology:
with the above also genetic, demographic, and
lifestyle factors contribute in varying degrees to Some of the mechanisms which leads to
the overall risk with diabetes mellitus. Howev-
er, the risk of ischemic stroke in patients with

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Cardio Diabetes Medicine 2018 133

stroke in diabetes affected are: vascular en- has also been associated with CVD.
dothelial dysfunction, increased early-age
arterial stiffness, systemic inflammation and Management:
thickening of the capillary basal membrane.
Vascular endothelium dysfunction is one Proper prevention and management of the
of major reasons for stroke in diabetes pa-
major risk factors is very important to prevent

the substantial number of these disabling

strokes among patients with diabetes.

tients. Diabetes impairs the vasodilation of •Hyperglycemia: Hyperglycemia is a com-

vascular endothelium by inhibiting the nitric mon phenomenon presented in the early acute

oxide (NO), which mediates the vasodila- stroke phase. Hyperglycemia is associated with

tion, and the decreased availability of NO poor outcomes; proper management of post-

can cause endothelial dysfunction and trig- stroke hyperglycemia is critical for improving

ger atherosclerosis. outcomes. The American Heart Association

Hyperglycemia-induced overproduction of (AHA)/American Stroke Association guidelines

reactive oxygen species (ROS) inhibits the for the early management of patients with acute

action of glyceraldehyde 3-phosphate de- ischemic stroke recommends “to achieve serum

hydrogenase (GADPH), a key enzyme in glucose concentrations in the range of 140–180

glycolysis. When free radicals induce DNA mg/dL (7.8–10 mmol/L) during the first 24 hours

strand break, ROS activates the DNA re- after acute ischemic stroke in all hospitalized

pair enzyme Poly (ADP-ribose) polymerase patients.” Mortality is higher and poststroke out-

(PARP). Active PARP then modifies GAPDH and comes are poorer in patients with stroke who

inhibits its activity. This results in the accumula- have uncontrolled glucose levels.Randomized

tion of glycolytic intermediates upstream of GAP- controlled trials ACCORD and ADVANCE have
DH which contributes to vascular endothelial shown that it is safe to aim for a HbA1c of 53
dysfunction.15Individuals with T2DM have stiffer mmol/mol (7.0%) in those with long duration of
arteries and decreased elasticity compared with diabetes and established cardiovascular disease.
subjects having normal glucose level. T1DM

is more often associated with an early struc- • Hypertension which usually coexists with di-
tural impairment of the common carotid artery, abetes is also one of the major risk factors for
commonly reflected as increased intima-medial stroke. Controlling the blood pressure (BP) has
thickness, and is considered as early sign of ath- been proven to be effective in preventing stroke
erosclerosis. Vasculopathy induced by chronic in individuals with diabetes. National High Blood
hyperglycemia related endothelial damage re- Pressure Education Program recommended
sults in acceleration of atherosclerosis inherent “patients with diabetes and chronic kidney dis-
to diabetes. Therefore, higher prevalence and ease, BP goal should be < 130/80 mm Hg”.
incidence of cardiovascular disease including
stroke are common in the diabetic population. The risks of Macrovascular and microvascular
An increased inflammatory response is fre- complications are increased by hypertension.10
quently seen in individuals with diabetes, in- The Action to Control Cardiovascular Risk in Di-
flammation plays an important role in the de- abetes (ACCORD) BP Trail reported intensive
velopment of the atherosclerotic plaque. systolic BP (sBP) control to 120 mmHg, com-
The C-reactive protein, cytokines and adi- pared with a goal of 140 mmHg, among T2DM
ponectin are the main serum markers of in- patients was associated with a significant re-
flammation. The C-reactive protein and the duction in total stroke.16 In the UKPDS, T2DM
plasma levels of these cytokines including patients in the tight control arm had a signifi-
interleukin-1, interleukin-6 and tumor necro- cantly lower BP (144/82 mmHg) compared
sis factor-α are independent predictors of car- with those in the standard control arm (154/87
diovascular risk. Adiponectin appears to be a mmHg) and this was associated with a 44% re-
modulator of lipid metabolism and systemic duction in stroke.15 The Heart Outcomes Pre-
inflammation. A low level of adiponectin itself vention Evaluation study reviewed the use of

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Cardio Diabetes Medicine 2018 134

an ACE-inhibitor in high risk patients for cardio- References
vascular event.15 AHA/ASA guidelines recom-
mend the choice of antihypertensive be individ- 1. Edward CJ. Ischemic Stroke. https://emedicine.
ualized to the patient with specific consideration medscape.com/article/1916852-overview. Accessed
based on clinical indication. on 27thAug, 2018

• Dyslipidemia, which is characterized by pres- 2. schemic S t r o k e . Av a i l a b l e a t
ence of low levels of High Density Lipoprotein https://www.cedars-sinai.edu/
(HDL) cholesterol, hypertriglyceridemia, and Patients/Health-Conditions/Isch-
postprandial lipemia is also one of the major risk emic-Stroke.aspx. Accessed on
factors for stroke in diabetes mellitus. A MRC/ 27th Aug, 2018
HF Haert Protecrtion Study Showed that a daily
3 . D i a b e t e s . World Health Organisation.
dose of 40 mgof simvastatin administered to India. Available at http://www.searo.
5963 patients with diabetes have reduced the who.int/india/topics/diabetes_mellitus/en/.
first major vascular events by about a quarter Accessed on 27 Aug, 2018
in a wide range of diabetic patients studied.17
In a multicenter randomized placebo-controlled 4. Kissela BM, Khoury J, Kleindorfer
trial [Collaborative Atorvastatin Diabetes Study D, et al. Epidemiology of ischemic
(CARDS)] which was conducted on 2838 pa- stroke in patients with diabetes: the
tients have shown that a daily dose of 10 mg greater Cincinnati/Northern Ken-
atorvastatin is safe and efficacious in reducing tucky Stroke Study. Diabetes Care.
the risk by 37% in cardiovascular events and 2005;28(2):355-9.
48% in all types of stroke, in patients with di-
abetes without high LDL-cholesterol.\Likewise, 5. Chen R, Bruce O, Feng W. Diabetes
healthy living, good diet, exercise, moderation and Stroke: Epidemiology, Pathophysiology,
of alcohol, and weight loss are just as important Pharmaceuticals and Outcomes. Am J Med
for the diabetic person as those without diabe- Sci. 2016;351(4):380–386.
tes, for stroke prevention. They should be rec-
ommended for all and form part of routine clin- 6. Cade WT. Diabetes-Related Microvascu-
ical care. Smoking cessation should be offered lar and Macrovascular Diseases in the
to all patients, regardless of diabetes. Physical Therapy Setting. Phys Ther.
2008;88(11):1322–1335.
Conclusion:
7. Owolabi L, Mansur N, Aliyu I, et al.
Ischemic stroke is one of the major causes of Stroke in patients with diabetes mellitus:
disability in adult population. With the greater a study from North Western Nigeria. Afr
incidence of Ischemic stroke in diabetic patients Health Sci. 2016;16(3):781–789.
it is very necessary to control diabetes in order
to prevent Ischemic stroke. Intensive blood glu- 8. Hewitt J, Guerra LC, Maria del Carman FM,
cose control by oral hypoglycemics or insulins et al., Diabetes and Stroke Prevention: A
or life style modifications plays a very vital role Review. Stroke Research and Treatment.
in maintaining blood glucose which will help in Volume 2012, Article ID 673187, 6 pages
reducing the incidents of diabetes causing the
Ischemic stroke. 9. Anyanwu AC. Awareness of Stroke among
Subjects with Diabetes Mellitus attend-
ing a tertiary diabetes outpatient clinic in
South-East Nigeria. Int J Endocrinol Me-
tab Disord. 2018;4(1). DOI: http://dx.doi.
org/10.16966/2380-548X.148

10. Tuttolomondo A, Maida C, Maugeri R,et al.

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Relationship between Diabetes and Isch- al. Primary prevention of cardiovascular dis-
emic Stroke: Analysis of Diabetes- Relat- ease with atorvastatin in type 2 diabetes in
ed Risk Factors for Stroke and of Specific the Collaborative Atorvastatin Diabetes Study
Patterns of Stroke Associated with Diabe- (CARDS): multicentre randomised place-
tes Mellitus. J Diabetes Metab. 2015;6:544. bo-controlled trial. Lancet. 2004;364:685–
doi:10.4172/2155-6156.1000544 696.Hewitt J, Guerra LC, Maria del Car-
11. Pandian JD, Sudhan P. Stroke Epidemiology man FM, et al., Diabetes and Stroke
and Stroke Care Services in India. J Stroke. Prevention: A Review. Stroke Research
2013; 5(3): 28–134. and Treatment. Volume 2012, Article ID
12. Nath PR, Beg MA, Ahmad K. Epidemiological 673187, 6 pages.
study of incidence and risk factors of Ischemic
stroke subtypes according to Trial of ORG
10172 in acute stroke treatment criteria: A 3
years, hospital-based study. International Jour-
nal of Medicine and Public Health.2015;5(1):50-
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13. Jaakko T , Daiva R, Pekka J,et al. Diabetes Mel-
litus as a Risk Factor for Death From Stroke. Pro-
spective Study of the Middle-aged Finnish Popula-
tion. Stroke. 2018;27:210-215.

14. Kissela B M , K h o u r y J , D a w n K , e t a l .
Epidemiology of Ischemic Stroke
in Patients With Diabetes. The
Greater Cincinnati/Northern Ken-
tucky Stroke Study. Diabetes Care
2005;28(2):355-359.

15. Tu n N N , G a n e s a n A , S u n i k K M , e t
al. Diabetes mellitus and stroke:
A c l i n i c a l u p d a t e . World J Diabetes.
2017;8(6):235–248.

16. Bangalore S , K u m a r S , L o b a c h I , e t
al. Blood pressure targets in sub-
j e c t s w i t h t y p e 2 d i a b e t e s mellitus/
impaired fasting glucose: observations
from traditional and bayesian random-ef-
fects meta-analyses of randomized trials.
Circulation. 2011;123(24):2799-810,

17. Collins R, Armitage J, Parish S, et al.
MRC/BHF Heart Protection Study of
cholesterol-lowering with simvastatin
in 5963 people with diabetes: a ran-
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2003;361(9374):2005-16.

18. Colhoun HM, Betteridge DJ, Durrington, et
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Cardio Diabetes Medicine 2018 136

DIABETES AND NERVOUS SYSTEM

Dr.Kannan. B, MD,DM(Neuro)
Consultant Neurologist,Sundaram Arulraj Hospital,Tuticorin

Co-Author:Dr.Aarathy Kannan,MD,Dip.Diab

INTRODUCTION DIABETES AND CENTRAL
NERVOUS SYSTEM (CNS)
Diabetes mellitus (DM) is a metabolic disorder
with multiple etiologies, in which hyperglycemia Glucose is the primary fuel for the brain. It en-
is a common phenotype. Hyperglycemia results ters brain by facilitated diffusion across blood-
from defects in reduced glucose Utilization, in- brain barrier. The brain stores small amount of
sulin secretion, and glucose over production.At glucose, mainly in the form of astrocytic glyco-
presents, diabetes is classified as type 1 and gen and these storages are influenced by circu-
type 2. Type 1 DM is characterized by complete lating glucose levels. Glucose once inside brain
insulin deficiency, whereas type 2 DM is char- is converted into glycogen or oxidized to ATP.
acterized by the insulin resistance, or impaired There is a complex regulatory mechanism that
insulin secretion and increased glucose produc- ensures constant delivery of glucose of brain.
tion. These complex mechanisms are disrupted in di-
abetes leading to CNS complications. Common-
Prevalence of DM has increased worldwide. ly encountered CNS emergencies are cerebro-
WHO report states that there were 30 million di- vascular disease, extrapyramidal involvement,
abetes in 1985, whereas in 2010 it jumped to seizures, cranial neuropathy, CNS infection. A
285 million and expected to reach 430 million by newer entity called diabetic encephalopathy is
2030. In India it is estimated there are round 69 also recently debated. Seizures are also seen
million people affected by diabetes as of 2014. in diabetics commonly due to hypoglycemia and
India and South East Asian countries will have rarely to hyperglycemia also.
the majority of diabetics by 2030. As the prev-
alence of diabetes increases, the complications CEREBROVASCULAR DISEASE
secondary diabetes is also on rise.
Diabetes is one of the most significant risk fac-
Hyperglycemic emergencies like D.K.A, tors for the development of stroke. Framingham
Non ketotic hyperosmolar coma which affects study among diabetic men and women found 2.5
the nervous system and to be treated aggres- and 3.6 fold increased risk of stroke respectively.
sively and managed by fluid, electrolyte and in- The Greater Cincinnati/Northern Kentucky stroke
sulin and had high mortality. study showed the major risk factor for stroke is
diabetes in patients less than 65 years. The study
The complications of diabetes are cat- reported risk hazard ratio for ischemic stroke in
egorized as acute and chronic complications. diabetes at 2.3. Hyperglycemia contributes to
Chronic complications are further classified the macro-vascular complication by producing
into microvascular and macrovascular which endothelial dysfunction. Endothelial dysfunction
include retinopathy, nephropathy, neuropathy is mainly due to formation of advanced glycation
and peripheral arterial diseases, coronary artery end products (AGE), that binds to receptors in
disease, cerebrovascular disease respective- endothelium promoting or accelerating athero-
ly. Diabetes affects both central and peripheral sclerosis. Increased LDL uptake and oxidation
nervous system. This chapter mainly focuses on
acute complications of Diabetes which predomi-
nantly affects the Nervous system.

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Cardio Diabetes Medicine 2018 137

also adds up to the process. These pathogenic theoretically reduce the risk of hypoglycemia

mechanisms lead to chronic state of low grade arising as a result of infusion or device failure.

inflammation, hypercoagulability and endothelial

dysfunction leading to stroke. DIABETIC ENCEPHALOPATHY
Most strokes are ischemic events, main-
Diabetic encephalopathy has widely accepted
ly small artery strokes followed by large artery and diabetic complication. There are charac-
stroke. Stroke is common among type 2 diabetes terized by defect in learning ability, intelligence,
mainly because of the age and associated co- memory and orientation. They differ mildly be-
morbidities like systemic hypertension and coro- tween type 1 and type 2 diabetes. In type I it
nary artery disease. is associated with poor learning ability and im-
paired scholastic performance, whereas in type
HYPERGLYCEMIA IN ACUTE STROKE 2, it predominantly affects recent memory. The

Hyperglycemia and hyperthermia are recog-

nized risk factors that predict poor outcome in insulin deficiency associated with diabetics

post-stroke patients. Hyperglycemia is noted in seems to downstream the expression of neuro-

30-40% of patients with acute stroke. Hypergly- trophic factors, neurotransmitters along with oxi-

cemia can occur in nondiabetic stroke patients dative and apoptotic stressors leading to loss of

also due to release of control and epinephrine neural integrity has been postulated as a possi-

and due to autonomic imbalance. Hyperglyce- ble mechanism for the development of diabetic

mia could aggravate cerebral damage in post encephalopathy.

stroke, by altering recanalization, release of ni-

trous oxide and advanced glycation end-prod- EXTRAPYRAMIDAL INVOLVEMENT
ucts that promote endothelial dysfunction, oxida-
tion and inflammation. All these promote cerebral Hyperglycemia is known to affect basal ganglia
damage and increases ischemic penumbra. In structures especially subthalamic nucleus result-
30 day mortality the relative risk after ischemic ing in hemiballism-hemichorea. It is commonly
stroke was 3.3 in diabetics and 2.0 is non-dia- seen in nonketotic hyperglycemic states. In di-
betics. Alvarez-Sabin et al. found that admission abetes, the proposed hypothesis for the cause
sugar values more than 140 mg/dL to be the sin- of these movement disorders includes hypergly-
gle independent predictor in patients who were cemia-induced minimal ischemia in the putamen
thrombolysed within 6 hours of poor outcome at via anaerobic metabolism and hypoperfusion
3 months even after excluding the patients with which leads to GABA depletion. Imaging re-
symptomatic ICH. Maintenance of normoglyce- vealed hyper-intense lesion at striatum (Fig. 2.2).
mia is post-stroke patients is clinically challeng- Hyperdensity is due to protein hydration inside
ing, even with intensive monitoring and carries the cytoplasm. Correction of hyperglycemia will
a risk of hypoglycemia. However, randomized give dramatic improvement of clinical features,
controlled trials on strokes failed to demonstrate especially ballistic moments.

improved outcomes with intensive hyperglyce-

mic treatment.

A various methods of insulin administration

exist, like multiple subcutaneous dosing by slid-

ing scale, continuous intravenous (IV) infusion,

intravenous delivery of a reconstituted infusion

containing dextrose, potassium supplementation

and insulin (the GKI regime). Sliding scale regi-

mens are largely reactive, correcting changes as

and when they occur, whereas GKI regimens are

largely proactive, maintaining euglycemia within

a therapeutic range in predicting insulin require-

ments. Concurrent administration of dextrose, Fig. 2.2: CT brain showing hyperdensity in
potassium and insulin as a GKL infusion may
caudate and putamen.

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Cardio Diabetes Medicine 2018 138

SEIZURES randomized control trials to decide on duration
of AED’s to be given, general consensus is to
Too low or too high glucose levels can cause sei- consider tapering AED’s once seizures are con-
zures. The problem is especially applicable to in- trolled and glucose level normalizes.
dividuals with diabetes, whose blood glucose lev-
els can fluctuate widely over the course of a day, HYPOGLYCEMIA AND CNS EFFECT
as a result of other metabolic factors, variations
in insulin levels and intercurrent illness. Hypogly- Fig. 2.3: MRI changes in persistent neuroglyco-
cemic seizures are commonly seen as the blood penia-T2 hyperintense lesion in posterior limb of
sugar levels drop below 20 mg/dL, however dif- the internal capsule. cerebral cortex (in partic-
ferent studies quote different values. Hypoglyce- ular parieto-occipital and insula). hippocampus
mic seizures appear to originate in the amygdale and basal ganglia
and hippocampus, suggesting that these struc-
tures have a lower seizure threshold compared Acute hypoglycemia causes disturbances in ion
to other brain regions. Reduced glucose levels homeostasis, leading to persistent membrane
can lead to the release of excitatory aminoacids depolarization, reduction in protein synthesis,
(Glutamate) which induce hyperexcitability with- alteration in amino acid metabolism, rise in in-
in the brain. Since paediatric population had de- tracellular calcium, increased hydrolysis of phos-
veloping brain which is more excitatory, seizures pholipids, alteration in the nucleotide metabolism
are common in paediatric population. Recurrent and increased concentrations of arachidonate
seizures due to hypoglycemia, especially, in type and other free fatty acids. During the episodes of
1 diabetics have been found to be associated acute hypoglycemia it has been shown that per-
with cognitive impairments. formance on immediate visual memory, imme-
diate verbal memory, delayed memory, working
Since type I Diabetes is auto immune origin memory, visual-motor skills, visual-spatial skills
there is lot of interest relating type I D.M. and and global cognitive dysfunction are all impaired.
seizures. In this aspect, auto antibodies more at- Hypoglycemia in the initial stages leads to anxi-
tracted is Glutamate decarboxylase (GAD).GA- ety, perspiration, and tachycardia late leading to
DAs (80%)are very common in type I D.M and drowsiness, coma and death. Prolonged hypo-
which is associated with Neurological disorders glycemia leads to neuroglycopenia which results
Stiff person syndrome(36%), cerebellar ataxia in persistent deficits. One consequence of the
(18%), epilepsy(4%). GADAs epilepsy is drug neuroglycopenia is a failure of energy-depen
resistant focal epilepsy and is treated by high Fig. 2.3: MRI changes in persistent neuroglyco-
dose steroid, plasmapharesis and intravenous
immunoglobulin.
Hyperosmolar nonketotic state precipitates sei-
zures more commonly than ketotic hyperglyce-
mia because of anticonvulsive nature of ketones.
Focal motors seizures, complex partial seizures,
visual hallucination and Epilepsia Partialis Con-
tinua are more common in NKH patients. The
exact mechanism of seizures is poorly under-
stood. There is positive correlation of blood sug-
ar, serum osmolality and serum sodium with fre-
quency and duration of seizures. Seizures due
to hyperglycemia seem to be better controlled
with midazolam followed by routine anti-epilep-
tics, valproate and phenytoin. Though there no

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Cardio Diabetes Medicine 2018 139

dent reuptake of excitatory neurotransmitters sacral Radiculo plexus Neuropathy, throcoab-

and synaptic release of glutamate (or aspartate). dominal radiculopathy, diabetic cachexia, crani-

Excitotoxic cellular damage, which is mediated al neuropathy present as acute presentation in
through NMDA specific receptors, as with stroke, D.M. Radiculopathy and cranial neuropathy are
is common in neuroglycopenia. It may lead to reversible while sensorimotor symmetrical poly-
hypoglycemic encephalopathy characterized by neuropathy is progressive and irreversible

confusional state, loss of recent memory and

orientation. On imaging abnormalities are seen Diabetic Lumbosacral Radiculo plexus

in basal ganglia, hippocampus and cortex more Neuropathy

of occipital cortex (Fig. 2.3). Cortical laminar ne- It presents with acute and severe proximal low-

crosis is the characteristic MRI findings in hy- er limb pain, followed by muscle weakness and
poglycemic encephalopathy. EEG shows slow atrophy. The clinical presentation often involves
waves and occasionally triphasic images. Burst the distributionof the femoral nerve and may
suppression is also documented in comatose be called as “Diabetic Amyotrophy” or Femoral
patients. The prognosis depends on duration of Neuropathy. The course is prolonged for months
hypoglycemia, severity and effective treatment with major disability and limitation in ambulation,
strategy. spontaneous remission is observed in most cas-
es. Microscopic vasculitis producing nerve isch-

DIABETES AND CNS INFECTION- emia is the pathophysiology of this disorder.

Diabetes mellitus (DM) remains a major comor- Throcoabdominal radiculopathy
bid disorder for several rare but potentially le-
thal infections, including rhino-orbital-cerebral Focal radiculopathy presents with acute radicu-
mucormycosis and malignant external otitis.
DM is also a commonly associated condition in lar pain in the throcoabdominal region and inves-
patients with nontropical pyomyositis, pyogenic
tigations such as spinal Mri do not show structur-

al cause.

spinal infections, Listeria meningitis, and blasto- Diabetic Cachexia
mycosis.  DM was identified as a risk factor for
herpes zoster. The relationships among infec- It is manifested as severe diffuse pain and par-
tion, DM, and the nervous system are multidirec- esthesia and weight loss in diabetic patients that
tional. Viral infections have been implicated in can be precipitated by rapid glycaemic control
the pathogenesis of type 1 and type 2 DM, while with insulin therapy. Symptomatic recovery is as-
parasitic infections have been hypothesized to sociated with recovery of nerve function, indicat-
protect against autoimmune disorders, including ing that the pathogenesis is likely due to nerve
type 1 DM. DM-related neurologic disease can hypoxia but not irreversible nerve destruction.

predispose to systemic infection - polyneurop-

athy is the predominant risk factor for diabetic Cranial Neuropathy

foot infection. Because prognosis for many neu- Oculomotor palsy in Diabetics typically presents

rologic infections depends on timely institution with acute onset of ipsilateral severe headache,

of antimicrobial and sometimes surgical therapy, diplopia, ptosis with sparing of the pupil. Recov-

neurologists caring for diabetic patients should ery is complete or near complete over a period

be familiar with the clinical features of the neu- of few days to few months. Seventh nerve palsy

roinfectious syndromes associated with DM. has been associate with D.M. in 6% to 66% of

cases.

DIABETES AND PERIPHERAL CONCLUSION

NERVOUS SYSTEM
The complications of diabetes in peripheral ner- Diabetes affects various organs in our body and
vous system include small and large fiber neu- its neurological complications are well known.
ropathy, distal sensory/sensorimotor polyneurop- Hyperglycemic emergencies D.K.A In nervous
athy, cranial neuropathy, autonomic neuropathy system its effects are poorly understood and dif-
and polyradiculoneuropathy. Diabetic Lumbo- fuse. Regular screening to look for its complica-
tions is necessary to prevent mortality and mor-
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Cardio Diabetes Medicine 2018 140

tality due to the disease.

REFERENCES

1. Definition, diagnosis and classification of dia-
betes mellitus and its complications: report of
WHO consultation. Part 1, Diagnosis and classi-
fication of diabetes mellitus. Geneva 1999.
2. American Diabetes Association. Diagnosis
and classification of diabetes mellitus. Diabetes
Care. 2010;33(Suppl 1):S62-S69.
3. Forouhi NG, Wareham NJ. Epidemiology of
diabetes. Medicine (Abingdon, England: UK
Ed), 2014;42(12):698-702.
4. Kaveeshwar, Seema Abhijeet, Jon Cornwall.
"The Current State of Diabetes Mellitus in
India." The Australasian Medical Journal 7.1
(2014):45-48.
5. Diabetes mellitus and its chronic complica-
tions. AORN J. 2002;76(2):266-76, 278-82.
6. Henry WL. The complications of diabetes mel-
litus. Journal of the National Medical
Association. 1987;79(6):677-80.
7. Leys D, Deplanque D, Mounier-Vehier C, et
al. Stroke prevention: management of modifiable
vascular risk factors. J Neurol. 2002;249(5):507-
17.
8. Mahmood SS, Levy D, Vasan RS, et al. The
Framingham Heart Study and the Epidemiology
of Cardiovascular Diseases: a Historical Per-
spective. Lancet. 2014;383(9921):999-1008.
9. Broderick J, Brott T, Kothari R, et al. The great-
er cincinnati/Northern Kentucky Stroke Study:
preliminary first-ever and total incidence rates of
stroke among blacks. Stroke. 1998;29(2):
415-21.
10. Chilelli NC, Burlina S, Lapolla A. AGEs, rath-
er than hyperglycemia, are responsible for
microvascular complications in diabetes: a "gly-
coxidation-centric" point of view. Nutr Metab
Cardiovasc Dis. 2013;23(10):913-9.

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Cardiovascular risk factor assessment in healthy individuals: Is the glass 141

half empty or half full?

CARDIOVASCULAR RISK FACTOR ASSESSMENT IN HEALTHY INDIVIDUALS:
IS THE GLASS HALF EMPTY OR HALF FULL?

Dr.Kaushal chattrapati,MD,DM(Cardio),FACC(USA),FCSC(EUROPE)

Interventional cardiologist,Mumbai

Abstract: Traditional CV Risk Factors:

India is fast emerging as the epicentre of Car- Traditional CV Risk factors are Non Modifiable
diovascular Disease epidemic. The cardiovas-
cular disease in Indians is both more aggressive and Modifiable.
and more fatal, and occurs at a younger age.
Traditional risk factors like age, sex, family his- The Non Modifiable Risk Factors are :
tory, Lipid profile, blood pressure, diabetes, obe- 1. Age : Increase image increases the CV
sity, lack of exercise, smoking and stress collab-
risk.

2. Gender: CV disease is commoner n

males before 60 years.

orate to give this grim picture. However, even 3. Family history: of CVD in close blood
after meticulous control of these risk factors, a
small risk of CV diseases remains. Novel Car- relatives.
diovascular risk factors: such as hs-CRP, Lp(a), These, of course can not be changed. So, in
S. Homocysteine, IL-6 etc have been proposed spite of all advances in medicine, a finite risk of
to further refined risk assessment by European CVD is always going to persist.
Society of Cardiology. Although a plethora of risk However, luckily there are a host of other risk
factors makes management of CAD complicat- factors which you can alter. These are referred
ed, especially in healthy individuals, it also adds to as Modifiable Risk Factors.

another layer in risk stratification and enables The Modifiable Risk Factors are:
us to offer more comprehensive risk reduction
strategies to our patients. 1. High Blood pressure: Framingham

and other epidemiological studies established

Introduction: the undeniable risk of high blood pressure with
cardiovascular risk which was both independent
Cardiovascular disease has plagued mankind and linear In several clinical trials, it has been
since the beginning, but with the control of com- shown that treatment of blood pressure reduc-
municable diseases and adoption of modern es the stroke risk by 35-40%, Myocardial infarc-
lifestyle, cardiovascular disease has started as- tion risk by 20-25%, and heart failure risk by as
suming epidemic proportions in India and rest much as 50%(7)
of the world. A review of epidemiological stud-
ies from various parts of India have indicated 2. Diabetes: Diabetes increases cardio-
that the prevalence of Cardiovascular disease
hovers between 7-13% in Urban population vascular risk. The risk is 2-3 fold in diabetics,
(1,2), and 2-7%% in rural population.(3,4). CHD and 1-5 fold in those with impaired glucose tol-
deaths account for 23% of total and 32% of erance. Diabetes is associated with metabolic
adult deaths between 2010-2013 (5). The glob- syndrome, atherogenic dyslipedemia and insu-
al burden of disease study estimate the age lin resistance. Presence of diabetes is an inde-
standardized CVD death rate in India is 272 per pendent risk factor for CVD, and is an indication
100000, higher than the global average of 235 for starting statins irrespective of the lipid val-
per 1000000(6) . There are some alarming as- ues.
pect to this CVD epidemic in India. Early age of
presentation, accelerated atherosclerosis and 3. Smoking: The Framingham and the
high case fatality rate of index CVD event differ-
entiate Indian CVD epidemic from other nations. Albany Cardiovascular Health Centre study
A large part of controlling this burgeoning CVD showed that smokers were at an increased
epidemic is search for risk factors in apparently riskHigh LDL) , others require patient co-oper-
healthy individuals. ation(Regular Exercise), and yet others need
hydrolysis. Moreover, it is a marker of plaque
rupture and atherothrombo-embolism. both in-
volvement of Health care providers and patient
cooperation(e.g Losing weight, controlling dia-

Cardio Diabetes Medicine

Cardio Diabetes Medicine 2018 142

of both heart attack and sudden death. It was betes).However, even after control of
also seen that this risk increased linearly with these traditional risk factors, some patients con-
the number of cigarettes smoked and returned tinue to suffer from CVD, and indeed the disease
to non smoker levels if the person stopped continues to progress relentlessly. Evidently,
smoking. Today, cessation of smoking after a there are many more such risk factors , which
heart attack is the single most important inter- need addressing for managing the enigmatic
vention to prevent a repeat heart attack. entity known as “Residual Cardiovascular Risk”

4. Hyperlipedemia: Framingham and “Residual Cardiovascular Risk”:

other studies show that Total Cholesterol, LDL CV risk remaining after control of traditional risk
Cholesterol and CVD risk are intimately linked factors, particularly the LDL target is commonly
(8). Although Triglycerides have also been linked referred to as “Residual Cardiovascular Risk”.
with CVD, its independent association with CVD
is controversial. Atherogenic Dyslipedemia,(AD) is often

5. Obesity/Overweight: Obesity is as- associated with Residual Cardiovascular risk.
High TGs, low HDL with normal LDL is a part
sociated with CHD, CVD, diabetes and hyper- of Atherogenic Dyslipedemia. Smaller LDL par-
tension . Special attention should be paid to ticle size, and higher Apo B levels are associat-
childhood obesity which is related to free avail- ed with this type of Atherogenic Dyslipedemia,
ability of highly processed, carbohydrate-rich ,common in diabetics. Interestingly, Non HDL
junk food, and lack of physical exercise n young Cholesterol is a single parameter to evaluate
children. Atherogenic dyslipedemia. It is already recog-
nized by International Guidelines, endorsed as
6. Physical Inactivity/ Lack of Exer- a secondary target for patients with DM, High
cise: People who are sedentary have almost a TGs and Metabolic Syndrome. National Institute
of Health and Care Excellence Lipid Modifica-
two fold increase in the relative risk of CVD. This tion Guidelines recommend Non HDL Choles-
effect of Physical inactivity is multifactorial and terol Values as a Primary treatment Target.
occurs via reduction of obesity, control of diabe-
tes, reduction of blood pressure and reduction Novel Cardiovascular Risk Factors:
of inflammatory biomarkers. Exercise helps at
all ages: childhood, adulthood and old age.

7. Excess Alcohol: Excess alcohol use Other than these well-known markers, certain
Novel Markers are proposed. These are use-
causes several cardiovascular disturbances in- ful supplementary markers in early diagnosis
cluding Atrial fibrillation, hypertension, sleep ap- of CVD in patients with suspected myocardial
nea, diabetes and heart failure. Recent studies schema but without corroborative electrocardio-
show that there is no dose of alcohol which ben- graphic and Echocardiographic findings, espe-
cially when traditional risk factors are absent.
efits the heart.

8. Physical and Mental Stress: However, they remain expensive and should be

Stress; both physical and mental is paramount carefully used as an arbitrator only in selected

these days. There is enormous data showing cases. Moreover, many of these “risk factors”

the deleterious effect of stress on the human can not be treated or lowered by any known

body. Yoga, Transcendental Meditation, Cog- Pharmacological intervention. Routine use of

nitive behavioral therapy and other relaxation these Novel Risk Factors is hence neither rec-

therapies may attenuate the body’s response to ommended nor necessary.

stress and prevent cardiovascular diseases.

It goes without saying, that the healthcare pro- 9. Lipoprotein-associated phospho
viders need to diagnose and treat these modifi-
able risk factors. Some of the risk factors can be lipase A2(Lp-PLA2):
relatively easily controlled (e.g. Statins for
Lp-PLA2 favors lipid accumulation in the media,

lipid peroxidation, and FFA
Cardio Diabetes Medicine

Cardiovascular risk factor assessment in heMetabolic Syndrome in PCOS – 143

the South Asian Profile 

Some of the important ones of the Novel Risk 10. Growth Differentiation Factor-15
Factors are: (GDF-15): This novel biomarker, produced ex-

1. High-Sensitivity C-Reactive Pro- clusively by ischemic cardiomyocytes, strong-
tein (hs-CRP): ly indicates a markedly increased risk for CV
death.
JUPITER trial showed that hs-CRP levels above
2 mg/dl is an independent predictors of fatal Finally, the question remains: Can we really
heart attack and stroke. prevent CV mortality altogether? Probably not.
So, is finding these Risk factors- Traditional and
2. Fibrinogen: Novel- an exercise in futility? The answer is an
emphatic: No!. The increasing risk factors in
The latest ESC Guidelines recommend Fibrino- modern day life means that their recognition and
gen levels as a part of refined risk assessment control is necessary. Although a sharp increase
in patients with unusual or moderate CVD risk in the number of “ modifiable risk factors” means
profile (Class IIB, Level of Evidence: B) an increased stress on our already strained re-
sources, there is also an other side of the coin.
3. Interleukin-6 (IL-6) : A thorough study of these risk factors will even-
tually give us a more detailed understanding
This Acute phase reactant is implicated in both of the enigma of cardiovascular diseases, and
atherosclerosis and Atherothrombosis definitely equip us with more therapeutic arma-
mentarium to combat this deadly foe.
4. Lipoprotein (a) [Lp(a)]:
The glass is indeed half full. Cautious optimism
CV Risk increases with rising Lp(a) levels. Al- is the need of the hour. Immortality is neither
though no specific therapy targets Lp(a), a high- possible nor desirable. However, a long and
er Lp (a) level may lower the threshold for Statin healthy life is a realistic goal eminently achiev-
initiation in patients with borderline LDL choles- able with multiple risk factor intervention.
terol.
To this thought let us raise a toast. With the
5. Homocysteine: glass half full.

There is an association of Homocysteine levels
with CVD risk, especially in females. Vit B12
and Folate supplementation can effectively low-
er raised Homocysteine levels.

6. Brain-Type Natriuretic Peptide: References:
1. D Prabhakaran,P Jeemon, A Roy: Car-
Raised BNP levels denote CV Risk. BNP levels diovascular Diseases in India Current Ep-
idemiology and Future Directions: Circula-
more than 500 pg/ml represents a strong risk tion.2016;133:1605-1620

factor for sudden death in heart failure popula-

tion.

7. D-Dimer: 2. 2. Gupta R, Gupta VP, Sarna M, Bhat-
nagar S, Thanvi J, Sharma V, Singh AK, Gupta
D-Dimer denotes prognosis of several CV JB, Kaul V. Prevalence of coronary heart dis-
events, including but not limited to Pulmonary ease and risk factors in an urban Indian pop-
Embolism ulation: Jaipur Heart Watch-2. Indian Heart J.
2002;54:59–66.
8. Matrix Metalloproteinase-9(MMP-9): 3. Kumar R, Singh MC, Singh MC, Ahlawat SK,
Thakur JS, Srivastava A, Sharma MK,Malhotra
Along with CRP and IL-6, MMP-9 may predict
the development of atherosclerosis and athero-
thrombosis.

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Cardio Diabetes Medicine 2018 144

P, Bali HK, Kumari S.: Urbanization and coro-
nary heart disease: a study of urban-rural dif-
ferences in northern India. Indian Heart J.
2006;58:126–130.
4. Mohan V., Deepa R., Rani S.S. Prevalence of
coronary artery disease and its relationship to
lipids in a selected population in South India. J
Am Coll Cranial. 2001;38:682-687
5. Kamili M.A., Dar I.H., Ali G. Prevalence of cor-
onary heart disease in Kashmiris. Indian Heart
J. 2007; 61:44-49
6. Global, regional, and national age-sex spe-
cific all-cause and cause-specific mortality for
240 causes of death, 1990–2013: a systematic
analysis for the Global Burden of Disease Study
2013.Lancet. 2015;385:117–171
7. John G. Kanto, Ami E. Iskandrian. Major Risk
Factors for Cardiovascular Disease: Debunking
the “Only 50%” Myth JAMA. 2003;290(7):947-
949.
8. Roberto Ferrari, Albertico L. Catapano. Re-
sidual Cardiovascular Risk. European Heart
Journal Supplements, 2016 18(Supplement C)
C1
9. Dana Pop, Alaxandra Dadarlat, D Zdrenghea.
Novel Cardiovascular risk markers in women
with ischemic heart disease.Cardiovasc J Afr.
2014;25 : 137-141

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Cardio Diabetes Medicine 2018 145

GENETIC BASIS FOR COEXISTENCE OF DIABETES
NEPHROPATHY AND CARDIOVASCULAR COMPLICATIONS –

A SYSTEMIC REVIEW

Dr.Vijay Viswanathan , Dr.Udyama Juttada
M.V. Hospital for diabetes & Prof. M. Viswanathan Diabetes Research Centre, Royapuram, Chen-

nai, India.
(WHO Collaborating centre for Research, Education and Training in Diabetes)

Abstract: nearly by 20%, of patients with diabetes in Asia
were diagnosed before the age of 40 years (4).
Development of Vascular complications rep- Longer exposure to hyperglycemia putting the
resents a major healthcare burden associated individual at a higher risk of developing compli
with the treatment of diabetes. Even with ad-
vanced new therapies for controlling hyper- cations. Many genetic basis of Type 1 and type
glycemia, the burden associated with diabetic 2 diabetes are exploring the pathogenesis of di-
complications remains high, especially with that abetes. Genome wide association studies are
of cardiovascular and renal complications. Fur- beginning to expand our understanding of the
thermore, the early onset of diabetes at a young genetic architecture relating to diabetic compli-
age, putting the individuals at higher risk of de- cations. The pathogenesis of Diabetic Nephrop-
veloping complications, due to increased ex- athy (DN) is clearly multifunctional and several
posure to hyperglycemia. Diabetes has shown genes, proteins and environmental factors are
a greater association with end-stage renal dis- likely to contribute to the onset of the disease.
ease in many countries. Although there have Several metabolic, hemodynamic and intracellu-
been many important strategies in understand- lar causes have been proposed to play a role in
ing the genetics of type 1 and type 2 diabetes, the pathogenesis of DN.
which will insights towards the pathogenesis of
diabetes, there has been comparatively less Pathogenesis of Diabetes
progress in our understanding of the genetic complication:
basis of diabetic complications. Genome-wide
association studies are beginning to expand our The metabolic pathway in type-2-diabetes is
understanding of the genetic makeup relating to characterized by hyperglycemia and insulin re-
diabetic complications. Improved understand- sistance, often with coexisting hyperlipidemia
ing of the genetic basis of diabetic cardiorenal and hypertension. In addition to pathways ac-
complications might provide an opportunity for tivated by hyperglycemia, recent studies have
improved risk prediction, as well as the develop- highlighted the importance of endogenous pro-
ment of new therapies. tective pathways that could protect against the
development of diabetic vascular complications.
Introduction: These protective factors include insulin, plate-
let-derived growth factors vascular endothelial
The spectra of diabetes epidemic is the major growth factors and activated protein C, which
concern all over the world, an estimated 592 could provide new candidate genes for studying
million people are predicted to be diabetic by genetic factors protective against diabetic com-
2035, which is close to 50% residing in Asia and plications, as well as being targets for potential
the Western Pacific region (1-3).Diabetes is as- therapies to reduce vascular complication.
sociated with development of many micro and
macro vascular complications which is making it
difficult for treatment and health care of the dis-
ease. The proportion of young individuals being
diagnosed with diabetes is drastically increased

Cardio Diabetes Medicine

Cardio Diabetes Medicine 2018 146

Figure 1: The key role of genetics and epigenetics in modulating the pathogenesis of diabetes.

AGE, advanced glycation end –products PDGF, Platelet-derived growth factors, AS rennin-angio-
tensin system, VEGF, vascular endothelial growth factor (5-6).

Cardio Diabetes Medicine

Cardio Diabetes Medicine 2018 147

Link between Renal and Cardiovascu- these have yet to be discovered

lar Complications
It is well established that there is a close link Strategies for identifying susceptibili-
between coronary heart disease and renal dys- ty genes:

function (8, 9). Meta-analysis of studies sug- To identify the genetic variants in developing

gests that reduced eGFR rate and increased cardiorenal complications, two major strategies

albuminuria have an independent and multipli- have been commonly used to identify disease

cative effect on cardiovascular mortality (10, 11) susceptibility.

and this relationship is similar in individuals with 1. Linkage analysis: In linkage studies if the

or without diabetes (12). In a cohort of 2,434 logarithm of odds (LOD) Score is greater than

Chinese patients with type 2 diabetes, elevated 3.0 is considered evidence for linkage (A score

serum creatinine, eGFR <60 mL/min and urine of 3.0 means that likelihood of observing the giv-

albumin/creatinine ratio (ACR) >30 mg/g were en pedigree if the two loci are not linked is less

independent risk factors for coronary artery dis- than 1 in 1000) .On the other hand LOD score

ease (13). In a study utilizing nationally repre- less than -2.0 is considered evidence to exclude

sentative cohorts from Taiwan, the synergistic linkage.

effects of diabetes and ESRD in modifying the

risk of cardiovascular complications was shown, 2. Genome-wide association analysis: This
with diabetes and ESRD associated with twofold analysis is based on the association between
and fourfold increased risk of acute myocardial disease and highly correlated single nucleotide
infarction, respectively, but the presence of both polymorphism (SNP’S). These SNP’S lie with-
is associated with an almost 12-fold increased in a candidate gene or region and are selected
risk for acute myocardial infarction(14). This link from the literature or from the HapMap database.
between CHD and CKD is partly due to a sharing Several candidate genes have been identified for
of predisposing risk factors. In addition to hyper- association with DN using case-control studies.
tension, other metabolic syndrome traits, such

as central obesity and hyper triglyceridemia,

have also been identified to predict the risk of in-

cident CKD among patients with type 2 diabetes

(15). Integrated management of multiple risk fac-

tors has been emphasized for the management

of patients with diabetes and renal disease (16).

In addition to an overlap of predisposing clinical

risk factors, it is possible that the two conditions

could also have shared genetic factors though

Cardio Diabetes Medicine