Tackling the Diabetes epidemic in India

posted Jan 26, 2017, 1:13 AM by sourav ghosh   [ updated Jan 26, 2017, 3:10 AM ]
Nihal Thomas
Department of Endocrinology, Diabetes and Metabolism,Christian Medical College, Vellore, India

The questions which concern the pathogenesis of diabetes mellitus in the Indian Subcontinent are many, owing to the high prevalence of the disease, the comparatively lower age of onset and a relatively low body mass index amongst Asian Indians.
The foetal origins of diseases- propounded by Barker and colleagues may in part be responsible. This maybe a critical factor, considering that the prevalence of low birth weight (LBW) in India is amongst the highest in the world and approaches a figure of 15 to 20% of all live births in some parts of the country. The fetal insulin hypothesis (FIH) proposed by Hattersley states that genetic variants associated with insulin resistance may lead to impaired insulin – mediated growth prenatally, leading to low birth weight and adverse metabolic outcomes in adulthood. Thus, low birth weight is part of a syndrome that may be associated with in utero insulin resistance which in turn may manifest with diabetes and hypertension at the time of adulthood.
We successfully enrolled 60 LBW and 60 NBW males, born in and still living in rural environments around the city of Vellore. We confirmed that low birth weight adult males who had fully completed puberty were shorter in height and lighter in body weight when compared to their NBW counterparts. Moreover, the LBW individuals had a significantly lower lean body mass when compared to their NBW counterparts. This difference was present in the total body lean mass and extended to include the upper and lower limbs of these subjects and was associated with a lower bone mineral content in the LBW group.
Interestingly, 8% of the LBW individuals had impaired glucose tolerance, which was not present in the NBW individuals. However, this was not reflected in the 'm' values (measure of insulin sensitivity) - that were obtained from the hyperinsulinemic euglycaemic clamp studies done on these individuals, who were all incidentally associated with a low median BMI (19.5kg/m2) in both the LBW and NBW groups. The LBW subjects had a marginally significant higher supine resting diastolic blood pressure level when compared to NBW subjects, when adjusted for height and weight. Measurement of High Density Lipoprotein Levels (HDL levels) showed values which were low, which bore similarity to what is seen in the Southern Indian population, moreover there was no difference in the measurements in HDL between the LBW and NBW subjects.
There was no difference in resting energy expenditure when measured by indirect calorimetry between the LBW and the NBW group of subjects, nor was there any difference in Glucose or Fat oxidation between the groups. When the data of all 120 subjects were taken as a whole, and the m-value correlated with the insulin resistance indices including HOMA-IR, QUICKI, Fasting Insulin levels, Glucose insulin ratio, McCauley’s index and Matsuda Index: the strongest correlation was obtained in the association between the m-value and the McCauley’s index and the Matsuda index. In fact more recent studies by our group have shown that complex calculations apart, that the fasting glucose-insulin ratio correlates well with the hyperinsulinemic euglycaemic clamp studies and is superior to HOMA-IR, QUICKI and McCauley's index.
The Dietary intake of protein was significantly lower in quantum in the LBW subjects when compared to the normal birth weight subjects at the time of recruitment into the study. This was associated with a lower proportion of energy being extracted from the protein intact per se. The mothers and the fathers of the LBW subjects were shorter than the NBW subjects, suggesting the possibility of an intergenerational influence on birth weight (though the difference did not achieve statistical significance.
The LBW group had agreater Fat mass/ fat free mass reduction when compared to their pre-exercise baseline status and a significant decline in FM/body weight followinga 45 minute exercise intervention for a 6 week period on a bicycle. The NBW subjects had a small but significant increase in fat percentage. Moreover, there was a statistically significant reduction in fasting plasma insulin levels in the LBW group, while the reduction was not statistically significant in the NBW group. Regarding reductions in insulin secretion, HOMA-IS a change were significant in the LBW and NBW groups, while reductions in HOMA-IR was only significant in the NBW group.
The subjects had spectroscopic assessment of micro-quantitities of fat in the liver and the muscle, through NMR spectroscopy. It was found that there was a negligible quantum of ectopic fat storage in the liver in particular, and to some extent in the muscle, which is unlike what is seen in Caucasian subjects at a similar age. There was no difference in ectopic fat storage between the NBW and LBW subjects. Measurements of insulin resistance (HOMA-IR) , did not have any relationship with hepatic, intramyocellular or extramyocellular fat content In factthe only independent predictor of intra-myocellular and extramyocellular fat content was with the total body fat percentage. Our study has shown a significant elevation in diastolic blood pressure, alterations in systolic pressure have been shown in LBW subjects in a number of cohorts, and occur in both gender groups.
MODY genetic testing to identify mutations in a comprehensive panel of ten MODY genes was carried out in 80 subjects of Asian-Indian origin with young onset diabetes A novel multiplex polymerase chain reaction (PCR) based target enrichment was established, followed by Next Generation Sequencing (NGS) on the Ion Torrent Personal Genome Machine (PGM). All the mutations and rare variants were confirmed by Sanger sequencing.We identified mutations in 11 (19%) of the 56 clinically diagnosed MODY subjects and seven of these mutations were novel.The identified mutations include p.H241Q, p.E59Q, c.-162G>A 5’ UTR in NEUROD1, p.V169I co-segregating with c.493-4G>A and c.493-20C>T, p.E271Kin HNF4A, p.A501S in HNF1A, p.E440Xin GCK, p.V177M in PDX1, p.L92F in HNF1B and p.R31L in PAX4 genes.. Interestingly two patients with NEUROD1 mutation were also positive for the p.E224K mutation in PDX1 gene. These patients with co-existing NEUROD1-PDX1 mutations showed a marked reduction in glucose induced insulin secretion. None of the 24 subjects who had not met the clinical criteria of MODY were positive for mutations. To the best of our knowledge, this is the first report of PDX1, HNF1B, NEUROD1 and PAX4 mutations from India. Multiplex PCR coupled with NGS provides a rapid, cost-effective and accurate method for comprehensive parallelized genetic testing of MODY. When compared to earlier reports, we have identified a higher frequency and a novel digenic mutation pattern involving NEUROD1 and PDX1 genes.
The work performed above clearly established next generation sequencing as he modality of choice for looking to the genetic profile of young onset diabetes, MODY, syndromic disorders and neonatal diabetes and at present CMC, Vellore as a single library preparation capable of handling 30 genes simultaneously in a cost effective manner.
In summary, there are a number of factors which are responsible for that shift in the phenotype of towards the left in India with regards to the leanness of body habitus as well as the age of these patients. More work is required to be done to identify these pathogenic factors at a cellular level to establish the reasons for this propensity.

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