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Genetic Studies of Type 2 Diabetes in South Asians: A Systematic Overview
Abstract
Diabetes Mellitus, which affects 366 million people worldwide, is a leading cause of mortality, morbidity, and loss of quality of life. South Asians, comprising 24% of the world's population, suffer a large burden of type 2 diabetes. With intriguing risk phenotypes, unique environmental triggers, and potential genetic predisposition, South Asians offer a valuable resource for investigating the pathophysiology of type 2 diabetes. Genomics has proven its potential to underpin some of the etiology of type 2 diabetes by identifying a number of susceptibility genes, but such data are scarce and unclear in South Asians. We present a systematic review of studies on the genetic basis of type 2 diabetes or its complications in South Asians published between 1987-2012, and discuss the findings and limitations of the available data. Of the 91 eligible studies meeting our inclusion criteria, a vast majority included Indian populations, followed by a few in those of Pakistani origin, while other South Asian countries were generally under-represented. Though a large number of studies focused on the replication of findings from genome-wide association studies (GWAS) in European populations, a few studies explored new genes and pathways along with GWAS in South Asians and suggested the potential to unravel population-specific susceptibility genes in this population. We find encouraging improvements in study designs, sample sizes and the numbers of genetic variants investigated over the last five years, which reflect the existing capacity and scope for large-scale genetic studies in South Asians.
... СДВТ -полиэтиологическое заболевание, которое имеет генетическую предрасположенность [4]. Более чем в 80 % случаев, если один из однояйцевых близне цов страдает сахарным диабетом, то у второго близне ца также выявляется сахарный диабет. ...
... Если у одного из родителей в анамнезе есть указа ние на СДВТ, вероятность его возникновения у потомка в течение жизни составляет 40 %. Тем не менее, досто верно утверждать о генетической предрасположен ности к СДВТ не представляется возможным, пока не обнаружен какой либо определенный ген, изменение или нарушение функционирования которого обуслав ливает эту предрасположенность [4]. Большое значение в реализации наследственной предрасположенности к СДВТ играют факторы окружающей среды, в первую очередь, особенности образа жизни пациентов [5]. ...
... • ожирение, особенно висцеральное [3]; • этническая принадлежность [4]; ...
Purpose: To determine the role of nuclear medicine techniques in the early detection of angiopathy in patients with diabetes and to estimate their accuracy in comparison with routine diagnostic methods for evaluation of target organ damage. Material and methods: A literature review, selected from the Russian and international bibliographic databases (RSCI, Medline, Google Scholar), dedicated to diagnostic technologies for identification of angiopathy in patients with diabetes mellitus. Results: 193 sources dedicated to the diagnosis of micro- and macrovascular damage were analyzed, 66 of which were included in this study, 54 of them international and 12 domestic ones responding to the purpose of the study. The analysis revealed that the radionuclide methods of investigation reflecting the functional state of the tissues were evaluated in a small number of publications on early diagnosis angiopathy caused by diabetes mellitus type 2. Most often, high blood glucose concentration damages kidney tissue and myocardium. It is shown that the methods of dynamic nephroscintigraphy and ECG- gated myocardial perfusion SPECT allow to evaluate the progression of micro- and macrovascular disease before the manifestation of paraclinical signs according to other diagnostic methods. Key determined parameter in dynamic nephroscintigraphy is glomerular filtration rate, which declines on the early stages of the disease. Myocardial perfusion SPECT imaging provides a possibility to assess frequency and severity of ischemic myocardial injury. Conclusions: The use of nuclear medicine techniques in the diagnosis of angiopathy in diabetes allows verification of early damage to target organs. The most effective diagnostic methods for this purpose are dynamic nephroscintigraphy and myocardial perfusion SPECT which sensitivity is substantially higher than conventional diagnostic methods.
... Genetic heterogeneity across populations and limited knowledge of gene-environment interactions hinder the identification of universally applicable markers and individualized prevention strategies [22]. While research has largely focused on common variants with modest effects, rare variants with potentially greater impact remain underexplored due to technical and financial constraints [10,23,24]. ...
... Addressing this gap may enhance our understanding of T2DM pathogenesis and support tailored interventions. Moreover, such research has global implications, contributing to the broader effort to map genetic diversity and advance precision medicine in diabetes care [24,30,31]. Population-specific differences in the association between CAPN10 polymorphisms and T2DM have been observed globally, with varying results reported in Hispanic, Asian, African, and European cohorts ( Table 6). ...
Introduction
Type 2 diabetes mellitus (T2DM) is a major public health challenge, with rising prevalence in low- and middle-income countries such as Pakistan. Genetic susceptibility plays a critical role in its pathogenesis. Calpain-10 (CAPN-10), a gene implicated in insulin secretion and glucose homeostasis, has been studied for its potential involvement in T2DM. This study aimed to evaluate the association of CAPN-10 polymorphisms—SNP44 (rs2975760) and SNP43 (rs3792267)—with T2DM in a Pakistani cohort.
Methods
This case-control study included 164 T2DM patients and 164 healthy controls (mean age ± SD: 57.2 ± 8.2 vs. 53.9 ± 6.3 years; age range: 41–82 years). The male-to-female ratio was 41.4–58.6% in cases and 37.2–62.8% in controls. Participants were enrolled using non-probability convenience sampling. Genomic DNA was extracted from whole blood, and genotyping of CAPN-10 SNPs (rs3792267 and rs2975760) was performed using PCR-RFLP. Genotype distributions were assessed for Hardy-Weinberg equilibrium. Associations with T2DM were evaluated using odds ratios (ORs) and 95% confidence intervals (CIs) via logistic regression. Chi-square tests were used for categorical comparisons, with p < 0.05 considered statistically significant. Analyses were conducted using SPSS version 26.
Results
For SNP44, no significant association with T2DM was observed under dominant, heterozygous, or recessive models after Bonferroni correction (adjusted p > 0.05). Similarly, SNP43 showed no statistically significant association with T2DM in either dominant or recessive models (adjusted p > 0.05), although the AA genotype appeared more frequently among T2DM cases. These findings suggest no significant role of CAPN-10 polymorphisms in T2DM susceptibility in this population.
Conclusion
CAPN-10 polymorphisms SNP44 and SNP43 showed no significant association with T2DM in this population, suggesting limited predictive value for disease susceptibility.
... While research has largely focused on common variants with modest effects, rare variants with potentially greater impact remain underexplored due to technical and nancial constraints. [10,23,24]. ...
... Addressing this gap may enhance our understanding of T2DM pathogenesis and support tailored interventions. Moreover, such research has global implications, contributing to the broader effort to map genetic diversity and advance precision medicine in diabetes care [24,30,31]. Population-speci c differences in the association between CAPN10 polymorphisms and T2DM have been observed globally, with varying results reported in Hispanic, Asian, African, and European cohorts (Table 6) Middle Eastern CAPN10 (varied) Limited/inconclusive [15] Study Limitations ...
Introduction: Type 2 diabetes mellitus (T2DM) is a major public health challenge, with rising prevalence in low-and middle-income countries such as Pakistan. Genetic susceptibility plays a critical role in its pathogenesis. Calpain-10 (CAPN-10), a gene implicated in insulin secretion and glucose homeostasis, has been studied for its potential involvement in T2DM. This study aimed to evaluate the association of CAPN-10 polymorphisms-SNP44 (rs2975760) and SNP43 (rs3792267)-with T2DM in a Pakistani cohort. Methods: This case-control study included 164 T2DM patients and 164 healthy controls (mean age ± SD: 57.2 ± 8.2 vs. 53.9 ± 6.3 years; age range: 41-82 years). The male-to-female ratio was 41.4% to 58.6% in cases and 37.2% to 62.8% in controls. Participants were enrolled using non-probability convenience sampling. Genomic DNA was extracted from whole blood, and genotyping of CAPN-10 SNPs (rs3792267 and rs2975760) was performed using PCR-RFLP. Genotype distributions were assessed for Hardy-Weinberg equilibrium. Associations with T2DM were evaluated using odds ratios (ORs) and 95% confidence intervals (CIs) via logistic regression. Chi-square tests were used for categorical comparisons, with p < 0.05 considered statistically significant. Analyses were conducted using SPSS version 26. Results: For SNP44, no significant association with T2DM was observed under dominant, heterozygous, or recessive models after Bonferroni correction (adjusted p > 0.05). Similarly, SNP43 showed no statistically significant association with T2DM in either dominant or recessive models (adjusted p > 0.05), although the AA genotype appeared more frequently among T2DM cases. These findings suggest no significant role of CAPN-10 polymorphisms in T2DM susceptibility in this population. Conclusion: CAPN-10 polymorphisms SNP44 and SNP43 showed no significant association with T2DM in this population, suggesting limited predictive value for disease susceptibility.
... Several factors are known to explain why diabetes is highly prevalent in Bangladeshi and other South Asian communities. These include, but are not limited to, biological components (genetic predisposition, increased visceral fat) [7][8][9], rapid urbanization [10], sedentary lifestyle [11,12], unhealthy dietary habits [13,14], and decreased health awareness [15,16]. ...
Background/Aim
Adequate knowledge, attitude, and self-care practice (KAP) are paramount in reducing diabetes complications. This study examined diabetes-related KAP in individuals who have been previously reported to be at a higher risk of blindness such as those on insulin treatment or with a longer (>6 years) duration of diabetes in Bangladesh.
Methods
Six hundred community-dwelling individuals (mean age = 52.7±11.6 years) who had been diagnosed with diabetes by their doctor were interviewed. A semi-structured questionnaire obtained self-reported information about diabetes-related KAP, duration, treatment of diabetes, and sociodemographic parameters including age, gender, and education level. Data were collected using a purposive sample technique and analyzed using Fischer’s exact test or independent samples t-tests.
Results
There were 271 males (45.2%) and 329 (54.8%) females. Of the total participants (mean diabetes duration = 6.6±6.2 years), 36.5% had diabetes for more than the median duration of 6 years, 80.7% were receiving insulin or insulin combined with tablets (insulin group) and the remaining 19.3% were on tablet only and/or diet control (non-insulin group). One-fifth (19.8%) of all the participants did not consider diabetes a serious disease, 31.3% were unaware that uncontrolled diabetes can cause blindness, 40.5% had never had their eyes tested for diabetic retinopathy and 41.5% stated that they would not attend diabetic retinopathy screening until their eyesight became worse. Among those in the insulin group, 42.1% reported being unaware that smoking may be harmful to diabetes compared to 30.2% of those in the non-insulin group (p= 0.02). Additionally, 64.7% of those in the insulin group were unaware that a diabetic retinal screening is different from a routine eye test for spectacles, compared to 44.8% in the non-insulin group (p< 0.001). Sixty-two percent of participants with diabetes duration of more than 6 years reported that diabetes management was a shared responsibility between the doctor and the patient compared to 48.3% with a shorter duration (p< 0.001). Those with a longer duration of diabetes (>6 years) also reported forgetting to take their medication more often than those with a shorter duration (p = 0.02). Twenty-one percent of participants with a duration of diabetes longer than six years had checked their eyes within the previous year compared to 63.5% of those with a shorter duration of diabetes (p< 0.001).
Conclusion
Individuals on insulin treatment demonstrated poorer knowledge and awareness of diabetes and diabetes eye screening. Those with a longer diabetes duration exhibited poorer self-care practices, particularly not taking the medication regularly, and neglecting diabetic retinal checkups. These issues need to be addressed in designing targeted educational interventions to prevent blindness from uncontrolled diabetes in the high-risk groups in Bangladesh.
... Genomewide association studies have identified several potential single nucleotide polymorphisms (SNP) that significantly contribute to the genetic basis of T2D [6]. Still, it is recognized that the strength of association of these SNPs with T2D can vary across world populations [7][8][9][10]. In that vein, a search for population-specific genetic determinants of T2D still continues. ...
Type 2 diabetes (T2D) is a complex metabolic derangement that has a strong genetic basis. There is substantial population-specificity in the association of genetic variants with T2D. The Indian urban Sindhi population is at a high risk of T2D. The genetic basis of T2D in this population is unknown. We interrogated 28 pooled whole blood genomes of 1402 participants from the Diabetes In Sindhi Families In Nagpur (DISFIN) study using Illumina’s Global Screening Array. From a total of 608,550 biallelic variants, 140 were significantly associated with T2D after adjusting for comorbidities, batch effects, pooling error, kinship status and pooling variation in a random effects multivariable logistic regression framework. Of the 102 well-characterized genes that these variants mapped onto, 70 genes have been previously reported to be associated with T2D to varying degrees with known functional relevance. Excluding open reading frames, intergenic non-coding elements and pseudogenes, our study identified 22 novel candidate genes in the Sindhi population studied. Our study thus points to the potential, interesting candidate genes associated with T2D in an ethnically endogamous population. These candidate genes need to be fully investigated in future studies.
... The Mediators of Atherosclerosis in South Asians Living in America study reports South Asians have a high prevalence of atherogenic dyslipidemia and increased visceral fat, which predisposes to atherosclerosis, coronary artery disease, and myocardial infarction [44,45]. In addition, data from genome-wide association studies in South Asians, suggest a potential genetic predisposition to type 2 diabetes mellitus with a higher incidence of insulin resistance [46,47]. Accurate risk assessment remains challenging in certain populations. ...
Purpose of Review
Research on sex and gender aspects cardiovascular disease has contributed to a reduction in cardiovascular mortality in women. However, cardiovascular disease remains the leading cause of death of women in the United States. Disparities in cardiovascular risk and outcomes among women overall persist and are amplified for women of certain ethnic and racial subgroups. We review the evidence of racial and ethnic differences in cardiovascular risk and care among women and describe a path forward to achieve equitable cardiovascular care for women of racial and ethnic minority groups.
Recent Findings
There is a disproportionate effect on cardiovascular outcomes in women and certain racial and ethnic groups in part due to disparities in triage, diagnosis, treatment, which lead to amplification of inequalities in women of minority racial and ethnic background. Data suggest gender and racial bias, underappreciation of nontraditional risk factors, underrepresentation of women in clinical trials and undertreatment of disease contributes to persistent differences in cardiovascular disease outcomes in women of color.
Summary
Understanding the myriad of factors that contribute to increased cardiovascular risk, and disparities in treatment and outcomes among women from racial/ethnic minority backgrounds is imperative to improving cardiovascular care for this patient population.
... Overall, the evolving fields of genetics and epigenetics are likely to continue providing important insights regarding the pathobiology of T2D and CVD risk in SA [109]. Whether these approaches will help identify modifiable risk factors that can be targeted for reducing the morbidity and mortality associated with T2D and CVD in this high-risk population remains to be seen. ...
Background
South Asians are at a significantly increased risk of type 2 diabetes (T2D) and cardiovascular disease (CVD), are diagnosed at relatively younger ages, and exhibit more severe disease phenotypes as compared with other ethnic groups. The pathophysiological mechanisms underlying T2D and CVD risk in South Asians are multifactorial and intricately related.
Method
Narrative review of the pathophysiology of excess risk of T2D and CVD in South Asians.
Result
T2D and CVD have shared risk factors that encompass biological factors [early life influences, impaired glucose metabolism, and adverse body composition] as well as behavioral and environmental risk factors (diet, sedentary behavior, tobacco use, and social determinants of health). Genetics and epigenetics also play a role in explaining the increased risk of T2D and CVD among South Asians. Additionally, South Asians harbor several lipid abnormalities including high concentration of small-dense low-density lipoprotein (LDL) particles, elevated triglycerides, low highdensity lipoprotein (HDL)-cholesterol levels, dysfunctional HDL particles, and elevated lipoprotein(a) that predispose them to CVD.
Conclusion
In this comprehensive review, we have discussed risk factors that provide insights into the pathophysiology of excess risk of T2D and CVD in South Asians.
... Ma et al. has termed the sub-continental population to have "starvation genes" which cause their adipocytes to accumulate extra fat making a mildly obese person to be vulnerable to cardiovascular diseases (CVD) [8]. Similarly, studies comparing sub-continental population from India, Pakistan and Bangladesh housing more than 24% of people from the world indicate an extremely high population of diabetics with many yet to be diagnosed [9]. While a clear trend in this population is visible in terms of decreasing height and swollen tummies bringing with it all possible metabolic curses including diabetes mellitus, there remains no denial for this diabetic problem swiftly taking over the hospitals and sucking the poor country's economy in all possible ways [10]. ...
As we write about T2DM we had in our hindsight the growing nature of this metabolic plague with current prevalence racing to 451 million sufferers worldwide with next milestone peaking around 693 million by the year 2045. There could be some discrepancies in exactness of the statistical calculations from Zhang et al., still the suggested yearly spending of 376 billion USD in 2010 to 490 billion USD by 2030 among age 20-79 years group seem to an optimal depiction of this T2DM disease burden. These statistical calculation will never be able to calculate time lost from non-productivity, indirect spending to modify lifestyles and long-term financial loss form its complications. The myriad of complications tailed to T2DM are not just micro vascular diseases like neuropathy, retinopathy, nephropathy, but the real breakpoint for mankind remains coronary artery disease and stroke now surfacing as the world wide champions on mortality charts. Considering the T2DM direct and indirect impacts on health economy along with effects on quality of life with related effects in the shape of atherosclerotic cardiovascular disease (ASCVD), the pandemic now emerging as a Tsunami which can sweep the next generations from this modern-day metabolic disaster.
... The term "developing countries" has been used synonymously with "lowand middle-income" countries. Although we shall discuss several important issues, we would not discuss diabetes management in detail, and some other topics (eg, genetics [14][15][16][17][18], which have been covered by others. It is important to note that although examples and statements refer to characteristics derived from data from a particular country, this information cannot always be generalized to all developing countries because they may differ in culture, diet, terrain, level of urbanization and health care systems. ...
There has been a rapid escalation of type 2 diabetes (T2D) in developing countries, with varied prevalence according to rural vs urban habitat and degree of urbanization. Some ethnic groups (eg, South Asians, other Asians, and Africans), develop diabetes a decade earlier and at a lower body mass index than Whites, have prominent abdominal obesity, and accelerated the conversion from prediabetes to diabetes. The burden of complications, both macro- and microvascular, is substantial, but also varies according to populations. The syndemics of diabetes with HIV or tuberculosis are prevalent in many developing countries and predispose to each other. Screening for diabetes in large populations living in diverse habitats may not be cost-effective, but targeted high-risk screening may have a place. The cost of diagnostic tests and scarcity of health manpower pose substantial hurdles in the diagnosis and monitoring of patients. Efforts for prevention remain rudimentary in most developing countries. The quality of care is largely poor; hence, a substantial number of patients do not achieve treatment goals. This is further amplified by a delay in seeking treatment, "fatalistic attitudes", high cost and non-availability of drugs and insulins. To counter these numerous challenges, a renewed political commitment and mandate for health promotion and disease prevention are urgently needed. Several low-cost innovative approaches have been trialed with encouraging outcomes, including training and deployment of non-medical allied health professionals and the use of mobile phones and telemedicine to deliver simple health messages for the prevention and management of T2D.
© 2019 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.
... A genetic basis has also been postulated for the higher prevalence of T2DM among South Asians when compared to Europeans. However, a recent systematic review that compared the risk alleles of SNPs that predispose to T2DM between South Asians and Europeans revealed no substantial difference to indicate that South Asians possess a greater genetic risk [15]. ...
India is estimated to have the second highest number of cases of diabetes mellitus in the world after China. Recent epidemiological evidence indicates that people of lower socioeconomic group in India are equally or even more susceptible to diabetes. Family history is a very strong risk factor for developing type 2 diabetes mellitus; the lifetime risk is nearly 40% for individuals who have one parent affected and approaches 70% if both parents are affected. Genome-wide association studies identified more than 50 genetic variants associated with type 2 diabetes mellitus, but these risk alleles identified to date could only explain less than 10% of the observed heritability. Acquisition of the same unhealthy lifestyle from the parents could be the major reason for the observed heritability that genetics could not explain. The global age-standardised prevalence of diabetes has nearly doubled since 1980, rising from 4.7 to 8.5% in the adult population. If genes are responsible for this doubling of prevalence, the responsible gene pool should also amplify to the same extent in the population. The Hardy–Weinberg law states that allele and genotype frequencies in a population will remain constant from generation to generation in the absence of other evolutionary influences, making genetics as the etiology for this ongoing epidemic less likely. Indians have a tendency to become metabolically obese and develop type 2 diabetes mellitus with normal weight; thus, body mass index cut-off for overweight and obesity is kept lower in Indians. Primary and secondary prevention strategies should be more emphasised at the community level. Physical activity recommended is at least 150 min/week. All adults should decrease the amount of time spent in daily sedentary behaviour. Dietary modifications by reducing carbohydrate intake and increasing the intake of proteins, green leafy vegetables, fruits, and nuts should be promoted.
... The lack of sufficient GWAS in T2DM is troublesome, particularly in the context of the epidemic of obesity and diabetes in Arab populations. A recent systematic overview of genetic studies of T2DM in South Asians reported that the only 2 GWAS performed in South Asian diabetics were able to identify susceptibility genes that were not detected in European GWAS (103). Other studies in Caucasian Europeans reported significant variations in serum adiponectin levels after 4 weeks of high monounsaturated fatty acids diets; variations were attributed to genetic polymorphisms at the ADI-POQ gene locus (104). ...
... 16,27,28 Although the underlying cause of this excess risk in these population groups is still not completely understood, several possibilities have been suggested, including innate biological susceptibilities, lifestyle behaviors, and environmental triggers. [29][30][31] It is likewise well established that baseline glucose level is significantly associated with an increased risk of progression to diabetes 13,32 ; however, the present study results demonstrated that the risk of progression did not vary linearly with the baseline glucose level. Instead the risk appeared to be lower in those with baseline glucose of 100-110 mg/dL, but increased substantially among those with baseline glucose of 111 mg/dL or higher. ...
Thirty-seven percent of US adults have prediabetes. Various interventions can delay diabetes progression; however, the optimum target group for risk reduction is uncertain. This study estimated rate of progression to diabetes at 1 and 5 years among a cohort of patients from 3 primary care clinics and modeled the potential magnitude in diabetes incidence risk reduction of an intervention program among specific subgroups. Records of 106,821 empaneled patients in 2005 were reviewed. Generalized population attributable risk (PAR) statistics were calculated to estimate the impact of reducing fasting blood glucose on diabetes progression. Multiple intervention effects (varying levels of glucose reduction along with multiple adherence rates) were examined for those with baseline glucose from 110 to 119 mg/dL and ≥120 mg/dL. Ten percent of patients (n = 10,796) met criteria for prediabetes. The 1- and 5-year diabetes incidence rate was 38.6 and 40.24 per 1000 person-years, respectively. Age and obesity were independent predictors of increased progression rate. The generalized PAR for a 10-point reduction in the 110-119 mg/dL subgroup with 25% adherence was 7.6%. The generalized PAR for similar percent reduction and adherence level in patients with baseline glucose of ≥120 mg/dL was only 3.0%. Rate of progression to diabetes increased over time and with associated independent risk factors. Greater risk reduction in diabetes progression within the target population can be achieved when the intervention is successful in those with baseline glucose of 110-119 mg/dL. Modeling an optimum target group for a diabetes prevention intervention offers a novel and useful guide to planning and allocating resources in population health management.
... Therefore, just like trans-ethnic fine mapping, resequencing efforts are also needed to uncover novel signal and functional coding alleles in transcripts close to loci known to be causally related with T2D in other populations [36,37]. In line with findings of the MEDIA Consortium [35] , metaanalyses of GWAS have consistently demonstrated that some genetic diabetes risk signals were transferrable across populations, while others were population specific [6,38]. Our review found only two studies that had examined the human genome using GWAS in the same African population, but which were underpowered to possibly uncover those diabetes risk loci that are specific to populations within Africa [15,16]. ...
... The lack of sufficient GWAS in T2DM is troublesome, particularly in the context of the epidemic of obesity and diabetes in Arab populations. A recent systematic overview of genetic studies of T2DM in South Asians reported that the only 2 GWAS performed in South Asian diabetics were able to identify susceptibility genes that were not detected in European GWAS (103). Other studies in Caucasian Europeans reported significant variations in serum adiponectin levels after 4 weeks of high monounsaturated fatty acids diets; variations were attributed to genetic polymorphisms at the ADI-POQ gene locus (104). ...
The Arab world is experiencing an epidemic of obesity and type 2 diabetes mellitus. This review summarizes the major pathological factors linking obesity to diabetes, focussing on current epidemiological data related to obese diabetic patients in the Arab world, the etiology of the disease and the genetic determinants of diabetes and obesity. There are alarming data related to the rising prevalence of obesity and type 2 diabetes mellitus in children of Arab ethnicity. Replication studies identify several genetic variants in Arabs with obesitylinked diabetes. For example, variants of the ADIPOQ gene (the rs266729 single-nucleotide polymorphism) are associated with obesity and diabetes in various Arab countries. Gaps exist in our information about diabetes and obesity in Arab populations in relation to ethnic-specific cut-off points for diagnosis and treatment of diabetes. Further genome-wide association studies in obese and diabetic Arab populations could add to our understanding of the pathophysiology, prevention and reversal of this disease.
This review integrates new developments in psychology with updated physiological insight on the complex relationships among chronic psychological stress (arising from weight stigmatization and body shaming), food composition, physical activity and metabolic health for the example of diabetes. We address how visual measures of health, such as body mass index (BMI) and waist-to-hip ratio, do not adequately capture metabolic health and can instead contribute to weight stigmatization, chronic stress, and system-wide impairment of metabolic health. We also emphasize the importance of food composition over calorie counting. We summarize how chronic stress interacts with nutritional deficiencies and physical inactivity to disrupt the stress response, immune response, gut microbiome, and function of fat depots. We specifically address how interactions among lifestyle factors and the gut microbiome regulate whether fat stored around the waist has a negative or positive effect on metabolic health. We aim to provide a resource and updated framework for diabetes prevention and health promotion by (i) highlighting metabolic imbalances triggered by lifestyle changes during the transition to industrialized society and (ii) detailing the potential to support metabolic health through access to modest, but comprehensive lifestyle adjustments.
Background
A cluster randomised trial of mHealth and participatory learning and action (PLA) community mobilisation interventions showed that PLA significantly reduced the prevalence of intermediate hyperglycaemia and type 2 diabetes mellitus (T2DM) and the incidence of T2DM among adults in rural Bangladesh; mHealth improved knowledge but showed no effect on glycaemic outcomes. We explore the equity of intervention reach and impact.
Methods
Intervention reach and primary outcomes of intermediate hyperglycaemia and T2DM were assessed through interview surveys and blood fasting glucose and 2-hour oral glucose tolerance tests among population-based samples of adults aged ≥30 years. Age-stratified, gender-stratified and wealth-stratified intervention effects were estimated using random effects logistic regression.
Results
PLA participants were similar to non-participants, though female participants were younger and more likely to be married than female non-participants. Differences including age, education, wealth and marital status were observed between individuals exposed and those not exposed to the mHealth intervention.
PLA reduced the prevalence of T2DM and intermediate hyperglycaemia in all age, gender and wealth strata. Reductions in 2-year incidence of T2DM of at least 51% (0.49, 95% CI 0.26 to 0.92) were observed in all strata except among the oldest and least poor groups. mHealth impact on glycaemic outcomes was observed only among the youngest group, where a 47% reduction in the 2-year incidence of T2DM was observed (0.53, 95% CI 0.28 to 1.00).
Conclusion
Large impacts of PLA across all strata indicate a highly effective and equitable intervention. mHealth may be more suitable for targeting higher risk, younger populations.
Trial registration number
ISRCTN41083256 .
Precision diabetes is a concept of customizing delivery of health practices based on variability of diabetes. The authors reviewed recent research on type 2 diabetes heterogeneity and -omic biomarkers, including genomic, epigenomic, and metabolomic markers associated with type 2 diabetes. The emerging multiomics approach integrates complementary and interconnected molecular layers to provide systems level understanding of disease mechanisms and subtypes. Although the multiomic approach is not currently ready for routine clinical applications, future studies in the context of precision diabetes, particular in populations from diverse ethnic and demographic groups, may lead to improved diagnosis, treatment, and management of diabetes and diabetic complications.
Clinical Case
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A 54-year-old immigrant South Asian woman presents with a strong family history of diabetes mellitus type II (DM) and premature coronary artery disease (CAD). She is a vegetarian and her diet consists of lentils, naan bread, rice, curries and stews, and occasional “fast food” when out of the home. She is a nonsmoker, body mass index (BMI) 27, abdominal circumference of 35 in., blood pressure 125/85, and heart rate 90. She is perimenopausal and her cholesterol panel reveals: high-density lipoprotein (HDL) 32, triglyceride (TG) 160, and low-density lipoprotein (LDL) 108. Her hemoglobin A1c (HbA1c) is 7.5 on oral medication. She does not exercise routinely. Recently, with walking uphill and stairs, she experiences exertional back pain, neck “tightness,” leg cramps, dyspnea, and anxiety. Baseline electrocardiogram (ECG): nonspecific ST-T wave abnormality. An echocardiogram (echo) revealed normal left ventricular (LV) function with ejection fraction (EF) 60% with mildly reduced global longitudinal strain of − 15%. She subsequently underwent exercise stress myocardial perfusion where she completed 5 min on the Bruce protocol. She experienced neck and back pain with peak exercise. There were 0.5 mm horizontal ST segment depressions in leads II, III, aVF, and V4–V6 starting at 2:00 min following exercise at heart rate (HR) 107 bpm and persisted 3:00 min in recovery. Her perfusion imaging revealed severe reversible defects in the mid-distal inferolateral wall with transient ischemic dilatation (Figure 1). Coronary angiography revealed severe three-vessel disease. [Proximal left anterior descending (LAD) 80%, mid-LAD 80%, OM1 99%, OM2 diffuse 99%; and small right coronary artery (RCA) 90%.] Despite small caliber of vessels with suboptimal bypass targets, she underwent coronary artery bypass grafting (CABG) × 5. On optimal medication, 1 week later two obtuse marginal (OM) grafts closed and she sustained a non-ST-elevation myocardial infarction.
What were this woman’s cardiovascular risk factors and what is her pretest probability for developing coronary atherosclerosis?
Abstract
There has been an appropriate focus, since the turn of the 21st century, on sex- and gender-specific cardiovascular disease (CVD) as evidence suggests that there are substantial differences in the risk factor profile, social and environmental factors, clinical presentation, diagnosis, and treatment of CVD in women compared to men. As a result of increased awareness, detection, and treatment of CVD in women, there has been significant reduction (greater than 30%) in cardiovascular mortality in the United States [1], [2], [3]. Presently, more men than women die of CVD. Nevertheless, continued efforts are required as CVD remains the leading cause of cardiovascular morbidity and mortality of women in the Western world and in women younger than 55 there has been a rise in cardiovascular mortality [4]. The 2010 landmark Institute of Medicine (IOM) report, “Women’s Health Research: Progress, Pitfalls, and Promise,” highlighted that although major progress had been made in reducing cardiovascular mortality in women, there were disparities in disease burden among subgroups of women, particularly those women who are socially disadvantaged because of race, ethnicity, income level, and educational attainment [5]. The IOM recommended targeted research on these subpopulations with the highest risk and burden of disease. Causes of disparities are multifactorial and are related to differences in risk factor prevalence, access to care, use of evidence-based guidelines, and social and environmental factors. In this chapter, we review a few of the contributing factors to the disparities in CVD in women with a focus on the high-risk subgroups of women from black, Latino, and South Asian descent.
Background
South Asians are at a significantly increased risk of atherosclerotic cardiovascular disease (ASCVD). For a major portion of the South Asian population, the cardiovascular disease events occur at a relatively younger age, are associated with worse outcomes and have potentially more severe socioeconomic implications compared to their western counterparts.
Method
The term "South Asian" typically constitutes individuals from India, Pakistan, Nepal, Bhutan, Bangladesh, Sri Lanka, and Maldives and expatriates as well as their families from these countries. Based on this, South Asian form approximately 25% of the world’s population with a high ASCVD burden this group. In this review, we discuss the pathophysiological factors underlying ASCVD in South Asians, the dyslipidemia types and management as well as discuss approaches to improve the overall ASCVD prevention efforts in this large subset population of the world. Although the pathophysiological mechanisms underlying the excess risk of cardiovascular disease in South Asians are multifactorial, dyslipidemia is a primary risk factor for the incidence and prevalence of this disease. The traditional “South Asian” dyslipidemia pattern include levels of low-density lipoprotein cholesterol (LDL-C) in the normal range with high concentration of LDL particles, elevated triglycerides, low levels of high-density lipoprotein cholesterol (HDL-C) with dysfunctional HDL particles, and high levels of lipoprotein(a).
Conclusions
While combined efforts to study the expatriate South Asians in western countries have been able to identify South Asian specific dyslipidemias, causal associations and optimal management remains relatively less explored. Larger scale studies are needed to better quantify the relationship of each lipid parameter with ASCVD risk among South Asians as well as optimal lipid targets and management strategies to reduce morbidity and mortality in this high-risk group.
The intersection of tuberculosis (TB) with non-communicable diseases (NCDs), including diabetes mellitus (DM), chronic lung disease (CLD), and cardiovascular disease (CVD), has emerged as a critical clinical and public health challenge. Rapidly expanding NCD epidemics threaten TB control in low- and middle-income countries, where the prevention and treatment of TB disease remain a great burden. However, to date, the notion that TB may adversely impact NCD risk and severity has not been well explored. This review summarizes biomedical hypotheses, findings from animal models, and emerging epidemiologic data related to the progression of DM, CLD and CVD during and after active TB disease. We conclude that there is sufficient empirical evidence to justify a greater research emphasis on the syndemic interaction between TB and NCD.
The purpose of this chapter is to provide a brief overview of recognized models of health (Health Belief Model, Theory of Planned Behavior, Health Locus of Control, Transtheoretical Model of Health Behavior Change) and psychological intervention originating from South Asian culture (mindfulness meditation, yoga, transcendental meditation, prayer) with the exception of cognitive-behavioral therapy. Given the increasing population of South Asian Americans and cultural differences in their health beliefs and behavior, it becomes imperative to discuss the suitability of implementing Western-influenced models and intervention among ethnic populations. Indeed, research emphasizes the importance of cultural sensitivity when assessing and treating either physical and/or mental health issues among South Asian American patients. Overall, through increasing awareness of the existing models of health and their weaknesses in application to South Asian Americans, identifying biopsychosocial factors unique to this population’s culture, and examining the existing forms of intervention and therapy indigenous to South Asians, researchers and practitioners can begin to create culturally adaptive and individualized treatments and models targeted towards the improvement of South Asian American health. This chapter aims to support the contention that the biopsychosocial approach to health may be especially useful among ethnic populations and improving the trajectory of health (studies, treatment, etc.). Research findings and descriptions regarding the mentioned models of health and intervention are discussed.
In the last decades, neuroscientific research has supported the fact that addictions are diseases of the brain such as epilepsy or Parkinson’s disease. The punitive approach to manage addictions has not yielded satisfactory results, therefore the basic and clinical research provides growing evidence that addiction could be better considered and treated as an acquired brain disease which constitute the brain disease model of addictions. With the development of this model, significant progress has been achieved in the implementation of prevention and more effective treatment strategies and also better informed public health policies. However, the concept of addiction as a brain disease is still being questioned. This article presents arguments to consider substance use disorder as a disease caused by alterations in the structure and functioning of specific areas of the brain, as well as to visualize the clinical implications and the public policies of this disease model.
On a worldwide scale, the total number of migrants exceeds 200 million and is not expected to reduce, fuelled by the economic crisis, terrorism and wars, generating increasing clinical and administrative problems to National Health Systems. Chronic non-communicable diseases (NCD), and specifically diabetes, are on the front-line, due to the high number of cases at risk, duration and cost of diseases, and availability of effective measures of prevention and treatment. We reviewed the documents of International Agencies on migration and performed a PubMed search of existing literature, focusing on the differences in the prevalence of diabetes between migrants and native people, the prevalence of NCD in migrants vs rates in the countries of origin, diabetes convergence, risk of diabetes progression and standard of care in migrants. Even in universalistic healthcare systems, differences in socioeconomic status and barriers generated by the present culture of biomedicine make high-risk ethnic minorities under-treated and not protected against inequalities. Underutilization of drugs and primary care services in specific ethnic groups are far from being money-saving, and might produce higher hospitalization rates due to disease progression and complications. Efforts should be made to favor screening and treatment programs, to adapt education programs to specific cultures, and to develop community partnerships.
Over the last decade, we have witnessed major advances in the understanding of the molecular basis of neonatal and infancy-onset diabetes. It is now widely accepted that diabetes presenting before 6 months of age is unlikely to be autoimmune type 1 diabetes. The vast majority of such patients will have a monogenic disorder responsible for the disease and, in some of them, also for a number of other associated extrapancreatic clinical features. Reaching a molecular diagnosis will have immediate clinical consequences for about half of affected patients, as identification of a mutation in either of the two genes encoding the ATP-sensitive potassium channel allows switching from insulin injections to oral sulphonylureas. It also facilitates genetic counselling within the affected families and predicts clinical prognosis. Importantly, monogenic diabetes seems not to be limited to the first 6 months but extends to some extent into the second half of the first year of life, when type 1 diabetes is the more common cause of diabetes. From a scientific perspective, the identification of novel genetic aetiologies has provided important new knowledge regarding the development and function of the human pancreas.
Diabetes is highly prevalent in India and the proportion of younger patients developing diabetes is on the increase. Apart from the more universally known type 1 diabetes and obesity related type 2 diabetes, monogenic forms of diabetes are also suspected to be prevalent in many young diabetic patients. The identification of the genetic basis of the disease not only guides in therapeutic decision making, but also aids in genetic counselling and prognostication. Genetic testing may establish the occurrence and frequency of early diabetes in our population. This review attempts to explore the utilities and horizons of molecular genetics in the field of maturity onset diabetes of the young (MODY), which include the commoner forms of monogenic diabetes.
Type 2 diabetes mellitus (T2DM) is one of the leading causes of morbidity and mortality. While all ethnic groups are affected, the prevalence of T2DM in South Asians, both in their home countries and abroad, is extremely high and is continuing to rise rapidly. Innate biological susceptibilities coupled with rapid changes in physical activity, diet, and other lifestyle behaviors are contributing factors propelling the increased burden of disease in this population. The large scope of this problem calls for investigations into the cause of increased susceptibility and preventative efforts at both the individual and population level that are aggressive, culturally sensitive, and start early. In this review, we outline the biological and environmental factors that place South Asians at elevated risk for T2DM, compared with Caucasian and other ethnic groups.
Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes-associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10(-9)). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10(-12)) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D.
The prevalent Ala222Val single nucleotide polymorphism of the MTHFR gene has been shown to be associated with type II diabetes. The objective of the present study was to find out whether there is genetic predisposition for development of acute myocardial infarction in type II diabetes mellitus among South Indian Tamil population. PCR-based restriction enzyme analysis was performed in DNA isolated from 120 acute myocardial infarction patients with diabetes mellitus and 100 non diabetic healthy individuals with no documented cardiovascular diseases. The results indicate that the MTHFR 677TT genotype is absent in both case and controls. The MTHFR 677CT genotype was observed among 32 (26.7 %) cases and 20 (20%) controls and the MTHFR 677CC genotype among 88 (73.3%) cases and 80 (80%) controls. The allelic frequencies were in accordance to Hardy Weinberg equilibrium. There was no statistical difference in genotype distribution between cases and controls. In conclusion, we suggest that the analysis of MTHFR genotyping for C677T polymorphism alone need not be considered to find out whether there is genetic predisposition for development of acute myocardial infarction in type II diabetes mellitus among South Indian Tamil population.
To determine any association between serum paraoxonase-1 (PON1) activity, protein and coding region genetic polymorphisms and coronary artery calcification (CACS) and to determine factors which modulate serum PON1 in type 2 diabetes (T2DM).
589 patients (419 Caucasian, 120 South Asian, 50 other) from the PREDICT Study were investigated. All patients were asymptomatic for coronary disease and had established T2DM. CACS, lipids, lipoproteins, inflammatory markers, insulin resistance and PON1 activity, concentration and Q192R and L55M genotypes were measured. Independent associations were: 1) PON1 activity negatively with insulin resistance, triglycerides and PON1-55 genotype and positively with PON1-192 genotype; 2) PON1 concentration negatively with Caucasian ethnicity, duration of diabetes and statin use and positively with plasma creatinine and PON1-192 genotype. There was no association between CACS and any of the PON1 activity, concentration or genotype and this finding was not different in the various ethnic groups within the PREDICT study.
PON1 is modulated by a number of factors, some of which are reported here for the first time, including ethnicity and insulin resistance in subjects with T2DM. No association between CACS and PON1 was found.
The INSR gene, which encodes the insulin receptor, is a candidate gene for type 2 diabetes (T2D). The objective of the present study was to sequence some of the crucial exons in the INSR gene such as exon 2, which encodes the insulin-binding domain of the INSR protein, and exons 17-21, which encode the protein tyrosine kinase domain for mutations/polymorphisms, and to study their association with T2D in the South Indian population.
The INSR gene was sequenced in 25 normal glucose-tolerant (NGT) and 25 T2D subjects, and the variant found was genotyped by polymerase chain reaction-restriction fragment length polymorphism in 1,016 NGT and 1,010 T2D subjects, randomly selected from the Chennai Urban Rural Epidemiology Study.
Only one previously reported polymorphism, His1085His [rs1799817, (C→T)], in exon 17 was detected by sequencing. The frequency of the "T" allele of the His1085His polymorphism was significantly lower in the T2D subjects (31%) compared with the NGT subjects (35%) and showed significant protection against diabetes (odds ratio 0.85, 95% confidence interval 0.75-0.97, P=0.019). Regression analysis according to a recessive model taking the CC+CT genotype as the reference showed that the TT genotype was protective against diabetes (odds ratio 0.71, 95% confidence interval 0.50-0.99, P=0.048). Adjusting this P value by the number of competing models (three) using Bonferroni's correction, we found that the association finding did not remain significant.
The "T" allele of the His1085His polymorphism in the INSR gene shows significant protection against diabetes. This study gains importance because there are no data available to date on the role of INSR variants in T2D in the Indian population.
Aims/hypothesis:
Evaluation of the association of 31 common single nucleotide polymorphisms (SNPs) with fasting glucose, fasting insulin, HOMA-beta cell function (HOMA-β), HOMA-insulin resistance (HOMA-IR) and type 2 diabetes in the Indian population.
Methods:
We genotyped 3,089 sib pairs recruited in the Indian Migration Study from four cities in India (Lucknow, Nagpur, Hyderabad and Bangalore) for 31 SNPs in 24 genes previously associated with type 2 diabetes in European populations. We conducted within-sib-pair analysis for type 2 diabetes and its related quantitative traits.
Results:
The risk-allele frequencies of all the SNPs were comparable with those reported in western populations. We demonstrated significant associations of CXCR4 (rs932206), CDKAL1 (rs7756992) and TCF7L2 (rs7903146, rs12255372) with fasting glucose, with β values of 0.007 (p = 0.05), 0.01 (p = 0.01), 0.007 (p = 0.05), 0.01 (p = 0.003) and 0.08 (p = 0.01), respectively. Variants in NOTCH2 (rs10923931), TCF-2 (also known as HNF1B) (rs757210), ADAM30 (rs2641348) and CDKN2A/B (rs10811661) significantly predicted fasting insulin, with β values of -0.06 (p = 0.04), 0.05 (p = 0.05), -0.08 (p = 0.01) and -0.08 (p = 0.02), respectively. For HOMA-IR, we detected associations with TCF-2, ADAM30 and CDKN2A/B, with β values of 0.05 (p = 0.04), -0.07 (p = 0.03) and -0.08 (p = 0.02), respectively. We also found significant associations of ADAM30 (β = -0.05; p = 0.01) and CDKN2A/B (β = -0.05; p = 0.03) with HOMA-β. THADA variant (rs7578597) was associated with type 2 diabetes (OR 1.5; 95% CI 1.04, 2.22; p = 0.03).
Conclusions/interpretation:
We validated the association of seven established loci with intermediate traits related to type 2 diabetes in an Indian population using a design resistant to population stratification.
To examine the effect of genetic variation in KCNJ11 on the risk of Type 2 diabetes mellitus in Trinidadians.
The coding and bordering intron-exon regions of the KCNJ11 gene were sequenced in 168 diabetic and 61 non-diabetic subjects who historically were thought to be of South Asian Indian ancestry as well as 66 diabetic and 59 non-diabetic subjects of African ancestry. Allele and haplotype frequency differences were calculated between cases and controls and linkage equilibrium was assessed across the KCNJ11 region.
We identified novel missense mutations in both subject groups including A94P and R369C in a diabetic Indo-Trinidadian subject, S113G in a non-diabetic Indo-Trinidadian subject, and S118L in a diabetic Afro-Trinidadian subject. It is unknown if these mutations are pathogenic as other family members were not available for study. Additionally, the common variant E23K was associated with Type 2 diabetes in the Indo-Trinidadian group (OR = 1.797 [1.148-2.814], p = 0.0098).
Rare variants in KCNJ11 are segregating in the Indo- and Afro-Trinidadian populations and further studies are needed to determine their contribution, if any, to the overall prevalence of diabetes in these groups. Common variants such as E23K may increase the risk in the Indo-Trinidadian population.
Many disease-susceptible SNPs exhibit significant disparity in ancestral and derived allele frequencies across worldwide populations. While previous studies have examined population differentiation of alleles at specific SNPs, global ethnic patterns of ensembles of disease risk alleles across human diseases are unexamined. To examine these patterns, we manually curated ethnic disease association data from 5,065 papers on human genetic studies representing 1,495 diseases, recording the precise risk alleles and their measured population frequencies and estimated effect sizes. We systematically compared the population frequencies of cross-ethnic risk alleles for each disease across 1,397 individuals from 11 HapMap populations, 1,064 individuals from 53 HGDP populations, and 49 individuals with whole-genome sequences from 10 populations. Type 2 diabetes (T2D) demonstrated extreme directional differentiation of risk allele frequencies across human populations, compared with null distributions of European-frequency matched control genomic alleles and risk alleles for other diseases. Most T2D risk alleles share a consistent pattern of decreasing frequencies along human migration into East Asia. Furthermore, we show that these patterns contribute to disparities in predicted genetic risk across 1,397 HapMap individuals, T2D genetic risk being consistently higher for individuals in the African populations and lower in the Asian populations, irrespective of the ethnicity considered in the initial discovery of risk alleles. We observed a similar pattern in the distribution of T2D Genetic Risk Scores, which are associated with an increased risk of developing diabetes in the Diabetes Prevention Program cohort, for the same individuals. This disparity may be attributable to the promotion of energy storage and usage appropriate to environments and inconsistent energy intake. Our results indicate that the differential frequencies of T2D risk alleles may contribute to the observed disparity in T2D incidence rates across ethnic populations.
IntroductionType 2 diabetes mellitus (T2DM) affects huge populations in India and abroad. Genetic polymorphisms (SNPs) in scavenger receptors such as CD36 have been implicated in the pathogenesis of diabetic atherosclerosis and cardiovascular diseases. Since CD36 gene expression contributes to T2DM, we proposed to study the association of two of its polymorphisms.MethodsA population of 400 subjects from North India was analyzed according to clinical parameters. Out of them 150 controls and 250 T2DM patients were genotyped for two SNPs namely rs1761667 (G > A) and rs1527483 (C > T) in the CD36 gene using polymerase chain reaction and restriction fragment length polymorphism (PCR–RFLP) followed by statistical analysis.Results and discussionNo association of rs1527483 (C > T) SNP was observed in T2DM patients. The GA genotype was prevalent in 76.0% diabetic population and a highly significant genotypic association of rs1761667 (G > A) SNP in CD36 gene was observed in them (P = <0.001; OR 3.173; CI 1.098–9.174). Sample characteristics showed a highly significant association with lipid profile (P = <0.001). The ‘GA’ genotype in combination with CC genotype showed a significant association with TC (P = 0.020), LDL (P = 0.005) and VLDL (P = 0.029). In addition, the haplotype analysis CC/GA (−/+) and CT/GA (−/+) showed a strong association with TC and LDL (P < 0.05). The presence of −31118 A∗ allele in haplotypes showed strong association with T2DM (P = <0.005).ConclusionOut of the two CD36 gene polymorphisms tested, rs1761667 SNP is significantly associated with T2DM with the GA heterozygous genotype showing highest frequency among the T2DM patients.
Though multiple studies link chromosomal regions 1q21-q23 and 20q13 with type 2 diabetes, fine mapping of these regions is yet to confirm gene(s) explaining the linkages. These candidate regions remain unexplored in Indians, which is a high-risk population for type 2 diabetes. Hypothesizing regulatory regions to have a more important role in complex disorders, we examined association of 207 common variants in proximal promoter and untranslated regions of genes on 1q21-23 and 20q13 with type 2 diabetes in 2115 North Indians. Further, top signals were replicated in an independent group of 2085 North Indians. Variants-rs11265455-SLAMF1 (odds ratios (OR)=1.32, P=1.1 × 10(-3)), rs1062827-F11R (OR=1.36, P=1.7 × 10(-3)) and rs12565932-F11R (OR=1.35, P=1.8 × 10(-3)) were top signals for association with type 2 diabetes whereas rs1333062-ITLN1 (OR=1.28, P=3.4 × 10(-3)) showed strongest association in body mass index-stratified analysis. Replication of these four variants confirmed associations of rs11265455-SLAMF1 (OR=1.27, P=9.1 × 10(-3)) and rs1333062-ITLN1 (OR=1.25, P=1.1 × 10(-3)) with type 2 diabetes. Meta-analysis further corroborated the association of rs11265455-SLAMF1 (OR random effect=1.29, P random effect=3.9 × 10(-5)) and rs1333062-ITLN1 (OR random effect=1.19, P random effect=1.8 × 10(-4)). In conclusion, the study demonstrates that variants of SLAMF1 and ITLN1, both implicated in inflammation, are associated with type 2 diabetes in Indians.
In this first report on the association of an IL-10 promoter polymorphism with type 2 diabetes mellitus in a North Indian population, the -592A/C SNP (rs1800872) was genotyped by PCR-RFLP and the IL-10 level measured using ELISA. Although no significant difference was observed in the genotypic frequencies (P = 0.657), diabetes patients carried a significantly higher number of A alleles at the -592 position, 25.6% (P < 0.001, odds ratio 0.887, 95% CI 0.670-1.184). Significant correlations were detected in postprandial glucose levels of CC-genotype patients and controls (P = 0.025), age and waist-hip ratio of CA patients and controls (P ≤ 0.001), and fasting glucose (P = 0.045) and low-density lipoprotein (P = 0.049) in all patients and controls. The serum IL-10 level was significantly higher in patients than in controls (P = 0.033). The polymorphism was significantly associated with disease incidence and its biochemical manifestations.
The role of cholesteryl ester transfer protein (CETP) in the metabolism of high-density lipoprotein cholesterol (HDL-C) is well studied but still controversial. More recently, genome-wide association studies and meta-analyses reported the association of a promoter variant (rs3764261) with HDL-C in Caucasians and other ethnic groups. In this study, we have examined the role of genetic variation in the promoter region of CETP with HDL-C, CETP activity, coronary artery disease (CAD), CAD risk factors, and the interaction of genetic factors with environment in a unique diabetic cohort of Asian Indian Sikhs.
We genotyped four variants; three tagging single nucleotide polymorphisms from promoter (rs3764261, rs12447924, rs4783961) and one intronic variant (rs708272 Taq1B) on 2431 individuals from the Sikh Diabetes study. Two variants (rs3764261 and rs708272) exhibited a strong association with HDL-C in both normoglycemic controls (β=0.12; P=9.35×10 for rs3764261; β=0.10, P=0.002 for rs708272) and diabetic cases (β=0.07, P=0.016 for rs3764261; β=0.08, P=0.005 for rs708272) with increased levels among minor homozygous 'AA' carriers. In addition, the same 'A' allele carriers in rs3764261 showed a significant decrease in systolic blood pressure (β=-0.08, P=0.002) in normoglycemic controls. Haplotype analysis of rs3764261, rs12447924, rs4783961, and rs708272 further revealed a significant association of 'ATAA' haplotype with an increased HDL-C (β=2.71, P=6.38×10) and 'CTAG' haplotype with decreased HDL-C levels (β=-1.78, P=2.5×10). Although there was no direct association of CETP activity and CETP polymorphisms, low CETP activity was associated with an increased risk to CAD (age, BMI, and sex-adjusted odds ratio=2.2; 95% confidence interval: 1.4-3.4; P=0.001) in this study. Our data revealed a strong interaction of rs3764261 and rs708272 for affecting the association between CETP activity and HDL-C levels (P=2.2×10 and P=4.4×10, respectively).
Our results, in conjunction with earlier reports confirm low CETP activity to be associated with higher CAD risk. Although there was no direct association of CETP activity with CETP polymorphisms, our findings revealed a significant interaction between CETP variants and CETP activity for affecting HDL-C levels. These results urge a deeper evaluation of the individual genetic variation in the CETP before implementing pharmaceutical intervention of blocking CETP for preventing CAD events.
The Meta-Analysis of Glucose and Insulin related traits Consortium (MAGIC) recently identified 16 loci robustly associated with fasting glucose, some of which were also associated with type 2 diabetes. The purpose of our study was to explore the role of these variants in South Asian populations of Punjabi ancestry, originating predominantly from the District of Mirpur, Pakistan.
Sixteen single nucleotide polymorphisms (SNPs) were genotyped in 1678 subjects with type 2 diabetes and 1584 normoglycaemic controls from two Punjabi populations; one resident in the UK and one indigenous to the District of Mirpur. In the normoglycaemic controls investigated for fasting glucose associations, 12 of 16 SNPs displayed β values with the same direction of effect as that seen in European studies, although only the SLC30A8 rs11558471 SNP was nominally associated with fasting glucose (β = 0.063 [95% CI: 0.013, 0.113] p = 0.015). Of interest, the MTNR1B rs10830963 SNP displayed a negative β value for fasting glucose in our study; this effect size was significantly lower than that seen in Europeans (p = 1.29×10(-4)). In addition to previously reported type 2 diabetes risk variants in TCF7L2 and SLC30A8, SNPs in ADCY5 (rs11708067) and GLIS3 (rs7034200) displayed evidence for association with type 2 diabetes, with odds ratios of 1.23 (95% CI: 1.09, 1.39; p = 9.1×10(-4)) and 1.16 (95% CI: 1.05, 1.29; p = 3.49×10(-3)) respectively.
Although only the SLC30A8 rs11558471 SNP was nominally associated with fasting glucose in our study, the finding that 12 out of 16 SNPs displayed a direction of effect consistent with European studies suggests that a number of these variants may contribute to fasting glucose variation in individuals of South Asian ancestry. We also provide evidence for the first time in South Asians that alleles of SNPs in GLIS3 and ADCY5 may confer risk of type 2 diabetes.
There has been no systematic evaluation of the association between genetic variants of type 2 receptor for TNFα (TNFR2) and type 2 diabetes, despite strong biological evidence for the role of this receptor in the pathogenesis of this complex disorder. In view of this, we performed a comprehensive association analysis of TNFRSF1B variants with type 2 diabetes in 4,200 Indo-European subjects from North India.
The initial phase evaluated association of seven SNPs viz. rs652625, rs496888, rs6697733, rs945439, rs235249, rs17883432 and rs17884213 with type 2 diabetes in 2,115 participants (1,073 type 2 diabetes patients and 1,042 control subjects). Further, we conducted replication analysis of three associated SNPs in 2,085 subjects (1,047 type 2 diabetes patients and 1,038 control subjects).
We observed nominal association of rs945439, rs235249 and rs17884213 with type 2 diabetes (P < 0.05) in the initial phase. Haplotype CC of rs945439 and rs235249 conferred increased susceptibility for type 2 diabetes [OR = 1.19 (95%CI 1.03-1.37), P = 0.019/Pperm = 0.076] whereas, TG haplotype of rs235249 and rs17884213 provided protection against type 2 diabetes [OR = 0.83 (95%CI 0.72-0.95, P = 7.2 × 10-3/Pperm = 0.019]. We also observed suggestive association of rs496888 with plasma hsCRP levels [P = 0.042]. However, the association of rs945439, rs235249 and rs17884213 with type 2 diabetes was not replicated in the second study population. Meta-analysis of the two studies also failed to detect any association with type 2 diabetes.
Our two-stage association analysis suggests that TNFRSF1B variants are not the determinants of genetic risk of type 2 diabetes in North Indians.
Common variants of fat mass and obesity-associated gene (FTO, fat mass- and obesity-associated gene) have been shown to be associated with obesity and type 2 diabetes in population of European and non-European ethnicity. However, studies in Indian population have provided inconsistent results. Here, we examined association of eight FTO variants (rs1421085, rs8050136, rs9939609, rs9930506, rs1861867, rs9926180, rs2540769 and rs708277) with obesity and type 2 diabetes in 5364 North Indians (2474 type 2 diabetes patients and 2890 non-diabetic controls) in two stages. None of the variants including previously reported intron 1 variants (rs1421085, rs8050136, rs9939609 and rs9930506) showed body mass index (BMI)-dependent/independent association with type 2 diabetes. However, rs1421085, rs8050136 and rs9939609 were associated with obesity status and measures of obesity (BMI, waist circumference and waist-to-hip ratio) in stage 2 and combined study population. Meta-analysis of the two study population results also revealed that rs1421085, rs8050136 and rs9939609 were significantly associated with BMI both under the random- and fixed-effect models (P (random/fixed)=0.02/0.0001, 0.004/0.0006 and 0.01/0.01, respectively). In conclusion, common variants of FTO were associated with obesity, but not with type 2 diabetes in North Indian population.
Variants in genes involved in pancreatic β-cell development and function are known to cause monogenic forms of type 2 diabetes and are also associated with complex form. In this study, we studied the genetic association of polymorphisms in such important genes with type 2 diabetes in the high-risk Indians. We genotyped 91 polymorphisms in 19 genes (ABCC8, HNF1A, HNF1B, HNF4A, INS, INSM1, ISL1, KCNJ11, MAFA, MNX1, NEUROD1, NEUROG3, NKX2.2, NKX6.1, PAX4, PAX6, PDX1, USF1 and WFS1) in 2025 unrelated North Indians of Indo-European ethnicity comprising of 1019 diabetic and 1006 non-diabetic subjects. HNF4A promoter P2 polymorphisms rs1884613 and rs2144908, which are in high linkage disequilibrium, showed significant association with type 2 diabetes (odds ratio (OR)=1.37 (95% confidence interval (CI) 1.19-1.57), P=9.4 × 10(-6) for rs1884613 and OR=1.37 (95%CI 1.20-1.57), P=6.0 × 10(-6) for rs2144908), as previously shown in other populations. We observed body mass index-dependent association of these variants with type 2 diabetes in normal-weight/lean subjects. Variants in USF1, ABCC8, ISL1 and KCNJ11 showed nominal association, while haplotypes in these genes were significantly associated. rs3812704 upstream of NEUROG3 significantly increased risk for type 2 diabetes in normal-weight/lean subjects (OR=1.68 (95%CI 1.25-2.24), P=4.9 × 10(-4)). Thus, pancreatic β-cell development and function genes contribute to susceptibility to type 2 diabetes in North Indians.
The greater tendency to diabetes in Indians may be due to genetic factors in addition to environment and diet. CD36, a class B scavenger cell surface receptor mediates internalization of oxidized low density lipoprotein (Ox-LDL) leading to the formation of macrophage foam cells. CD36 deficiency is related to phenotypic expression of the metabolic syndrome, frequently associated with atherosclerotic cardiovascular diseases resulting in raised levels of glucose thereby contributing to type 2 diabetes (T2DM). Therefore, the association of human CD36 gene mutation to T2DM needs investigation. We undertook this study to investigate CD36 gene status in north Indian subjects by screening for the deletion of exons 3, 4 and 5 and certain polymorphisms.
Clinical characteristics were compared between 300 T2DM patients and 100 healthy controls. Deletion analysis was carried out for exons 3, 4 and 5 of CD36 gene in 300 T2DM patients using PCR and agarose gel electrophoresis. Genotype analysis for two polymorphisms 478C>T and delAC in exons 4 and 5 respectively was carried out using PCR-RFLP method.
Biochemical parameters such as fasting and post-prandial glucose levels, total cholesterol, LDL-cholesterol and blood pressure were slightly raised in the T2DM patients when compared with controls with lowered HDL-cholesterol. No exonic deletion was observed in the 300 patients and 100 controls screened. All individuals were found to be homozygous (CC and -/-) for the two polymorphisms studied.
Although no exonic deletion was found in T2DM patients, our study suggests that all 15 exons need to be screened for mutations which lead to CD36 deficiency. Genotyping studies of the two SNPs in the CD36 gene confirmed the absence of exons 4 and 5 deletion. This is perhaps the first report from India suggesting that CD36 is one of the several important genes that need to be explored in relation to T2DM.
Genome wide association analyses have revealed large numbers of common variants influencing predisposition to type 2 diabetes and related phenotypes. These studies have predominantly featured European populations, but are now being extended to samples from a wider range of ethnic groups. The transethnic analysis of association data is already providing insights into the genetic, molecular and biological causes of diabetes, and the relevance of such studies will increase as human discovery genetics increasingly moves towards sequencing-based approaches and a focus on low frequency and rare variants.
To describe diabetes prevalence in New York City by race/ethnicity and nativity.
Data were from the New York City 2002-2008 Community Health Surveys. Respondents were categorized on the basis of self-reported race/ethnicity and birth country: foreign-born South Asian (Indian subcontinent), foreign-born other Asian, U.S.-born non-Hispanic black, U.S.-born non-Hispanic white, and U.S.-born Hispanic. Diabetes status was defined by self-reported provider diagnosis. Multivariable models examined diabetes prevalence by race/ethnicity and birth country.
Prevalence among foreign-born South Asians was nearly twice that of foreign-born other Asians (13.6 vs. 7.4%, P = 0.001). In multivariable analyses, normal-BMI foreign-born South Asians had nearly five times the diabetes prevalence of comparable U.S.-born non-Hispanic whites (14.1 vs. 2.9%, P < 0.001) and 2.5 times higher prevalence than foreign-born other Asians (P < 0.001).
Evaluating Asians as one group masks the higher diabetes burden among South Asians. Researchers and clinicians should be aware of differences in this population.
The recent observations that Peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC1A) is responsible for the induction of reactive oxygen species (ROS) detoxifying agents and that ROS triggers insulin resistance, support the role that this gene could play in the onset of Type 2 diabetes mellitus (T2DM). Two PGC1A variants Thr394Thr (rs2970847) and Gly482Ser (rs8192673) were genotyped in 822 subjects (351 T2DM cases and 471 controls) from two North Indian populations, represented as Group 1 (Kashmir population) and Group 2 (Punjab and Jammu population). Both Groups 1 and 2 showed a significant association of Thr394Thr variant with T2DM after applying Bonferroni corrections (P=0.001 and 0.012, respectively). Logistic regression analysis for Thr394Thr susceptible genotypes together (rs2970847 G/A and A/A) conferred a 1.89-(95%CI 1.25-2.85) fold higher risk for T2DM in Group 1 and 1.81-(95%CI 1.19-2.78) fold risk in Group 2. The susceptible, Ser482 (rs8192673 G/A and A/A) genotypes, gave a 2.04 (95%CI 1.47-3.03) fold higher risk for T2DM in Group 1. Mitochondrial genotype backgrounds observed in association with T2DM (Bhat et al. 2007), when studied in combination with PGC1A variants, showed an increased prevalence in controls with mt10398G and 16189T along with G/G genotype background at the two polymorphic loci of PGC1A. These observations suggest that the two genotype backgrounds together could provide protection against T2DM.
Recent genome-wide association (GWA) studies and subsequent replication studies have greatly increased the number of validated type 2 diabetes susceptibility variants, but most of these have been conducted in European populations. Despite the high prevalence of the disease in South Asians, studies investigating GWA-validated type 2 diabetes risk variants in this ethnic group are limited. We investigated 30 single nucleotide polymorphisms (SNPs), predominantly derived from recent GWA studies, to determine if and to what extent these variants affect type 2 diabetes risk in two Punjabi populations, originating predominantly from the District of Mirpur, Pakistan.
Thirty SNPs were genotyped in 1,678 participants with type 2 diabetes and 1,584 normoglycaemic control participants from two populations; one resident in the UK and one indigenous to the District of Mirpur.
SNPs in or near PPARG, TCF7L2, FTO, CDKN2A/2B, HHEX/IDE, IGF2BP2, SLC30A8, KCNQ1, JAZF1, IRS1, KLF14, CHCHD9 and DUSP9 displayed significant (p < 0.05) associations with type 2 diabetes, with similar effect sizes to those seen in European populations. A constructed genetic risk score was associated with type 2 diabetes (p = 5.46 × 10(-12)), BMI (p = 2.25 × 10(-4)) and age at onset of diabetes (p = 0.002).
We have demonstrated that 13 variants confer an increased risk of type 2 diabetes in our Pakistani populations; to our knowledge this is the first time that SNPs in or near KCNQ1, JAZF1, IRS1, KLF14, CHCHD9 and DUSP9 have been significantly associated with the disease in South Asians. Large-scale studies and meta-analyses of South Asian populations are needed to further confirm the effect of these variants in this ethnic group.
Neonatal diabetes mellitus (NDM) due to KCNJ11 gene mutation presents with diabetes in the first 3 months of life and sometimes with neurological features like developmental delay, muscle weakness and epilepsy.
A 5-week-old boy presented with diabetic ketoacidosis. Molecular genetic analysis of the patient revealed heterozygous missense mutation, L233F in the KCNJ11 gene, while his mother was mosaic for the same mutation.
The treatment strategy was changed from insulin injections to oral glibenclamide and with a better glycemic control.
The patient with NDM due to mutation L233F (not reported till date) in the KCNJ11 gene can be successfully treated with oral glibenclamide therapy.
the present study investigated the association of six variants-rs9940128, rs7193144, and rs8050136 (in intron 1), rs918031 and rs1588413 (in intron 8), and rs11076023 (3' untranslated region)-across three regulatory regions of the fat mass and obesity-associated (FTO) gene with obesity and type 2 diabetes mellitus (T2DM) in a South Indian population.
unrelated study subjects (n = 1,852; 1,001 normal glucose-tolerant [NGT] controls and 851 cases [T2DM]) were randomly selected from the Chennai Urban Rural Epidemiological Study (CURES). Genotyping was done by the polymerase chain reaction-restriction fragment length polymorphism method, and 20% of samples were sequenced to validate the genotypes obtained. Haplotype analysis was also carried out.
the three polymorphisms rs9940128 A/G, rs1588413 C/T, and rs11076023 A/T of the FTO gene were associated with T2DM in our study population. The rs8050136 C/A variant was associated with obesity, and its association with T2DM was also mediated through obesity. The rs1588413 C/T variant showed an association with obesity in the total study subjects, but when the NGT subjects alone were analyzed, the association with obesity was lost. The haplotype ACCTCT confers a lower risk of T2DM in this South Indian population.
among South Indians, the rs9940128 A/G, rs11076023 A/T, and rs1588413 C/T variants of the FTO gene were associated with T2DM, whereas the rs8050136 C/A variant was associated with obesity.
Diabetic retinopathy (DR) is classically defined as a microvasculopathy that primarily affects the small blood vessels of the inner retina as a complication of diabetes mellitus (DM).It is a multifactorial disease with a strong genetic component. The aim of this study is to investigate the association of a set of nine candidate genes with the development of diabetic retinopathy in a South Indian cohort who have type 2 diabetes mellitus (T2DM).
Seven candidate genes (RAGE, PEDF, AKR1B1, EPO, HTRA1, ICAM and HFE) were chosen based on reported association with DR in the literature. Two more, CFH and ARMS2, were chosen based on their roles in biological pathways previously implicated in DR. Fourteen single nucleotide polymorphisms (SNPs) and one dinucleotide repeat polymorphism, previously reported to show association with DR or other related diseases, were genotyped in 345 DR and 356 diabetic patients without retinopathy (DNR). The genes which showed positive association in this screening set were tested further in additional sets of 100 DR and 90 DNR additional patients from the Aravind Eye Hospital. Those which showed association in the secondary screen were subjected to a combined analysis with the 100 DR and 100 DNR subjects previously recruited and genotyped through the Sankara Nethralaya Hospital, India. Genotypes were evaluated using a combination of direct sequencing, TaqMan SNP genotyping, RFLP analysis, and SNaPshot PCR assays. Chi-square and Fisher exact tests were used to analyze the genotype and allele frequencies.
Among the nine loci (15 polymorphisms) screened, SNP rs2070600 (G82S) in the RAGE gene, showed significant association with DR (allelic P = 0.016, dominant model P = 0.012), compared to DNR. SNP rs2070600 further showed significant association with DR in the confirmation cohort (P = 0.035, dominant model P = 0.032). Combining the two cohorts gave an allelic P < 0.003 and dominant P = 0.0013). Combined analysis with the Sankara Nethralaya cohort gave an allelic P = 0.0003 and dominant P = 0.00011 with an OR = 0.49 (0.34 - 0.70) for the minor allele. In HTRA1, rs11200638 (G>A), showed marginal significance with DR (P = 0.055) while rs10490924 in LOC387715 gave a P = 0.07. No statistical significance was observed for SNPs in the other 7 genes studied.
This study confirms significant association of one polymorphism only (rs2070600 in RAGE) with DR in an Indian population which had T2DM.
Objective:
To study the etiology, clinical presentation and outcome of infantile onset diabetes mellitus (IODM).
Design:
Descriptive cohort study. Retrospective study from 1999-2007 and prospective from 2008-2012.
Setting:
The diabetic clinic at a Pediatric tertiary care referral institute in Chennai.
Methods:
All infants diagnosed to have diabetes at less than one year of age were studied. Study variables were age at onset, gender, mode of presentation, birth weight, initial blood glucose, serum HbA1c, serum c peptide levels, outcome at initial presentation, insulin requirement, associated comorbid conditions, genetic analysis and outcome at the end of the study or until they were followed up.
Results:
40 infants with infantile onset diabetes were studied, constituting 8% of all children with onset of DM at less than 12 years of age. 67.5% of these children presented with diabetic keto acidosis (DKA), only 30% had a provisional diagnosis of DM or DKA at first physician contact. 63% of IODM with onset less than 6 months and 30% with onset more than 6 months were of low birth weight. Nearly 85% of the study group had low C-peptide levels. 84.5% of IODM with onset less than 6 months and 55% of those with onset more than 6 months were monogenic. Wolcott Rallison syndrome was the commonest type encountered. Genetic diagnosis aided switching over from insulin to oral sulphonylurea in 5 children with KCNJ11 and ABCC8 mutations. Missed diagnosis, recurrent admissions for metabolic instability and developmental delay were common problems in IODM. Mortality at 12.5 year follow up was 32.5%.
Conclusions:
IODM with onset at less than 6 months is predominantly monogenic and low birth weight is more common. 55% of IODM were misdiagnosed at onset. Developmental delay is the common co morbid condition in IODM. Genetic diagnosis aids change of therapy to oral sulphonylurea.
Individuals of south Asian origin have a very high risk of developing type 2 diabetes compared with white Caucasians. We aimed to assess volume and activity of brown adipose tissue (BAT), which is thought to have a role in energy metabolism by combusting fatty acids and glucose to produce heat and might contribute to the difference in incidence of type 2 diabetes between ethnic groups.
We enrolled Dutch nationals with south Asian ancestry and matched Caucasian participants at The Rijnland Hospital (Leiderdorp, Netherlands). Eligible participants were healthy lean men aged 18-28 years, and we matched groups for BMI. We measured BAT volume and activity with cold-induced (18)F-fluorodeoxyglucose ((18)F-FDG) PET CT scans, and assessed resting energy expenditure, non-shivering thermogenesis, and serum parameters. This study is registered with the Netherlands Trial Register, number 2473.
Between March 1, 2013, and June 1, 2013, we enrolled 12 participants in each group; one Caucasian participant developed hyperventilation after (18)F-FDG administration, and was excluded from all cold-induced and BAT measurements. Compared with Caucasian participants, south Asian participants did not differ in age (mean 23·6 years [SD 2·8] for south Asians vs 24·6 years [2·8] for Caucasians) or BMI (21·5 kg/m(2) [2·0] vs 22·0 kg/m(2) [1·6]), but were shorter (1·74 m [0·06] vs 1·85 m [0·04]) and lighter (65·0 kg [8·5] vs 75·1 kg [7·2]). Thermoneutral resting energy expenditure was 1297 kcal per day (SD 123) in south Asian participants compared with 1689 kcal per day (193) in white Caucasian participants (difference -32%, p=0·0008). On cold exposure, shiver temperature of south Asians was 2·0°C higher than Caucasians (p=0·0067) and non-shivering thermogenesis was increased by 20% in white Caucasians (p<0·0001) but was not increased in south Asians. Although the maximum and mean standardised uptake values of (18)F-FDG in BAT did not differ between groups, total BAT volume was lower in south Asians (188 mL [SD 81]) than it was in Caucasians (287 mL [169]; difference -34%, p=0·04). Overall, BAT volume correlated positively with basal resting energy expenditure in all assessable individuals (β=0·44, p=0·04).
Lower resting energy expenditure, non-shivering thermogenesis, and BAT volumes in south Asian populations might underlie their high susceptibility to metabolic disturbances, such as obesity and type 2 diabetes. Development of strategies to increase BAT volume and activity might help prevent and treat such disorders, particularly in south Asian individuals.
Dutch Heart Foundation (2009T038) and Dutch Diabetes Research Foundation (2012.11.1500).
We assessed the relative associations of β-cell dysfunction and insulin sensitivity with baseline glycemic status and incident glycemic progression among Asian Indians in the United States.
A 5-sample oral glucose tolerance test was obtained at baseline. Normoglycemia, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes (T2DM) were defined by ADA criteria. The Matsuda Index (ISIM) estimated insulin sensitivity, and the Disposition Index (DIo) estimated β-cell function. Visceral fat was measured by abdominal CT. After 2.5years, participants underwent a 2-sample oral glucose tolerance test. Standardized polytomous logistic regression was used to examine associations with prevalent and incident glycemia.
Mean age was 57±8years and BMI 26.1±4.6kg/m(2). Log ISIM and log DIo were associated with prediabetes and T2DM after adjusting for age, sex, BMI, family history of diabetes, hypertension, and smoking. After adjusting for visceral fat, only DIo remained associated with prediabetes (OR per SD 0.17, 95% CI: 0.70, 0.41) and T2DM (OR 0.003, 95% CI: 0.0001, 0.03). Incidence rates (per 1,000 person-years) were: normoglycemia to IGT: 82.0, 95% CI (40, 150); to IFG: 8.4, 95% CI (0, 41); to T2DM: 8.6, 95% CI (0, 42); IGT to T2DM: 55.0, 95% CI (17, 132); IFG to T2DM: 64.0, 95% CI (3, 316). The interaction between sex and the change in waist circumference (OR 1.8, per SD 95% CI: 1.22, 2.70) and the change in log HOMA-β (OR 0.37, per SD 95% CI: 0.17, 0.81) were associated with glycemic progression.
The association of DIo with baseline glycemia after accounting for visceral fat as well as the association of the change in log HOMA-β with incident glycemic progression implies innate β-cell susceptibility in Asian Indians for glucose intolerance or dysglycemia.
This study describes the clinical and genetic evaluation of permanent neonatal diabetes due to Wolcott-Rallison syndrome (WRS) in south Indian consanguineous families. We aimed to evaluate the genetic basis of the disease in eight children with WRS from five South Indian families.
We studied eight children who presented with permanent neonatal diabetes from five South Indian families. Follow up clinical evaluation revealed features (like liver disease, skeletal dysplasia, and thyroid dysfunction) suggestive of WRS. All the coding exons along with splice sites of KCNJ11, ABCC8, INS, GCK and EIF2AK3 genes were sequenced in all the probands.
Two novel homozygous mutations (Trp658Ser, c.3150+1G>T) and one known homozygous mutation (Arg1065*, c.3193C>T) in EIF2AK3 gene were identified in children with WRS. Mutation Arg1065*was identified in four children.
Our results in these families show that the mutations in homozygous state are likely to be causative. We suggest the screening for EIF2AK3 gene mutations as WRS is now recognized as the most frequent cause of neonatal diabetes in children with consanguineous parents. As the mode of inheritance is recessive, screening for genetic mutations becomes important to aid in risk prediction and clinical management.
The respective roles of predisposing genetic factors and environmental factors in the development of type 2 diabetes (T2D) in obese subjects is poorly documented. Rodent models have been set up in an attempt to better understand of the differential effect of a prolonged metabolic stress induced by a high fat diet on glycaemic control according to the genetic background. In utero growth retardation resulting from a hypocaloric diet in pregnant rats induces a dramatic alteration of the development of islet cells leading to diabetes and insulin secretory defects in adult age. Experimentally induced diabetes in rodents results in hyperglycaemia and hyperinsulinemia in the fetus related to accelerated endocrine pancreas maturation responsible for the onset of diabetes in the adult. Deranged metabolic environment during fetal life may therefore further contribute to the onset of diabetes in the adult. Normal mouse strains with different genetic backgrounds show a wide range of responses to a high fat diet, with strains resistant to the diet and other more or less sensitive to the diet, the most sensitive exhibiting obesity diabetes and, insulin deficiency. The inability of the β cell to respond to the increased insulin demand related to insulin resistance seems to be pivotal in the pathophysiologic process and a new notion is emerging: "nutritional genetics" which studies the influence of nutrients on gene expression.
© 2013 médecine/sciences – Inserm.
Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Several pathogenic processes are involved in the development of diabetes. These range from autoimmune destruction of the beta-cells of the pancreas with consequent insulin deficiency to abnormalities that result in resistance to insulin action (American Diabetes Association, 2011). The vast majority of cases of diabetes fall into two broad categories. In type 1 diabetes (T1D), the cause is an absolute deficiency of insulin secretion, whereas in type 2 diabetes (T2D), the cause is a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. However, the subdivision into two main categories represents a simplification of the real situation, and research during the recent years has shown that the disease is much more heterogeneous than a simple subdivision into two major subtypes assumes.
Type 2 diabetes mellitus (T2DM) which used to be a disease of adults is now seen commonly at an early age in children and adolescents. T2DM is now an important diagnostic consideration in children who present with signs and symptoms of diabetes. The emerging epidemic of obesity in children throughout the world and the resultant insulin resistance contributes to the increasing prevalence of T2DM in this population. The recommended treatment options include metformin and insulin. Optimal glycemic control is essential considering the lifelong nature of the disease and therefore, the increased risk of long term complications - both microvascular and macrovascular. This review article summarizes the classification, diagnosis, pathogenesis, management, complications and screening of T2DM in children, incorporating and contextualizing guidelines from various professional associations.
Endothelial dysfunction is thought to be a significant risk factor for cardiovascular disease. This study determined the role of endothelial nitric oxide synthase (eNOS) Glu298Asp polymorphism and intergenotypic variation of plasma nitric oxide (NO) levels in coronary artery disease (CAD) patients with type 2 diabetes mellitus (DM).
This case-control study included 28 documented CAD patients with type 2 DM and 32 non-diabetic patients with CAD. Fifty healthy volunteers without any major cardiovascular risk factors served as controls. NO was estimated by modified Griess method. The eNOS gene polymorphism was studied by amplifying DNA by PCR and digesting with BanII restriction enzyme. Restriction fragment length polymorphism was studied by using a gel documentation system.
The genotype frequencies for Glu298Asp (GT) genotype were 10.71% in diabetic CAD patients, 28.1% in non-diabetic CAD patients and 12% in controls. The T allele frequency was higher in the non-diabetic CAD group (14%) as compared with the diabetic CAD (5.4%) and control group (6%). NO level was significantly lower in non-diabetic CAD patients (10.25mmol/L) but not in diabetic CAD patients (13.89mmol/L) as compared to controls (16.78mmol/L).
Glu298Asp polymorphism is not the mediator of increased incidence of CAD in diabetic patients.
Adiponectin (ADIPOQ) is an abundant protein hormone which belongs to a family of so-called adipokines. It is expressed mostly by adipocytes and is an important regulator of lipid and glucose metabolism. It was shown that decreased serum adiponectin concentration indicated insulin resistance and type 2 diabetes (T2DM) with the risk of cardiovascular complications. The fact that adiponectin is an insulin-sensitizing hormone with anti-diabetic, anti-inflammatory and anti-atherogenic properties, we proposed to study the association of ADIPOQ gene polymorphisms in subjects with T2DM. DNA was isolated from venous blood samples, quantified and subjected to Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) using suitable primers and restriction endonucleases. Adiponectin levels were measured in serum using ELISA. The genotypic, allelic and carriage rate frequencies distribution in patients and controls were analyzed by PSAW software (ver. 17.0). Odd ratios (OR) with 95% confidence interval (CI) were determined to describe the strength of association by logistic regression model. Out of the two polymorphisms studied, +10211T/G showed significant association (P=0.042), the 'G' allele association being highly significant (P=0.022). Further analysis showed that individuals with 'GG' haplotype were at increased risk of T2DM up to 15.5 times [P=0.015, OR (95% CI); 15.558 (1.690-143.174)]. The present study showed that the 'G' allele of ADIPOQ gene (+10211T/G) plays a prominent role with respect to T2DM susceptibility in North-Indian population.
Mutations in the pancreatic ATP sensitive K(+) channel proteins [sulfonyluea receptor 1 (SUR1) and inward rectifier K(+) channel Kir6.2 (Kir6.2), encoded by ATP-binding cassette transporter subfamily C member 8 (ABCC8) and potassium channel J11 (KCNJ11), respectively], are the most common cause of neonatal diabetes. We describe the clinical presentation and molecular characterization of Asian Indian children with neonatal diabetes mellitus and monogenic syndromes of diabetes. We sequenced KCNJ11, ABCC8 and insulin (INS) genes in 33 unrelated Indian probands with onset of diabetes below one year of age. A total of 12 mutations were identified which included ABCC8 mutations in seven, KCNJ11 mutations in three and INS mutations in two children. The Asp212Tyr mutation in ABCC8 was novel. We also detected two novel mutations (Val67Met and Leu19Arg) in children with syndromic forms of diabetes like Berardinelli Seip syndrome [1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2)] and Fanconi Bickel syndrome [solute carrier family 2A2 (SLC2A2)]. Children carrying the KCNJ11 (Cys42Arg, Arg201Cys) and ABCC8 (Val86Ala, Asp212Tyr) mutations have been successfully switched over from insulin therapy to oral sulfonylurea. Our study is the first large genetic screening study of neonatal diabetes in India.
The gene loci such as HLA (DRB1* and DQB1*), ACE I/D and ApoE were implicated in the spectrum of type 2 diabetes mellitus (T2DM) leading to secondary complications such as hypertension, retinopathy and cardiac complications. Two hundreds T2DM patients and 151 controls for ACE and ApoE and 156 T2DM patients and 102 controls for HLA-DRB1* and DQB1* were genotyped by PCR methods. The overall frequency of D allele (ID + DD) was higher in T2DM patients than controls (P = 0.056). Consistently higher frequency of ID genotype was noticed in T2DM patients (pooled) (69.50%), T2DM-without complications (71.71%) and T2DM-with complications (68.31%) than controls (49%). The genotype II was significantly elevated in controls than T2DM (p=0.0002), T2DM-WOC (p=0.0005) and T2DM-WC (p=0.0002). Further, we observed a complete absence of genotype II in patients with retinopathy, genotype DD in patients with hypertension and retinopathy and both II and DD genotype in patients with hypertension and neuropathy, conferring longevity and/or survival benefit to T2DM patients with these complications. The ApoE carrier ε2 (P = 0.007) and ε4 (P = 0.003) were strongly associated with T2DM. A preferential co-occurrence of ACE-ApoE was observed for ID–2/3 combination (P = 0.001) and ID-3/4 (P = 0.269) in T2DM patients than controls. For HLA, the allele frequency was the highest for DRB1*03 in patients than the controls (15.70 vs. 5.88%) and for DRB1*07 in controls than T2DM patients (23.52 vs. 12.17%) affording a susceptible and protective roles of these alleles respectively. Heterozygote combinations were preferentially seen in T2DM patients of higher age groups than controls.
The paraoxonase (PON1) gene polymorphisms are known to affect the PON1 activity and coronary artery disease (CAD) risk. Studies done so far have given conflicting results. In the present study, we determined the role of PON1 genetic variants and PON1 activity in the development of CAD in North-West Indian Punjabis, a distinct ethnic group, having high incidence of both CAD and type 2 diabetes. 300 angiographically proven CAD with type 2 diabetics and 250 type 2 diabetics with no clinically evident CAD were enrolled. Serum PON1 activity and genotyping of coding (Q192R, L55M) and promoter (-909G/C, -162A/G, -108C/T) region polymorphisms were carried out and haplotypes were determined using PHASE software. The serum PON1 activity was significantly lower in CAD with type 2 diabetics as compared to diabetics alone (51.0 vs. 114.2nmol/min/ml). In logistic regression model after adjusting for confounding variables, lower PON1 activity was found to be significantly associated with CAD risk in type 2 diabetics with OR being 16.8 (95% CI: 10.2-27.7). The lower serum PON1 activity, irrespective of genotypes and haplotypes is a risk factor for development of CAD in North-West Indian Punjabis with type 2 diabetics.
Recent studies have identified common variants in forkhead box O3 gene (FOXO3) to be strongly associated with longevity in different populations. But studies have not been carried out to analyse the role of common variants in FOXO3 with type 2 diabetes. Since type 2 diabetes is an age related disorder and FOXO proteins play an important role in the regulation of metabolism, we studied the role of common variants in FOXO3 for association with type 2 diabetes. The study was carried out in 994 type 2 diabetic samples and 984 normoglycemic control samples from a South Indian Dravidian population. In our analysis, we found that there was no association between any of the selected SNPs in FOXO3 with type 2 diabetes. Analysis of these SNPs with diabetes related biochemical and clinical parameters also did not reveal any significant association. Haplotype association of SNPs in FOXO3 with type 2 diabetes was observed, but the frequency of the haplotypes was considerably lower and they do not remain significant after correction for multiple testing. In conclusion, we did not observe any association of SNPs in FOXO3 with type 2 diabetes and related parameters suggesting an entirely different mechanism by which these SNPs influence longevity. However additional studies in other populations are required to completely rule out the association of common variants in FOXO3 with type 2 diabetes.
Coronary artery disease (CAD) is a major health concern and the leading cause of death in individuals with type-2 diabetes mellitus (T2DM). Glutathione peroxidase-1 (GPx-1) and NAD(P)H: quinone oxidoreductase (NQO1) are known for its broad range of detoxification. The role of functional variants of these genes in the development of various disorders is proven. Hereby, we investigated the possible role of these variants in the development of CAD in T2DM patients of South Indian population. In this case-control study, a total of 539 patients (T2DM = 241; T2DM-CAD = 298) and 285 controls were included. The C198T GPx-1 and C609T NQO1 single-nucleotide polymorphisms were analyzed by PCR-RFLP. Further, these genotypes were correlated with blood lipid profile. Regression analysis showed that GPx1-C/T genotype is associated with a 1.35-fold increase (95% CI = 1.000-1.824; P = 0.048) and GPx1-T/T genotype is associated with a 1.76-fold increase (95% CI = 1.011 to 3.066; P = 0.046) to the T2DM development. Increased odds ratio showed that NQO1-T/T genotype had a higher occurrence of CAD in diabetic patients with CAD (95% CI = 1.003-2.674, P = 0.049) than T2DM patients without CAD. The level of triglycerides alone showed significant increase for GPx-1-C/T and -T/T genotypes in Tukey's Post hoc analysis (177.1 ± 19.2 vs. 184 ± 23.5; P = 0.039 and 177.1 ± 19.2 vs. 190 ± 22.4; P = 0.006) among the patients with T2DM-CAD. Our work concludes that GPx-1 variants might contribute to the development of diabetes and both GPx-1 and NQO1 variants confirm the association of CAD in people with T2DM of South Indian population.
Genome-wide association studies recently found IGF2BP2 rs4402960 polymorphism associated with enhanced risk of type 2 diabetes mellitus (T2DM). Numerous studies have been published to replicate the association. However, results were inconsistent and inconclusive. To clarify the relationship of IGF2BP2 rs4402960 polymorphism and T2DM, we conducted this meta-analysis.
We searched PubMed for all eligible studies up to February 2011. Forty eight independent study groups from 28 case-control studies and two prospective studies were identified. Pooled odds ratio (OR) and 95% confidential interval (95% CI) were adopted to evaluate the association.
The pooled results indicated that the rs4402960 polymorphism of the IGF2BP2 gene was related to increased risk of T2DM for T allele vs. G allele (OR = 1.13, 95% CI 1.11-1.15) under additive genetic model. Significant associations were also found under dominant (OR = 1.17, 95% CI 1.14-1.20) and recessive (OR = 1.20, 95% CI 1.15-1.25) genetic models. There was no significant heterogeneity among all studies. Subgroup analyses stratified by ethnicity showed that significant increased risks were observed in European, East Asian and South Asian populations, and the effect sizes were similar. For Africans, no significant association was detected under all genetic models.
Our meta-analysis suggested that IGF2BP2 rs4402960 polymorphism conferred elevated risk of T2DM, especially in European, East Asian and South Asian populations.
Paraoxonase-1 (PON1), an HDL-C associated enzyme, protects lipoproteins from oxidation. There is evidence that PON1 enzyme activity is reduced in the patients with type 2 diabetes mellitus (T2DM). North-West Indian Punjabis, a distinct ethnic group has high incidence of T2DM. However till date there is no information regarding PON1 enzyme activities and PON1 polymorphisms in T2DM patients of this ethnic group.
We identified polymorphisms in the coding Q192R, L55M and promoter -909G/C, -162A/G, -108C/T of the PON1 gene by using PCR-RFLP, multiplex PCR and allele specific oligonucleotide PCR assays in 250 T2DM patients and 300 healthy controls. We also assessed paraoxonase (PONase) and arylesterase (AREase) activities of PON1 enzyme.
The serum PONase (114.2 vs. 178.0nmol/min/ml) and AREase (62.7 vs. 82.5μmol/min/ml) activities were significantly lower (p<0.0001) in patients as compared to controls. PONase activity was affected by all the studied PON1 polymorphisms. However, AREase activity was not affected by any of these polymorphisms. Coding Q192R and promoter -909G/C polymorphisms showed significant differences in genotypic distribution. QR, RR (Q192R) and GC, CC (-909G/C) genotypes and L-C-A-R-G, L-T-A-R-G, L-T-G-Q-C haplotypes showed significant association with type 2 diabetes. No significant linkage disequilibrium was observed among the five polymorphisms.
Both PONase and AREase activities are lower in patients and this could lead to increased lipid peroxidation and accelerated atherosclerosis in them. PONase activity, but not AREase activity is influenced by PON1 polymorphisms. QR, RR, GC, CC genotypes and L-C-A-R-G, L-T-A-R-G, L-T-G-Q-C haplotypes are commoner in diabetics as compared to controls and may be related to genetic susceptibility to type 2 diabetes.
The GLUT4 gene, which encodes glucose transporter 4, is a candidate gene for type 2 diabetes mellitus (T2DM). The aim of this study was to screen the GLUT4 gene for polymorphisms and to study association of such polymorphisms with T2DM in an Asian Indian population in southern India.
The GLUT4 gene was sequenced in 25 normal glucose tolerance (NGT) and 25 T2DM subjects, and the variants found were then genotyped by polymerase chain reaction-restriction fragment length polymorphism in a pilot study population of 552 NGT and 643 T2DM subjects, randomly selected from the Chennai Urban Rural Epidemiology Study. Two of the variants (rs5435 and the novel variant), which showed significantly higher minor allele frequency in T2DM compared with NGT individuals in the pilot study population, were then retested with an additional 465 NGT and 363 T2DM subjects, giving a final sample size of 1,017 NGT and 1,006 T2DM subjects.
Sequencing of the GLUT4 gene revealed three known polymorphisms (rs5418, rs5421, and rs5435) and one novel T→G variant in the 3' untranslated region (UTR) at nucleotide position 6787483. The rs5418 and rs5421 polymorphisms did not show any association with diabetes. The rs5435 [Asn130Asn(C→T)] polymorphism was found to be associated with diabetes, with the odds ratio for the CT+TT genotype being 1.26 (95% confidence interval, 1.00-1.57; P=0.043) when the CC genotype was taken as reference. The frequency of the TG genotype of the novel 3'UTR T→G variant was significantly higher in diabetes subjects (1%) compared with NGT subjects (0.2%) (P=0.021). There was a significant difference in the proportion of the ACGT haplotype of the rs5418(A→G), rs5435(C→T), rs5421(C→G), and the T→G 3'UTR variant between the NGT (7.5%) and diabetes (5%) groups (P=0.003).
The rs5435 (C→T) polymorphism of the GLUT4 gene is associated with type 2 diabetes in this south Indian population.
The insulin receptor substrate-1 (IRS1) gene is a candidate gene for type 2 diabetes. The aim of this study was to investigate the association of the IRS1 gene polymorphisms Gly972Arg and Ala513Pro with type 2 diabetes in an Asian Indian population in south India.
A total of 2,148 subjects (1,187 normal glucose-tolerant [NGT] and 961 type 2 diabetes subjects) were randomly selected from the Chennai Urban Rural Epidemiology Study. The IRS1 gene polymorphisms Gly972Arg and Ala513Pro were genotyped in these subjects using polymerase chain reaction-restriction fragment length polymorphism, and a few variants were confirmed by direct sequencing.
The frequency of the "A" allele of the Gly972Arg(G→A) single nucleotide polymorphism was similar between the NGT and diabetes subjects (2%). There was no significant difference in the genotypic frequency between the NGT and type 2 diabetes group (P = 0.25). When the study subjects were stratified based on body mass index (BMI) as per World Health Organization Asia Pacific guidelines as nonobese (BMI <25 kg/m(2)) and obese (BMI ≥25 kg/m(2)), neither the allelic frequency (nonobese, P = 0.44; obese, P = 0.37) nor the genotypic frequency (nonobese, P = 0.29; obese, P = 0.35) was significantly different between the NGT and type 2 diabetes groups. The Ala513Pro polymorphism was first genotyped in 500 NGT and 500 type 2 diabetes subjects. None of these subjects carried the Ala513Pro or the Pro513Pro genotype. Hence, the Ala513Pro polymorphism was not genotyped further.
The IRS1 gene variants Gly972Arg and Ala513Pro are not associated with type 2 diabetes in this south Indian population.
The association between peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) polymorphisms and type 2 diabetes mellitus (T2DM) has been investigated in several studies, but these studies yielded contradictory results. We conducted a meta-analysis to assess the association between three polymorphisms (Gly482Ser, Thr394Thr and Thr612Met) in PPARGC1A and T2DM.
A literature-based search was conducted to collect data. The additive model was chosen to investigate the association between the three polymorphisms and T2DM. The random effects model was used if there was heterogeneity between studies. In addition, subgroup meta-analyses were made according to the ethnic groups.
Twenty-three studies were enrolled in this meta-analysis (7539 cases and 9562 controls for Gly482Ser, 1818 cases and 2376 controls for Thr394Thr, 2042 cases and 1289 controls for Thr612Met). In the combined analysis of all eligible studies, a significant association was found between Gly482Ser, Thr394Thr and T2DM with pooled odds ratios 1.19 [95% confidence interval (CI) 1.05-1.34] and 1.33 (95% CI 1.04-1.70), respectively, but great heterogeneity was found between studies. In the subgroup meta-analyses, we found that Gly482Ser and Thr394Thr polymorphisms were associated with the risk of T2DM, and the pooled odds ratios were 1.66 (95% CI 1.28-2.15) and 1.72 (95% CI 1.45-2.03), respectively, in the Indian population; no significant evidence was found in the Caucasian and East Asian populations.
This meta-analysis indicated that Gly482Ser and Thr394Thr polymorphisms of PPARGC1A gene were significantly associated with the risk of T2DM, especially in the Indian population. No relationship was found between the Thr612Met and risk of T2DM.
this study examined the association of -866G/A, Ala55Val, 45bpI/D, and -55C/T polymorphisms at the uncoupling protein (UCP) 3-2 loci with type 2 diabetes in Asian Indians.
a case-control study was performed among 1,406 unrelated subjects (487 with type 2 diabetes and 919 normal glucose-tolerant [NGT]), chosen from the Chennai Urban Rural Epidemiology Study, an ongoing population-based study in Southern India. The polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. Haplotype frequencies were estimated using an expectation-maximization algorithm. Linkage disequilibrium was estimated from the estimates of haplotypic frequencies.
the genotype (P = 0.00006) and the allele (P = 0.00007) frequencies of Ala55Val of the UCP2 gene showed a significant protective effect against the development of type 2 diabetes. The odds ratios (adjusted for age, sex, and body mass index) for diabetes for individuals carrying Ala/Val was 0.72, and that for individuals carrying Val/Val was 0.37. Homeostasis insulin resistance model assessment and 2-h plasma glucose were significantly lower among Val-allele carriers compared to the Ala/Ala genotype within the NGT group. The genotype (P = 0.02) and the allele (P = 0.002) frequencies of -55C/T of the UCP3 gene showed a significant protective effect against the development of diabetes. The odds ratio for diabetes for individuals carrying CT was 0.79, and that for individuals carrying TT was 0.61. The haplotype analyses further confirmed the association of Ala55Val with diabetes, where the haplotypes carrying the Ala allele were significantly higher in the cases compared to controls.
Ala55Val and -55C/T polymorphisms at the UCP3-2 loci are associated with a significantly reduced risk of developing type 2 diabetes in Asian Indians.