Anjana Ranjit Mohan’s research while affiliated with Madras Diabetes Research Foundation and other places

Traditionally, treatment for type 2 diabetes (T2D) centered on the failure of insulin secretion from the beta cells of the pancreas and insulin resistance. Though effective in certain respects, these treatments are marred by multiple undesirable side effects. The discovery of the incretin defect and the role of glucagon in T2D shifted the focus to therapies that addressed not only the beta cell defect but also the alpha cell defect in the pancreas. Therapies addressing these defects, simultaneously, have switched the entire focus of T2D therapy by not only improving glycemic control but also reducing the risk of hypoglycemia and weight gain and improving outcomes. These newer modalities of treatment started off with dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RAs), and now further treatments in the form of twincretins (GLP1/GIP dual agonists) and triple agonists (GLP1/GIP/glucagon agonists) are unraveling. This article provides a summary of the evidence available with these newer antidiabetics, which address the glucagon defect in T2D.

Context Collaborative care models for depression have been successful in a variety of settings, but their success may differ by patient engagement. We conducted a post-hoc analysis of the INDEPENDENT trial to investigate the role of differential engagement of participants on health outcomes over 3 years. Settings and Design INDEPENDENT study was a parallel, single-blinded, randomised clinical trial conducted at four socio-economically diverse clinics in India. Participants were randomised to receive either active collaborative care or usual care for 12 months and followed up for 24 months. Method We grouped intervention participants by engagement, defined as moderate (≤7 visits) or high, (8 or more visits) and compared them with usual care participants. Improvements in composite measure (depressive symptoms and at least one of three cardio-metabolic) were the primary outcome. Statistical Analysis Mean levels of depression and cardio-metabolic measures were analysed over time using computer package IBM SPSS Statistics 25. Results The composite outcome was sustained the highest in the moderate engagers [27.5%, 95% confidence interval (CI): 19.5, 36.7] and the lowest in high engagers (15.8%, 95% CI: 8.1, 26.8). This pattern was observed for individual parameters – depressive symptoms and glycosylated haemoglobin. Progressive reductions in mean depressive symptom scores were observed for moderate engagers and usual care group from baseline to 36 months. However, in high engagers of collaborative care, mean depressive symptoms were higher at 36 months compared to 12 months. Conclusion Sustained benefits of collaborative care were larger in participants with moderate engagement compared with high engagement, although a majority of participants relapsed on one or more outcome measures by 36 months. High engagers of collaborative care for co-morbid depression and diabetes may need light touch interventions for longer periods to maintain health and reduce depressive symptoms.

Objective Certain ethnicities such as South Asians and East Asians have higher rates of type 2 diabetes mellitus, in part, driven by insulin deficiency. Insulin deficiency can be due to beta-cell insufficiency, low beta-cell mass, or early cell death. Transcription factor XBP1 maintains beta-cell function and prevents early cell death by mitigating cellular endoplasmic reticulum stress. We examine the role of XBP1 expression in maintaining glucose homeostasis, glycaemic control, and response to diabetes therapeutics. Research Design and Methods Colocalisation analyses were used to determine if expression of XBP1 in pancreatic islets and type 2 diabetes shared common causal genetic variants. We identify a lead eQTL variant associated exclusively with XBP1 expression and examine its association HOMA-B and stimulated glucose in cohorts of newly diagnosed Asian Indians from Dr. Mohans Diabetes Specialities Centre, India (DMDSC) and the Telemedicine Project for Screening diabetes and complications in rural Tamil Nadu (TREND). We then examine longer term glycaemic control using HbA1c in Asian Indian cohorts, the Tayside Diabetes Study (TDS) of white European ancestry in Scoltand, and the Genes & Health (G&H) study of British South Asian Bangladeshi and Pakistani ancestry. Finally, we assess the effect of eQTL variant on drugs designed to improve insulin secretion (sulphonylureas and GLP1-RA). Results Variants affecting XBP1 expression in the pancreatic islets colocalised with variants associated with T2DM risk in East Asians but not in white Europeans. Lower expression of XBP1 was associated with higher risk of T2DM. rs7287124 was the lead eQTL variant and had a higher risk allele frequency in East (65%) and South Asians (50%) compared to white Europeans (25%). In 470 South Asian Indians, the variant was associated with lower beta-cell function and higher stimulated glucose (Beta log HOMAB =-0.14, P=5x10-3). Trans-ancestry meta-analysed effect of the variant in 179,668 individuals was 4.32 mmol/mol (95%CI:2.60,6.04, P=8x10-7) per allele. In 477 individuals with young onset diabetes with non-obese BMI, the per allele effect was 6.41 mmol/mol (95%CI:3.04, 9.79, P =2x10-4). Variant carriers showed impaired response to sulphonylureas. Conclusion XBP1 expression is a novel target for T2DM with particular value for individuals of under-researched ancestries who have greater risk of young, non-obese onset diabetes. The effect of XBP1 eQTL variant was found to be comparable with or greater that the effect of novel glucose-lowering therapies.

Importance Diabetes mellitus (DM) is widespread and treatable. Little is known about the diabetes care continuum (diagnosis, treatment, and control) in India, and whether it varies by socio-demographic characteristics and vary at the national, state, and district levels. Objective To estimate the diabetes care continuum among individuals aged 18-98 years old at national, state, and district-levels, and by socio-demographic group. Design Cross-sectional, nationally representative survey Setting 28 states, 8 union territories, and 707 districts of India Participants 1,895,287 approached in the Fifth National Family Health Survey (NFHS-5), 2019-2021 Exposures District, state, urban vs rural residence, age (18-39, 40-64, >=65 years), sex, household wealth quintile Main Outcomes and Measures Diabetes was defined by self-report or high capillary blood glucose (>=126mg/dL [fasting] or >=220mg/dL [non-fasting]). Of those with diabetes, we estimated proportions that were diagnosed (self-reported). Among those diagnosed, we reported the proportions treated (self-reported medication use) and proportion controlled (blood glucose <126 [fasting] or & <= 180 mg/dL [non-fasting; corresponding to HbA1c < 8%]). We benchmarked findings against the World Health Organization's Global Diabetes Compact Targets (80% diagnosis, 80% control among those diagnosed). We partitioned the variance in indicators between state and district levels using variance partition coefficients (VPC). Results Among 1,651,176 adult respondents (52.6% female; mean age: 41.6 years) with blood glucose measures, the proportion with diabetes was 6.5% (95%CI: 6.4, 6.6). Among adults with diabetes, 74.2% [73.3, 75.0] were diagnosed. Among those diagnosed, 59.4% [58.1, 60.6] reported taking medication and 65.5% [64.5, 66.4] achieved control. Diagnosis and treatment were higher in urban areas, older age groups, and wealthier households. Of the 707 districts, 34.8% districts met diagnosis target, while 10.7% districts met the control target among those diagnosed. Most of the variability in diabetes diagnosis (VPC:69.9%), treatment (VPC:51.8%), and control (VPC:66.8%) were between districts in a state, and not between states. Conclusions and Relevance Nationally, the diabetes care continuum masks considerable state- and district-level variation, as well as age- and rural-urban disparities. Surveillance at the district-level can guide state health administrators to prioritize interventions and monitor achievement of global targets.

The Indian healthcare scenario presents a spectrum of contrasting landscapes. Socioeconomic factors, problems with medical infrastructure, insufficiency in the supply of medical requisites, economic disparities due to major differences in diabetes care delivery in the government and private sectors and difficulty in accessing quality health care facilities challenges effective diabetes care in India. The article gives insights into the practical solutions and the proposed White paper model to resolve major challenges faced by the Indian diabetes care sector for effective diabetes care delivered at Jothydev's Diabetes Educational Forum Global Diabetes Convention 2019.

As blood-derived miRNAs (c-miRNAs) are modulated by exercise and nutrition, we postulated that they might be used to monitor the effects of a lifestyle intervention (LI) to prevent diabetes development. To challenge this hypothesis, obese Asian Indian pre-diabetic patients were submitted to diet modifications and physical activity for 4 months (LI group) and compared to a control group which was given recommendations only. We have considered 2 periods of time to analyze the data, i.e.; a first one to study the response to the intervention (4 months), and a second one post-intervention (8 months). At basal, 4 months and 8 months post-intervention the levels of 17 c-miRNAs were quantified, selected either for their relevance to the pathology or because they are known to be modulated by physical activity or diet. Their variations were correlated with variations of 25 metabolic and anthropometric parameters and cytokines. As expected, fasting-glycaemia, insulin-sensitivity, levels of exercise- and obesity-induced cytokines were ameliorated after 4 months. In addition, the levels of 4 miRNAs (i.e.; miR-128-3p, miR-374a-5p, miR-221-3p, and miR-133a-3p) were changed only in the LI group and were correlated with metabolic improvement (insulin sensitivity, cytokine levels, waist circumference and systolic blood pressure). However, 8 months post-intervention almost all ameliorated metabolic parameters declined indicating that the volunteers did not continue the protocol on their own. Surprisingly, the LI positive effects on c-miRNA levels were still detected, and were even more pronounced 8 months post-intervention. In parallel, MCP-1, involved in tissue infiltration by immune cells, and Il-6, adiponectin and irisin, which have anti-inflammatory effects, continued to be significantly and positively modified, 8 months post-intervention. These data demonstrated for the first time, that c-miRNA correlations with metabolic parameters and insulin sensitivity are in fact only indirect and likely associated with the level systemic inflammation. More generally speaking, this important result explains the high variability between the previous studies designed to identify specific c-miRNAs associated with the severity of insulin-resistance. The results of all these studies should take into account the level of inflammation of the patients. In addition, this finding could also explain why, whatever the pathology considered (i.e.; cancers, diabetes, neurodegenerative disorders, inflammatory diseases) the same subset of miRNAs is always found altered in the blood of patients vs healthy subjects, as these pathologies are all associated with the development of inflammation.

This study aims to provide evidence on how the COVID-19 pandemic has impacted chronic disease care in diverse settings across Asia. Cross-sectional surveys were conducted to assess the health, social, and economic consequences of the pandemic in India, China, Hong Kong, Korea, and Vietnam using standardized questionnaires. Overall, 5672 participants with chronic conditions were recruited from 5 countries. The mean age of the participants ranged from 55.9 to 69.3 years. A worsened economic status during the COVID-19 pandemic was reported by 19% to 59% of the study participants. Increased difficulty in accessing care was reported by 8% to 24% of participants, except Vietnam: 1.6%. The worsening of diabetes symptoms was reported by 5.6% to 14.6% of participants, except Vietnam: 3%. In multivariable regression analyses, increasing age, female participants, and worsened economic status were suggestive of increased difficulty in access to care, but these associations mostly did not reach statistical significance. In India and China, rural residence, worsened economic status and self-reported hypertension were statistically significantly associated with increased difficulty in access to care or worsening of diabetes symptoms. These findings suggest that the pandemic disproportionately affected marginalized and rural populations in Asia, negatively affecting population health beyond those directly suffering from COVID-19.

Background South Asians have higher risk of type 2 diabetes compared to white Europeans and a younger age of onset. Reasons for the younger age of onset in relation to beta-cell function and insulin sensitivity are under-explored. Methods Two cohorts of Asian Indians, ICMR-INDIAB (Indian Council of Medical Research-INdia DIABetes Study) and DMDSC (Dr. Mohans Diabetes Specialties Centre) and one of white Europeans, ESDC (East Scotland Diabetes Cohort) were used. We examined the comparative prevalence of healthy, overweight, and obese BMI in young onset diabetes. We explored the role of clinically measured beta-cell function in diabetes onset in Asian Indians. Finally, the comparative distribution of a partitioned polygenic score (pPS) for risk of diabetes due to poor beta cell function was examined. Results Prevalence of young onset with normal BMI was 9.3% amongst white Europeans and 24%-39% amongst Asian Indians. In young diagnosed Asian Indians, after adjustment for family history of T2DM, sex, insulin sensitivity and HDL-c, stimulated C-peptide was 492pmol/mL (IQR: 353,616,P<0.0001) lower in lean compared to obese individuals. Asian Indians have lower genetically determined beta-cell function than white Europeans(P <0.0001). The pPS was associated with age of diagnosis in Asian Indians but not in white Europeans. The pPS explained 2% of variation in clinically measured beta cell function and 1.2%, 0.97%, and 0.36% of variance in age of diabetes amongst Asian Indians with normal, overweight, and obese BMI respectively. Conclusions Asian Indians have over two times the prevalence of lean BMI in young onset diabetes compared to white Europeans. This phenotype of lean, young onset diabetes appears driven in part by lower beta cell function. We demonstrate that Asian Indians with diabetes also have lower genetically determined beta cell function.