Young-onset diabetes in Asian Indians is associated with lower measured and genetically determined beta cell function

Abstract

Aims/hypothesis South Asians in general, and Asian Indians in particular, have higher risk of type 2 diabetes compared with white Europeans, and a younger age of onset. The reasons for the younger age of onset in relation to obesity, beta cell function and insulin sensitivity are under-explored. Methods Two cohorts of Asian Indians, the ICMR-INDIAB cohort (Indian Council of Medical Research-India Diabetes Study) and the DMDSC cohort (Dr Mohan’s Diabetes Specialties Centre), and one of white Europeans, the ESDC (East Scotland Diabetes Cohort), were used. Using a cross-sectional design, we examined the comparative prevalence of healthy, overweight and obese participants with young-onset diabetes, classified according to their BMI. 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. Replication of the genetic findings was sought using data from the UK Biobank. Results The prevalence of young-onset diabetes with normal BMI was 9.3% amongst white Europeans and 24–39% amongst Asian Indians. In Asian Indians with young-onset diabetes, after adjustment for family history of type 2 diabetes, sex, insulin sensitivity and HDL-cholesterol, stimulated C-peptide was 492 pmol/ml (IQR 353–616, p<0.0001) lower in lean compared with obese individuals. Asian Indians in our study, and South Asians from the UK Biobank, had a higher number of risk alleles than white Europeans. After weighting the pPS for beta cell function, 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 the 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 BMI, or classified as overweight and obese BMI, respectively. Conclusions/interpretation The prevalence of lean BMI in young-onset diabetes is over two times higher in Asian Indians compared with 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. Graphical abstract

Common and distinct genetic architecture of age at diagnosis of diabetes in South Indian and European populations

“…We also found evidence for ethnic-specific signals that were associated with an early age at diagnosis of T2D in Asian Indians that were very rare in the European cohort. Our findings emphasize and support our recently reported finding that Asian Indians have greater genetic beta-cell dysfunction compared to Europeans [26].…”

Dietary weight-management for type 2 diabetes remissions in South Asians: the South Asian diabetes remission randomised trial for proof-of-concept and feasibility (STANDby)

“… 2 The mechanism for their excess risk likely includes greater total fat mass and lower lean mass, leading, in turn, to more rapid ectopic fat gain when weight increases, 3 and potentially lower beta cell reserve. 4 Lack of South Asians in the DiRECT trial, and continuing uncertainty over detailed mechanisms behind excess diabetes risk in Souths Asians, have contributed to reluctance to offer remission by dietary means. Furthermore, recent qualitative research suggested that total dietary replacement (TDR) approach might be less acceptable to South Asians seeking T2D remission, and sub-optimal engagement, and outcomes with weight management among South Asians.…”

RSSDI Clinical Practice Recommendations for the Management of Type 2 Diabetes Mellitus 2022

“…The mechanisms of development of T2DM in young people are similar to those in older patients; however, the speed of onset, severity, and interplay of reduced insulin sensitivity and defective insulin secretion might differ in patients who develop the disease at a younger age 1180 . Studies suggest that loss of β-cell function plays a significant role in the development of T2DM in youth 1181,1182 , and that the decline in β-cell function is accelerated in youngonset T2DM compared to older onset T2DM (20-35% per year compared to 7%) 1183 . It has also been suggested that T2DM in adolescents and children might have a more aggressive course compared with adult later onset T2DM 1180 .…”