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.

Keywords: Beta cell function; Epidemiology; Genetics of type 2 diabetes; South Asian diabetes; Young-onset diabetes.

Fig. 1

Bar graphs for Asian Indians (blue, ICMR-INDIAB cohort; red, DMDSC cohort) and white Europeans (grey, ESDC cohort) with early-onset diabetes by proportion belonging to each BMI category. The normal BMI for Asian Indians was <23 kg/m²; overweight was defined as BMI 23–25 kg/m², obese was BMI >25 kg/m². The normal BMI for the white European population was <25 kg/m²; overweight was defined as BMI 25–30 kg/m², obese was BMI >30 kg/m² [16]. Early onset for both ethnicities was defined as those diagnosed at 40 years or younger (<40 years). Further data on cohorts are available in ESM Fig. 1 and ESM Table 1

Fig. 2

Boxplots demonstrating lower fasted C-peptide levels (a) and stimulated C-peptide levels (b) by BMI category. Data shown are from the DMDSC cohort of Asian Indians with type 2 diabetes. The normal BMI for Asian Indians was <23 kg/m²; overweight was defined as BMI 23–25 kg/m², obese was BMI >25 kg/m². Early onset is defined as those diagnosed at 40 years or younger (< 40 years). Light grey, male participants; dark grey, female participants. Those with normal BMI compared with those classified as overweight and obese had lower fasted and stimulated C-peptide levels and also lower beta cell function, with a compensatory increase in insulin sensitivity. When adjusted for insulin sensitivity, the association between stimulated C-peptide levels and age at diagnosis remained significant (p<0.0001)

Fig. 3

(a) Cumulative distribution of risk alleles for beta cell function pPS in all populations. The closed shapes are white Europeans and open shapes are South Asians. Dark pink open squares are Asian Indians from INSPIRED DMDSC cohort; light pink open circles are South Asians from UK Biobank; blue closed circles are white Europeans from INSPIRED ESDC, grey closed squares are white Europeans from UK Biobank. The difference in distribution of risk alleles (unweighted pPS) was significantly different between ethnicities in both study cohorts (Wilcoxon–Mann–Whitney p<0.0001). (b) Comparative histogram showing differences in the distribution of pPS weighted for HOMA-B in INSPIRED cohorts. Blue, white Europeans from INSPIRED ESDC; pink, Asian Indians from the INSPIRED DMDSC cohort. The difference in distribution was significantly different between ethnicities (Wilcoxon–Mann–Whitney p<0.0001)