Participants

People with T2D (n = 3111) being treated at the Diabetes Unit, KEM Hospital (Pune, India) and associated clinics were included in the WellGen cohort. T2D diagnosis was based on WHO guidelines using the following clinical criteria: age at diagnosis more than 20 years, no history of ketoacidosis, and response to treatment with oral glucose lowering agents.^2,17 People with a clinical diagnosis of type 1 diabetes (T1D) (diagnosis before 20 years of age and on continuous insulin treatment since then, history of ketoacidosis), fibrocalculous pancreatic diabetes (FCPD) or monogenic diabetes were excluded. In absence of GAD autoantibody measurements, we tested for the presence of genetic T1D by applying a T1D genetic risk score previously validated in Indian population.¹⁸

Phenotypic measurements were made as described previously.² Briefly, clinical information including age, sex, age at T2D diagnosis, family history and socioeconomic status was obtained through a standardised questionnaire. Height and weight were measured using standardised methods.^19,20 Fasting plasma glucose and HbA1c were measured using standard methods.^19,20 Fasting C-peptide was measured by ELISA (Diagnostic Biochem Canade, ON, Canada). Fasting glucose and C-peptide measurements were used to calculate Homeostatic Model Assessment 2 estimates of β-cell function (HOMA2-B) and insulin resistance (HOMA2-IR).^21,22 The characteristics of the participants are shown in Table 1.

Clinical characteristic of the WellGen according to sex.

Values are mean (SD).

p-values are calculated using ANOVA (unequal variances) adjusted for age and sex.

NGT: Normal glucose tolerance, PMNS: Pune Maternal Nutrition Study.

For controls, we included normal glucose tolerant (NGT) participants from the Pune Maternal Nutrition Study (PMNS), a birth cohort from the Diabetes Unit, KEM Hospital.²³ Briefly, ∼800 families were serially followed-up for anthropometric and biochemical measurements every six years. The participants were classified as having diabetes or NGT based on American Diabetes Association (ADA) 2014 criteria after an oral glucose tolerance test (OGTT, 75 g anhydrous glucose). In this analysis, we have considered the parents who were NGT at 12-year follow-up as controls (Table 1). WellGen and PMNS participants were from the same geographic area and the same background population. Moreover, all the anthropometric and clinical measurements in WellGen and PMNS were performed in the same department using the same instruments and laboratory assays.

The Ethics Committee of the KEM Hospital Research Centre, Pune approved both the studies, WellGen (KEM/HRC/Dir.off/977) and PMNS (KEMHRC/VSP/Dir.Off/EC/065), and all participants signed a written informed consent.

The ANDIS-MDC cohort has been described previously.⁵ Briefly the ANDIS (All new diabetes in Scania) project (http://andis.ludc.med.lu.se/) is aimed at recruiting all incident cases of diabetes within Scania (Skåne) County in southern Sweden. All healthcare providers in the region were invited. Individuals from ANDIS-MDC (n = 6986) with genome-wide association study (GWAS) data available were included in the current study.¹ For controls, participants from the MDC (Malmö Diet and Cancer) study including individuals from Malmö (the largest city in Scania, Sweden) and born between 1923 and 1950 were selected. Individuals without diabetes (n = 2744) from the MDC cardiovascular arm re-examination cohort (aged 61–85) were used as controls in the genetic analyses.²⁴

The ANDIS and MDC study protocols were approved by the regional ethics review committee in Lund (nos. 584/2006, 2011/354, 2011/367, 2012/676, 2014/198, LU 51-90 and 532/2006). All participants gave informed written consent. Study participants received no compensation.