Heterogeneity in the aetiology of diabetes mellitus in young adults: A prospective study from north India

Abstract

Background & objectives: In contrast to Caucasians of European origin, the aetiology of diabetes mellitus (DM) in young adults in other ethnic groups, including Indians is likely to be heterogeneous and difficult to determine. This study was undertaken to determine the aetiology of diabetes in young Indian adults using a protocol-based set of simple clinical and investigation tools.

Methods: In this prospective study, 105 Indian young adults with diabetes (age at onset 18-35 yr; duration <2 yr) were studied for a period of 1-3 years. Pancreatic imaging, fasting C-peptide, islet antibodies (against glutamic acid decarboxylase, tyrosine phosphatase and zinc transporter-8) and mitochondrial A3243G mutational analysis were performed in all patients. Four patients were screened for maturity-onset diabetes of the young (MODY) using next-generation sequencing.

Results: Type 1 and type 2 diabetes mellitus (T1DM and T2DM) were equally frequent (40% each), followed by fibrocalculous pancreatic diabetes (FCPD, 15%). Less common aetiologies included MODY (2%), mitochondrial diabetes (1%) and Flatbush diabetes (2%). There was considerable phenotypic overlap between the main aetiological subtypes. Elevated islet antibodies were noted in 62 per cent of T1DM patients [positive predictive value (PPV) 84%; negative predictive value (NPV) 78%] while low plasma C-peptide (<250 pmol/l) was present in 56 per cent of T1DM patients [PPV 96% (after excluding FCPD), NPV 72%]. Using these tests and observing the clinical course over one year, a final diagnosis was made in 103 (99%) patients, while the diagnosis at recruitment changed in 23 per cent of patients.

Interpretation & conclusions: The aetiology of diabetes in young adults was heterogeneous, with T1DM and T2DM being equally common. FCPD was also frequent, warranting its screening in Indian patients. Testing for islet antibodies and C-peptide in this age group had good PPV for diagnosis of T1DM.

Keywords: Aetiological heterogeneity; C-peptide; early-onset diabetes; fibrocalculous pancreatic diabetes; islet antibodies.

Fig. 1

Flow chart demonstrating recruitment of patients. GDM, gestational diabetes mellitus.

Fig. 2

Etiological subtypes of diabetes at recruitment and final follow up. Subtypes were defined using clinical criteria and abdominal imaging at initial visit and after one year of follow up and additional investigations i.e. fasting plasma C-peptide, islet antibodies and genetic testing. T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; FCPD, fibrocalculous pancreatic diabetes; MODY, maturity-onset diabetes of the young.

Fig. 3

Glutamic acid decarboxylase antibody (GADA) titres among different aetiological subtypes of early-onset diabetes mellitus. Cut-off for glutamic acid decarboxylase antibody positivity ≥47 units (shown as horizontal dotted line). Genetic aetiology included two patients with MODY and one with mitochondrial diabetes. Abbreviations are as given in Fig. 2.

Fig. 4

Family pedigree of patients with MODY and mitochondrial diabetes. Family pedigree of patients with MODY (A: HNF1A mutations and B: PDX1 mutation) and mitochondrial diabetes (C). Filled squares and circles, diabetes; open squares and circles, normal glucose tolerance; squares and circles with a question mark, not tested for diabetes. N denotes wild-type allele, and M denotes mutations (A, both p.R263H and p.H577D mutations; B, p.P101L mutation; C, mitochondrial A3243G mutation). Age of patient and age at onset of diabetes in years is written below each symbol. Proband is depicted with an arrow. MODY, maturity-onset diabetes in the young.