An Atypical Form of Diabetes Among Low Body Mass Index Individuals in India

Background: Diabetes among low BMI individuals has been recognized for over 60 years as an entity that is prevalent in low- and middle-income countries (LMICs), and formally classified as Malnutrition-Related Diabetes Mellitus by the World Health Organization (WHO) in 1985. However, the WHO withdrew this category in 1999, citing a lack of supportive evidence. Definitive metabolic characterization of these individuals is therefore essential to establish that this is a distinct form of diabetes.  Methods: State-of-the-art, dynamic metabolic studies were used to characterize a group of underweight (BMI 18.3±0.2 kg/m2) Southern Indian individuals with diabetes (“Low BMI Diabetes”; LD) in whom all currently known forms of diabetes were excluded by careful immunogenetic analysis. They were compared with four demographically-matched groups: type 1 diabetes (T1D), type 2 diabetes (T2D), and two groups of non-diabetic subjects who were BMI-matched to LD and T2D. To overcome ‘glucose toxicity‘, all subjects with diabetes underwent correction of hyperglycemia. Insulin secretion was assessed by C-peptide deconvolution, following a mixed-meal tolerance test. Hepatic and peripheral insulin sensitivity were analyzed using tracer-based stepped hyperinsulinemic-euglycemic pancreatic clamp studies. Body composition was measured by Dual Energy Absorptiometry (DEXA) and hepatic and myocellular lipid contents were assessed by  1 H-nuclear-magnetic-resonance-spectroscopy.  Findings: Metabolic profiles of LD subjects were distinct from T1D and T2D. Insulin secretion was substantially lower in LD than in T2D, yet higher than in T1D. Although insulin sensitivity varied among LD subjects, they were more insulin sensitive than T2D subjects. Their peripheral insulin sensitivity did not differ from T1D subjects. Endogenous glucose production, a marker of hepatic insulin resistance, was similar in LD compared to T1D subjects, yet lower than in T2D. LD subjects also showed heterogeneity of visceral adipose tissue (VAT) and hepatocellular fat, with VAT averaging higher than T1D subjects, while both were significantly lower than T2D subjects. Additionally, compared to lean-nondiabetic subjects, LD subjects had lower insulin secretion, similar peripheral and hepatic insulin sensitivity, and higher VAT and hepatocellular fat. Interpretation: These studies are the first to demonstrate that low BMI individuals with diabetes in LMICs have a unique metabolic profile. Following correction of glucose toxicity, these individuals are characterized by markedly impaired insulin secretion, variable peripheral insulin sensitivity, and heterogeneity in visceral and hepatocellular triglyceride levels. These findings demonstrate that diabetes among low BMI individuals in LMICs is a distinct entity that warrants further investigation. Funding Information: This study was supported by the Global Diabetes Institute of the Albert Einstein College of Medicine. Declaration of Interests: None declared. Ethics Approval Statement: These comprehensive metabolic studies were performed at the Department of Endocrinology, Christian Medical College (CMC) Vellore, India, in collaboration with the Global Diabetes Institute, Albert Einstein College of Medicine, New York, USA. Approval was obtained from the Institutional Review Boards of both institutions. The objectives of the study were explained to all participants and informed consent was obtained. The study protocol was conducted in accordance to the declaration of Helsinki.