Exploring the Molecular Basis of Lean Diabetes

Abstract

Diabetes mellitus (DM) has become a global pandemic affecting around 382 million people worldwide. A first phase national study had shown that there could be 62.4 million with diabetes and 77.2 million with pre-diabetes in India. Epidemiological studies have shown that majority of patients with type 2 DM are obese and the incidence of which rises sharply with the rise in body mass index (BMI). However, a sizeable proportion of diabetes patients in India are non-obese or lean. Despite its prevalence in India and many other countries, little is known about the aetiopathogenesis and the molecular basis of this condition.To establish and evaluate novel cost effective genetic testing strategies for MODY, Lipodystrophy/Insulin resistance genes in clinical settings. To study the role of genetic factors associated with lean or non-obese diabetes with a BMI of lt 25 kg/m2. In this study a Polymerase chain reaction (PCR) based enrichment strategy was utilized, since its specificity and uniformity would exceed that of hybrid capture. Till date genetic studies amongst individuals of Asian Indian origin related to MODY have been limited to the screening of HNF1A, HNF4A and GCK genes. We have established a Next Generation Sequencing based cost-effective, scalable, accurate method (2GDMODY protocol) for comprehensive parallelized genetic testing in clinical settings. We have utilized the 2GDMODY protocol to identify the MODY, Lipodystrophy, Insulin resistance causative or associated gene variants in young onset non-obese diabetes. At this point of time, due to a high rate of homopolymer stretches Ion torrent NGS could miss true insertions and deletions (indels) and therefore may require multiplex ligation-dependent probe amplification (MLPA) assay to detect deletions or duplications. However with better sequencing chemistry (Hi-Q), there may be a reduction in the indel errors with an improvement in accuracy even at homopolymer stretches.Hence would include MLPA and Hi-Q sequencing reagents to identify the insertions or deletion