Severe Obesity Associated with Severe Hyperinsulinism and T2D in a Family with Mutation in SH2B1 Gene

Genetic sequencing has become a critical part of the diagnosis of certain forms of familiar or isolated diabetes. Despite great advances in the speed and cost of DNA sequencing, determining the pathogenic variants remains a challenge. MODY is a form of monogenic diabetes caused by mutations occurring in different genes with a slightly different form of diabetes. Genetic testing for MODY has become a routine procedure allowing to set up proper treatment and discriminate from type 2 diabetes (T2D), whose symptoms often overlap. We analysed, in the last 2 years, about 100 Italian families with MODY/T2D diagnosis by high-throughput technology. We identified a novel missense mutation in SH2B1 gene in family with history of severe MODY/T2D. The proposita (16 years-old) presented severe obesity and secondary amenorrhea. The father and the grandfather have a severe obesity and T2D (from 27 and 22 years respectively). BMI was 43.8 Kg/m2. Basal hormonal investigation showed normal thyroid function, adrenal function, but severe hyperinsulinism (fasting insulin 69.5 μU/ml). Diffuse hepatic steatosis as well as a sonographic pattern suggested a polycystic ovary syndrome. The oral glucose tolerance test showed an impaired glucose tolerance with marked insulin resistance (respectively, peak insulin level 564 μU/mL; 120' insulin level 435 μU/mL). As the father, only liraglutide and metformin treatment was associated with significant weight loss (after 3 months BMI was 40.1 Kg/m2). Menstrual cycle normalized after 2 months. SNPs in SH2B1 have been shown to be associated with leptin resistance and obesity as well as chromosomal deletions that eliminate the gene, are also associated with severe obesity and insulin resistance. This approach may help in understanding the molecular aetiology of diabetes and in providing a more personalized treatment for each genetic subtype. Next-generation sequencing technologies are the perfect applications to study of the genetic etiology of complex diseases