Chandrashekhar L Athare, Chandrashekhar D Upasani

Abstract

Metabolic syndrome and type 2 diabetes are complex disorders that are associated with obesity, aging, and genetic predisposition. The increasing prevalence of metabolic abnormalities worldwide presents a serious public health problem, with rates of obesity and diabetes reaching unprecedented levels. A common feature of these disorders is the development of insulin resistance, resulting in decreased insulin-stimulated glucose uptake, failure to suppress hepatic glucose production, and accumulation of hepatic lipid. Recent studies in mice have shown that deficiency of the non-receptor protein tyrosine phosphatase, PTP1B, in liver leads to a host of improvements in metabolic parameters, including improved hepatic insulin sensitivity, reduced liver triglycerides, lower serum and hepatic cholesterol levels, and protection against high-fat diet induced endoplasmic reticulum (ER) stress. Based on these promising studies, PTP1B inhibitors may prove to be a valuable therapeutic tool in the fight against metabolic syndrome and its associated comorbidities. In this study, we investigate effect of NCE-9 in diet induced obese (DIO) mice. NCE-9 significantly improved hyperglycemia and insulin resistance in DIO mice when orally administered at a dose of 30 and 100 mg/kg/day for 28 days. Overall, these studies suggest that NCE-9 improves insulin sensitivity and improves glucose tolerance in animal models through inhibition of PTP1B and that it would be a new therapeutic candidate with potential for the treatment of type 2 diabetic patients.