Liver and Fat in Type 2 Diabetes: New Insights and Clinical Relevance

Abstract

Among various organs such as the pancreas, kidney, liver, skeletal muscle, and adipose tissue responsible for control of blood glucose levels, the liver is emerging as one of the principal organs involved in insulin resistance associated with type 2 diabetes mellitus. The liver is involved both short- as well as long-term maintenance of glucose concentrations in the blood. In type 2 diabetes, impaired insulin-mediated suppression of glucose production and diminished glucose uptake ultimately causes an increase in postabsorptive glucose production. Type 2 diabetes associated with liver dysfunction and the vicious circle between liver, adipose tissue, and pancreas leads to various other diseases including nonalcoholic fatty liver disease, cardiovascular complications, and cancer. Despite current advances in pharmacotherapy for diabetes, attaining optimal glycemic control and preventing micro- and macrovascular diabetic complications has remained intangible and daunting. Novel therapeutic targets and their modulators, which include protein tyrosine phosphatase 1B inhibitors, glycogen phosphorylase inhibitors, glucokinase activators, diacylglycerol acyltransferase inhibitors, acetyl-CoA carboxylases inhibitors, and sirtuin activators, show promising results in preclinical and clinical studies. Adding new options with new mechanisms of action to the treatment armamentarium may eventually help to improve outcomes and reduce the burden of type 2 diabetes, which is only possible if we explore and understand the involvement of liver and fats in the pathogenesis of type 2 diabetes.