Effect Of Exenatide Treatment on Liver Fat Content in Patients With Diabetes

Obesity is characterized as generalized expansion of all adipose tissue depots, an increase in tissue lipid content, and dyslipidemia, insulin resistance, and type 2 diabetes. The adipocyte functions not only as a storage depot for fat but as an endocrine organ that releases hormones in response to specific extracellular stimuli or changes in metabolic status. These secreted proteins, carry out a variety of diverse functions, and they have been referred to collectively as adipokines. The adipokines have been postulated to play important roles in the pathogenesis of insulin resistance, hypertension, disorders of coagulation, dyslipidemia, and glucose intolerance, abnormalities associated with insulin resistance syndrome.

These observations are of considerable interest because recent studies have provided evidence that increased hepatic fat content is an important determinant of hepatic insulin resistance in type 2 diabetic patients. Fatty liver is common in type 2 diabetic patients. The mechanisms responsible for the increase in hepatic fat content are unclear. It has been suggested that fatty liver results from accelerated fatty acid mobilization from expanded visceral fat stores and their deposition in the liver as well as decreased hepatic fatty acid oxidation. Weight loss in humans with Non Alcoholic Fatty Liver Disease (NAFLD) is associated with a decrease in hepatic fat content. In addition, thiazolidinediones have been shown to reduce hepatic fat content and improve hepatic insulin sensitivity in patients with type 2 diabetes as well as in non-diabetic patients with NAFLD. The thiazolidinediones initiate their action by binding the peroxisome proliferator activator receptors (PPAR) , which primarily are located on adipocytes. Treatment of insulin-resistant mice as well as type 2 diabetic patients with insulin sensitizing PPAR activators, such as thiazolidinediones, and increases plasma adiponectin levels. Indirect evidence suggests that adiponectin might mediate some of the insulin-sensitizing effects of PPAR agonists.

Exenatide, a Glucagon Like Peptide-1 (GLP-1) receptor agonist approved for treatment of type 2 diabetes, elicited dose-dependent reductions in body weight in association with improved glycemic control in type 2 diabetic patients. In animal models of obesity, exenatide reduces hepatic fat. However, the effect of exenatide treatment in combination with a thiazolidinedione on liver fat content and plasma adipocytokines levels in patients with type 2 diabetes remains to be investigated.