Liraglutide Actions on the Liver: Effects on Glucose Phosphorylation

It is known that liraglutide impacts favorably glucose homeostasis in type 2 diabetic patients, but not the exact mechanism of this effect. In particular, liraglutide's acute and chronic effects on the liver are not well understood. The aim of our study is to determine whether liraglutide acutely and/or chronically changes hepatic GCK activity in vivo in type 2 diabetic patients, and to quantify this effect. We hypothesize that liraglutide increases GCK activity and that this results in increased hepatic glucose uptake, contributing to a lowering of glycemia. Our specific aims are: 1. to measure liraglutide's acute effect on GCK activity changes in vivo in type 2 diabetic patients; 2. to assess whether chronic treatment with liraglutide determines a change in liver GCK activity in type 2 diabetic patients, as assessed during an IVGTT. We expect that liraglutide acutely and/or chronically increases GCK activity, thus contributing to higher liver glucose uptake and lower glycemia. Primary endpoints 1. GCK activity (acute effect) during IVGTTs with and without liraglutide administration. GCK activity will be calculated based on lactate and glucose measurements during the IVGTT 2. GCK activity during IVGTTs before and after 6 weeks of liraglutide treatment (IVGTT3). Secondary endpoints 1. SI-IVGTT (insulin sensitivity during an intravenous glucose tolerance test) as quantified by the MINMOD analysis of the IVGTT 2. Acute insulin response to glucose (AIRg) and the disposition index (DI-MINMOD), the ability of beta cell to compensate for changes in insulin sensitivity. This is a study designed to investigate the effect of liraglutide in type 2 diabetes therefore subjects are selected from type 2 diabetes population of the Los Angeles basin area. The study population is represented by type 2 diabetics (age 18-65 y old, T2DM diagnosed by current American Diabetes Association diagnostic criteria ( HbA1c ≥ 6.5 % or fasting plasma glucose ≥ 126 mg/dl or 2h plasma glucose ≥ 200 mg/dL during an OGTT or in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis a random plasma glucose ≥ 200 mg/dl).