Exenatide improves both hepatic and adipose tissue insulin resistance: A dynamic positron emission tomography study

Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1-RAs) act on multiple tissues, in addition to the pancreas. Recent studies suggest that GLP-1-RAs act on liver and adipose tissue to reduce insulin resistance (IR). Thus, we evaluated the acute effects of exenatide (EX) on hepatic (Hep-IR) and adipose (Adipo-IR) insulin resistance and glucose uptake. Fifteen male subjects (age = 56 +/- 8 years; body mass index = 29 +/- 1 kg/m2 ; A1c = 5.7 +/- 0.1%) were studied on two occasions, with a double-blind subcutaneous injection of EX (5 mug) or placebo (PLC) 30 minutes before a 75-g oral glucose tolerance test (OGTT). During OGTT, we measured hepatic (HGU) and adipose tissue (ATGU) glucose uptake with [18 F]2-fluoro-2-deoxy-D-glucose/positron emission tomography, lipolysis (RaGly) with [U-2 H5 ]-glycerol, oral glucose absorption (RaO) with [U-13 C6 ]-glucose, and hepatic glucose production (EGP) with [6,6-2 H2 ]-glucose. Adipo-IR and Hep-IR were calculated as (FFA0-120min ) x (Ins0-120min ) and (EGP0-120min ) x (Ins0-120min ), respectively. EX reduced RaO, resulting in reduced plasma glucose and insulin concentration from 0 to 120 minutes postglucose ingestion. EX decreased Hep-IR (197 +/- 28 to 130 +/- 37; P = 0.02) and increased HGU of orally administered glucose (23 +/- 4 to 232 +/- 89 [mumol/min/L]/[mumol/min/kg]; P = 0.003) despite lower insulin (23 +/- 5 vs. 41 +/- 5 mU/L; P < 0.02). EX enhanced insulin suppression of RaGly by decreasing Adipo-IR (23 +/- 4 to 13 +/- 3; P = 0.009). No significant effect of insulin was observed on ATGU (EX = 1.16 +/- 0.15 vs. PLC = 1.36 +/- 0.13 [mumol/min/L]/[mumol/min/kg]). CONCLUSION: Acute EX administration (1) improves Hep-IR, decreases EGP, and enhances HGU and (2) reduces Adipo-IR, improves the antilipolytic effect of insulin, and reduces plasma free fatty acid levels during OGTT. (Hepatology 2016;64:2028-2037).