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 μg) 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 [18F]2‐fluoro‐2‐deoxy‐D‐glucose/positron emission tomography, lipolysis (RaGly) with [U‐2H5]‐glycerol, oral glucose absorption (RaO) with [U‐13C6]‐glucose, and hepatic glucose production (EGP) with [6,6‐2H2]‐glucose. Adipo‐IR and Hep‐IR were calculated as (FFA0‐120min) × (Ins0‐120min) and (EGP0‐120min) × (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 [μmol/min/L]/[μmol/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 [μmol/min/L]/[μmol/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).