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 [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 ) × (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).