title: Exenatide improves both hepatic and adipose tissue insulin resistance: A dynamic positron emission tomography study.
abstract: 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]).
  
  
  
  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).
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, TX.|Institute of Clinical Physiology, Pisa, Italy.
authors.forename: Amalia
authors.initials: A
authors.lastname: Gastaldelli
authors.affiliation: Institute of Clinical Physiology, Pisa, Italy.
authors.forename: Melania
authors.initials: M
authors.lastname: Gaggini
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Daniele
authors.affiliation: Institute of Clinical Physiology, Pisa, Italy.
authors.forename: Demetrio
authors.initials: D
authors.lastname: Ciociaro
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Cersosimo
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Devjit
authors.initials: D
authors.lastname: Tripathy
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Curtis
authors.initials: C
authors.lastname: Triplitt
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Peter
authors.initials: P
authors.lastname: Fox
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Musi
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Ralph
authors.initials: R
authors.lastname: DeFronzo
authors.affiliation: Institute of Clinical Physiology, Pisa, Italy.
authors.forename: Patricia
authors.initials: P
authors.lastname: Iozzo
mesh_terms: D000273:Adipose Tissue / Q000000981:diagnostic imaging* / Q000187:drug effects* / Q000378:metabolism; D004311:Double-Blind Method; D000077270:Exenatide; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance; D008099:Liver / Q000000981:diagnostic imaging* / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000627:therapeutic use*; D049268:Positron-Emission Tomography; D014688:Venoms / Q000627:therapeutic use*
chemical_list: D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D005947:Glucose