title: Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes.
abstract: We examined the contributions of insulin secretion, glucagon suppression, splanchnic and peripheral glucose metabolism, and delayed gastric emptying to the attenuation of postprandial hyperglycemia during intravenous exenatide administration. Twelve subjects with type 2 diabetes (3 F/9 M, 44 +/- 2 yr, BMI 34 +/- 4 kg/m2, Hb A(1c) 7.5 +/- 1.5%) participated in three meal-tolerance tests performed with double tracer technique (iv [3-3H]glucose and oral [1-14C]glucose): 1) iv saline (CON), 2) iv exenatide (EXE), and 3) iv exenatide plus glucagon (E+G). Acetaminophen was given with the mixed meal (75 g glucose, 25 g fat, 20 g protein) to monitor gastric emptying. Plasma glucose, insulin, glucagon, acetaminophen concentrations and glucose specific activities were measured for 6 h post meal. Post-meal hyperglycemia was markedly reduced (P < 0.01) in EXE (138 +/- 16 mg/dl) and in E+G (165 +/- 12) compared with CON (206 +/- 15). Baseline plasma glucagon ( approximately 90 pg/ml) decreased by approximately 20% to 73 +/- 4 pg/ml in EXE (P < 0.01) and was not different from CON in E+G (81 +/- 2). EGP was suppressed by exenatide [231 +/- 9 to 108 +/- 8 mg/min (54%) vs. 254 +/- 29 to189 +/- 27 mg/min (26%, P < 0.001, EXE vs. CON] and partially reversed by glucagon replacement [247 +/- 15 to 173 +/- 18 mg/min (31%)]. Oral glucose appearance was 39 +/- 4 g in CON vs. 23 +/- 6 g in EXE (P < 0.001) and 15 +/- 5 g in E+G, (P < 0.01 vs. CON). The glucose retained within the splanchnic bed increased from approximately 36g in CON to approximately 52g in EXE and to approximately 60g in E+G (P < 0.001 vs. CON). Acetaminophen((AUC)) was reduced by approximately 80% in EXE vs. CON (P < 0.01). We conclude that exenatide infusion attenuates postprandial hyperglycemia by decreasing EGP (by approximately 50%) and by slowing gastric emptying.
authors.affiliation: Division of Diabetes, Department of Medicine,University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cervera
authors.forename: Estela
authors.initials: E
authors.lastname: Wajcberg
authors.forename: Apiradee
authors.initials: A
authors.lastname: Sriwijitkamol
authors.forename: Marianella
authors.initials: M
authors.lastname: Fernandez
authors.forename: Pengou
authors.initials: P
authors.lastname: Zuo
authors.forename: Curtis
authors.initials: C
authors.lastname: Triplitt
authors.forename: Nicolas
authors.initials: N
authors.lastname: Musi
authors.forename: Ralph A
authors.initials: RA
authors.lastname: DeFronzo
authors.forename: Eugenio
authors.initials: E
authors.lastname: Cersosimo
mesh_terms: D000082:Acetaminophen / Q000097:blood; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D000077270:Exenatide; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D005934:Glucagon / Q000097:blood; D005951:Glucose Tolerance Test; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000627:therapeutic use*; D019518:Postprandial Period / Q000187:drug effects* / Q000502:physiology*; D014280:Triglycerides / Q000097:blood; D014688:Venoms / Q000627:therapeutic use*
chemical_list: D018712:Analgesics, Non-Narcotic; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014280:Triglycerides; D014688:Venoms; D000082:Acetaminophen; D005934:Glucagon; D000077270:Exenatide