GIP does not potentiate the antidiabetic effects of GLP-1 in hyperglycemic patients with type 2 diabetes

Diabetes. 2011 Apr;60(4):1270-6. doi: 10.2337/db10-1332. Epub 2011 Feb 17.

Abstract

Objective: The incretin glucagon-like peptide 1 (GLP-1) exerts insulinotropic activity in type 2 diabetic patients, whereas glucose-dependent insulinotropic polypeptide (GIP) no longer does. We studied whether GIP can alter the insulinotropic or glucagonostatic activity of GLP-1 in type 2 diabetic patients.

Research design and methods: Twelve patients with type 2 diabetes (nine men and three women; 61 ± 10 years; BMI 30.0 ± 3.7 kg/m²; HbA(1c) 7.3 ± 1.5%) were studied. In randomized order, intravenous infusions of GLP-1(7-36)-amide (1.2 pmol · kg⁻¹ · min⁻¹), GIP (4 pmol · kg⁻¹ · min⁻¹), GLP-1 plus GIP, and placebo were administered over 360 min after an overnight fast (≥ 1 day wash-out period between experiments). Capillary blood glucose, plasma insulin, C-peptide, glucagon, GIP, GLP-1, and free fatty acids (FFA) were determined.

Results: Exogenous GLP-1 alone reduced glycemia from 10.3 to 5.1 ± 0.2 mmol/L. Insulin secretion was stimulated (insulin, C-peptide, P < 0.0001), and glucagon was suppressed (P = 0.009). With GIP alone, glucose was lowered slightly (P = 0.0021); insulin and C-peptide were stimulated to a lesser degree than with GLP-1 (P < 0.001). Adding GIP to GLP-1 did not further enhance the insulinotropic activity of GLP-1 (insulin, P = 0.90; C-peptide, P = 0.85). Rather, the suppression of glucagon elicited by GLP-1 was antagonized by the addition of GIP (P = 0.008). FFA were suppressed by GLP-1 (P < 0.0001) and hardly affected by GIP (P = 0.07).

Conclusions: GIP is unable to further amplify the insulinotropic and glucose-lowering effects of GLP-1 in type 2 diabetes. Rather, the suppression of glucagon by GLP-1 is antagonized by GIP.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Drug Interactions
  • Female
  • Gastric Inhibitory Polypeptide / therapeutic use*
  • Glucagon-Like Peptide 1 / therapeutic use*
  • Humans
  • Hyperglycemia / drug therapy*
  • Hypoglycemic Agents / therapeutic use*
  • Incretins / therapeutic use*
  • Male
  • Middle Aged

Substances

  • Hypoglycemic Agents
  • Incretins
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1