GIP contributes to islet trihormonal abnormalities in type 2 diabetes

J Clin Endocrinol Metab. 2014 Jul;99(7):2477-85. doi: 10.1210/jc.2013-3994. Epub 2014 Apr 8.


Context: Research and clinical treatments on type 2 diabetes mainly focus on insulin deficiency with little attention paid to other islet hormones.

Objective: This study tested the hypothesis that glucose-dependent insulinotropic polypeptide (GIP) is involved in diabetes-associated multiislet hormone dysregulation.

Design: This paper included a case-control study involving 92 community-based volunteers from the Baltimore Longitudinal Study of Aging (BLSA): 23 with type 2 diabetes on glucose-lowering agents, 25 with newly diagnosed drug-naïve type 2 diabetes, 19 with prediabetes, and 25 with normal glucose tolerance; a separate intervention study with 13 non-BLSA volunteers with type 2 diabetes treated with diet alone, metformin, and/or metformin/sulfonylurea combination; a rodent study; and an in vitro cell line study.

Interventions: An oral glucose tolerance test was performed in the BLSA participants. For the intervention study, saline (0.9% NaCl) or synthetic human GIP (20 ng · kg(-1) · min(-1)) was administered to type 2 diabetes subjects for 180 minutes together with a meal, and plasma samples were obtained at predetermined intervals for 360 minutes. A bolus of GIP or placebo was given to C57BL/6 mice.

Main outcome measures: Plasma glucose, insulin, glucagon, pancreatic polypeptide (PP), glucagon-like peptide-1 (GLP-1), and GIP were measured.

Results: After an oral glucose tolerance test, glucose, glucagon, PP, GLP-1, and GIP levels were significantly elevated in type 2 diabetes groups, compared with normal and prediabetes groups. GIP infusion in type 2 diabetes subjects was associated with significantly elevated PP levels compared with placebo. The GIP bolus given to C57BL/6 mice was followed by increased PP levels. GIP receptors were found in both human and mouse PP cells.

Conclusions: Up-regulation of GIP production may play an important role in multihormonal dysregulation in type 2 diabetes, most likely through interaction with GIP receptors on islets.

Trial registration: NCT00233272 NCT00239707.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Case-Control Studies
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetes Mellitus, Type 2 / metabolism
  • Female
  • Gastric Inhibitory Polypeptide / blood
  • Gastric Inhibitory Polypeptide / pharmacology
  • Gastric Inhibitory Polypeptide / physiology*
  • Humans
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism*
  • Longitudinal Studies
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Pancreatic Diseases / etiology*
  • Pancreatic Diseases / metabolism
  • Pancreatic Hormones / metabolism*


  • Pancreatic Hormones
  • Gastric Inhibitory Polypeptide

Associated data