The role of GIP in α-cells and glucagon secretion

Peptides. 2020 Mar:125:170213. doi: 10.1016/j.peptides.2019.170213. Epub 2019 Nov 27.


Glucose-dependent insulinotropic polypeptide (GIP) is an intestinally derived peptide that is secreted in response to feeding. The GIP receptor (GIPR) is expressed in many cell types involved in the regulation of metabolism, including α- and β-cells. Glucagon and insulin exert tremendous control over glucose metabolism. Thus, GIP action in islets strongly dictates metabolic control in the postprandial state. Loss of GIPR activity in β-cells is a characteristic of type 2 diabetes (T2D) which associates with reduced postprandial insulin secretion and hyperglycemia. Less is known about GIPR activity in α-cells or the control of glucagon secretion. GIP stimulates glucagon secretion in a glucose-dependent manner in healthy people, with enhanced activity at lower glycemia. However, GIP stimulates glucagon secretion even at hyperglycemia in people with T2D, suggesting that inappropriate GIPR activity in α-cells contributes to the pathogenesis of T2D. Here, we review the literature describing GIP action and GIPR activity in the α-cell, detailing the basic science that has shaped the view of how GIP regulates glucagon secretion. We also contrast the effects of GIP on glucagon secretion in healthy and T2D people. Finally, we contextualize these observations in light of recent work that redefines the role of glucagon in glucose homeostasis, suggesting that hyperglucagonemia per se does not drive hyperglycemia. As new medications for T2D that incorporate GIPR activity are being developed, it is clear that a better understanding of GIPR activity beyond the β-cell is necessary. This work highlights the importance of focusing on the GIPR in α-cells.

Keywords: Alpha cell; Diabetes; Glucose-dependent insulinotropic polypeptide; Incretin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Gastric Inhibitory Polypeptide / pharmacology*
  • Gastrointestinal Agents / pharmacology*
  • Glucagon / metabolism*
  • Glucagon-Secreting Cells / drug effects*
  • Glucagon-Secreting Cells / metabolism
  • Humans
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Receptors, Gastrointestinal Hormone / metabolism


  • Gastrointestinal Agents
  • Receptors, Gastrointestinal Hormone
  • Gastric Inhibitory Polypeptide
  • Glucagon
  • gastric inhibitory polypeptide receptor