Glucose-Dependent Insulinotropic Polypeptide Is Expressed in Pancreatic Islet α-Cells and Promotes Insulin Secretion
Background & Aims
Glucose-dependent insulinotropic polypeptide (GIP) and the proglucagon product glucagon-like peptide-1 (GLP-1) are gastrointestinal hormones that are released in response to nutrient intake and promote insulin secretion. Interestingly, a subset of enteroendocrine cells express both GIP and GLP-1. We sought to determine whether GIP also might be co-expressed with proglucagon in pancreatic α-cells.
Methods
We assessed GIP expression via reverse-transcription polymerase chain reaction, in situ hybridization, and immunohistochemistry. We developed a novel bioassay to measure GIP release from isolated islets, compared the biological activities of full-length and truncated GIP, and assessed the impact of immunoneutralization of islet GIP on glucose-stimulated insulin secretion in isolated islets.
Results
GIP messenger RNA was present in mouse islets; GIP protein localized to islet α-cells of mouse, human, and snake pancreas, based on immunohistochemical analyses. However, using a C-terminal GIP antibody, immunoreactivity was detected in islets from prohormone convertase (PC) 2 knockout but not wild-type mice. Bioactive GIP was secreted from mouse and human islets after arginine stimulation. In the perfused mouse pancreas, GIP1–42 and amidated GIP1–30 had equipotent insulinotropic actions. Finally, immunoneutralization of GIP secreted by isolated islets decreased glucose-stimulated insulin secretion.
Conclusions
GIP is expressed in and secreted from pancreatic islets; in α-cells, PC2 processes proGIP to yield a truncated but bioactive form of GIP that differs from the PC1/3-derived form from K-cells. Islet-derived GIP promotes islet glucose competence and also could support islet development and/or survival.
Keywords: Glucose-Dependent Insulinotropic Polypeptide, α–Cell, Islet, Insulin Secretion, GIP
Abbreviations used in this paper: Ab, antibody, GIP, glucose-dependent insulinotropic polypeptide, GIPR, glucose-dependent insulinotropic polypeptide receptor, GLP, glucagon-like peptide, IE, islet equivalents, IHC, immunohistochemistry, KRBB, Krebs–Ringer bicarbonate buffer, PC, prohormone convertase, PCR, polymerase chain reaction
To access this article, please choose from the options below
Conflicts of interest The authors disclose no conflicts.
Funding Timothy Kieffer is a Michael Smith Foundation for Health Research senior scholar and received grant funding from the Juvenile Diabetes Research Foundation and the Michael Smith Foundation for Health Research through the Centre for Human Islet Transplant and Beta-Cell Regeneration; Yukihiro Fujita received scholarship support from the Canadian Diabetes Association and the Stem Cell Network; Rhonda Wideman received scholarship support from the Michael Smith Foundation for Health Research and the Natural Sciences and Engineering Research Council; and Gary Yang received scholarship support from Natural Sciences and Engineering Research Council.
PII: S0016-5085(10)00158-7
doi:10.1053/j.gastro.2010.01.049
© 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
