Glucose-dependent insulinotropic polypeptide is expressed in pancreatic islet alpha-cells and promotes insulin secretion

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 138; no. 5; p. 1966
• Main Authors: Fujita, Yukihiro, Wideman, Rhonda D, Asadi, Ali, Yang, Gary K, Baker, Robert, Webber, Travis, Zhang, Tianjiao, Wang, Rennian, Ao, Ziliang, Warnock, Garth L, Kwok, Yin Nam, Kieffer, Timothy J
• Format: Journal Article
• Language: English
• Published: United States 01.05.2010
• Subjects: Animals; Boidae; Cell Line; Duodenum - metabolism; Female; Gastric Inhibitory Polypeptide - genetics; Gastric Inhibitory Polypeptide - metabolism; Glucagon-Like Peptide 1 - metabolism; Glucagon-Secreting Cells - metabolism; Glucose - metabolism; Humans; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - embryology; Islets of Langerhans - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptide Fragments - metabolism; Proglucagon - metabolism; Proprotein Convertase 2 - deficiency; Proprotein Convertase 2 - genetics; Rats; Rats, Wistar; Receptors, Gastrointestinal Hormone - genetics; Receptors, Gastrointestinal Hormone - metabolism; RNA, Messenger - metabolism; Time Factors; Tissue Culture Techniques; Transfection
• ISSN: 1528-0012
• DOI: 10.1053/j.gastro.2010.01.049

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 alpha-cells. 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. GIP messenger RNA was present in mouse islets; GIP protein localized to islet alpha-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, GIP(1-42) and amidated GIP(1-30) had equipotent insulinotropic actions. Finally, immunoneutralization of GIP secreted by isolated islets decreased glucose-stimulated insulin secretion. GIP is expressed in and secreted from pancreatic islets; in alpha-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.