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


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 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.


CONCLUSIONS
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.
Fujita
Yukihiro
Y
Laboratory of Molecular and Cellular Medicine, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Wideman
Rhonda D
RD
Asadi
Ali
A
Yang
Gary K
GK
Baker
Robert
R
Webber
Travis
T
Zhang
Tianjiao
T
Wang
Rennian
R
Ao
Ziliang
Z
Warnock
Garth L
GL
Kwok
Yin Nam
YN
Kieffer
Timothy J
TJ
D000818:Animals; D017821:Boidae; D002460:Cell Line; D004386:Duodenum / Q000378:metabolism; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000235:genetics / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000196:embryology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000378:metabolism; D052336:Proglucagon / Q000378:metabolism; D045706:Proprotein Convertase 2 / Q000172:deficiency / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D046509:Tissue Culture Techniques; D014162:Transfection
D007328:Insulin; D010446:Peptide Fragments; D012333:RNA, Messenger; D011964:Receptors, Gastrointestinal Hormone; C101760:gastric inhibitory polypeptide (1-42); D052336:Proglucagon; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; C041086:gastric inhibitory polypeptide receptor; C473668:Pcsk2 protein, mouse; D045706:Proprotein Convertase 2; D005947:Glucose