Gcg-deficient mice exhibited improved glucose tolerance and enhanced insulin secretion.
Glucose homeostasis and β-cell function were assessed in Gcg-deficient mice homozygous for a Gcg-GFP knock-in allele.
Gcg(gfp/gfp) mice showed improved responses in oral and intraperitoneal glucose tolerance tests.
Enhanced secretion of glucose-dependent insulinotropic polypeptide (GIP) was observed in response to glucose loads.
Immunohistochemistry localized GIP to pancreatic β-cells in Gcg(gfp/gfp) mice.
Ectopic GIP expression in β-cells may compensate for the absence of to maintain insulin secretion.
Simplified
Glucagon and glucagon-like peptide-1 (GLP-1) are produced in pancreatic α-cells and enteroendocrine L-cells, respectively, in a tissue-specific manner from the same precursor, proglucagon, that is encoded by glucagon gene (Gcg), and play critical roles in glucose homeostasis. Here, we studied glucose homeostasis and β-cell function of Gcg-deficient mice that are homozygous for a Gcg-GFP knock-in allele (Gcg(gfp/gfp)). The Gcg(gfp/gfp) mice displayed improved glucose tolerance and enhanced insulin secretion, as assessed by both oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT). Responses of glucose-dependent insulinotropic polypeptide (GIP) to both oral and intraperitoneal glucose loads were unexpectedly enhanced in Gcg(gfp/gfp) mice, and immunohistochemistry localized GIP to pancreatic β-cells of Gcg(gfp/gfp) mice. Furthermore, secretion of GIP in response to glucose was detected in isolated islets of Gcg(gfp/gfp) mice. Blockade of GIP action in vitro and in vivo by cAMP antagonism and genetic deletion of the GIP receptor, respectively, almost completely abrogated enhanced insulin secretion in Gcg(gfp/gfp) mice. These results indicate that ectopic GIP expression in β-cells maintains insulin secretion in the absence of (PGDPs), revealing a novel compensatory mechanism for sustaining incretin hormone action in islets.
Key numbers
2.8 to 16.7 mmol/L
Increased Insulin Secretion
Insulin secretion from islets was significantly higher in Gcg(gfp/gfp) mice.
5–6 mice per group
Improved Glucose Tolerance
Blood glucose levels during the OGTT in control and Gcg(gfp/gfp) mice.
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