Ectopic Expression of GIP in Pancreatic β-Cells Maintains Enhanced Insulin Secretion in Mice With Complete Absence of Proglucagon-Derived Peptides

Abstract

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 (Gcggfp/gfp). The Gcggfp/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 Gcggfp/gfp mice, and immunohistochemistry localized GIP to pancreatic β-cells of Gcggfp/gfp mice. Furthermore, secretion of GIP in response to glucose was detected in isolated islets of Gcggfp/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 Gcggfp/gfp mice. These results indicate that ectopic GIP expression in β-cells maintains insulin secretion in the absence of proglucagon-derived peptides (PGDPs), revealing a novel compensatory mechanism for sustaining incretin hormone action in islets.

Streptozotocin-induced diabetic state triggers glucose-dependent insulinotropic polypeptide (GIP) expression in the rat liver

“…liferation of β cells (Kim et al, 2005). Expression of GIP in pancreatic β cells has been reported by Fukami et al (2013), but the effect of hepatic GIP protein dynamics in diabetes was unclear. In this study, it should be considered that insulin concentration and the condition of pancreatic β cells after STZ treatment might affect the landscape of GIP-diabetes dynamics.…”

Physiological and Pathophysiological Control of Glucagon Secretion by Pancreatic α-Cells

“…A vast majority of these studies concluded that anti-glucagon strategies improve glucose tolerance and attributed the improvement to a decreased glucagon action. More recent studies using glucagon receptor or glucagon knockout mice showed that other mechanisms might also contribute to the improved glucose tolerance such as a compensatory action of incretins and particularly GLP-1, the levels of which dramatically increased when glucagon action is disrupted (Hayashi 2011;Hayashi et al 2009;Ali et al 2011;Gu et al 2010;Sorensen et al 2006;Fukami et al 2013). Interestingly, metformin, a first-line anti-diabetic agent, has been shown to improve glucose tolerance by suppressing hepatic glucagon signaling via a decreased production of cAMP (Miller et al 2013).…”

Aristaless-Related Homeobox Plays a Key Role in Hyperplasia of the Pancreas Islet α–Like Cells in Mice Deficient in Proglucagon-Derived Peptides

“…The number of islets and the area they encompass are significantly increased in the Gcg gfp/gfp mice [3], [15]. To address whether functionally defective mutation of ARX influence islet number and area, we performed a histological analysis of the pancreas of Gcg/Arx double mutant mice at 2 weeks of age.…”

“…The islet area was determined using slight modifications of the previously described method [13], [14], [15]. In brief, the complete pancreas in the paraffin block was cut into 6 µm sections.…”