The Expression and Function of Glucose-Dependent Insulinotropic Polypeptide in the Embryonic Mouse Pancreas

Abstract

OBJECTIVE-Glucose-dependent insulinotropic polypeptide (GIP) is a member of a structurally related group of hormones that also includes glucagon, glucagon-like peptides, and secretin. GIP is an incretin, known to modulate glucose-induced insulin secretion. Recent studies have shown that glucagon is necessary for early insulin-positive differentiation, and a similar role for incretins in regulating embryonic insulin-positive differentiation seems probable. Here we studied the role of GIP signaling in insulin-positive differentiation in the embryonic mouse pancreas.RESEARCH DESIGN AND METHODS-The ontogeny of the GIP ligand and GIP receptor in the embryonic pancreas was investigated by immunohistochemistry and RT-PCR. GIP signaling was inhibited in cultured embryonic pancreata using morpholinering antisense against GIP ligand and receptor, or small interfering RNA (siRNA) for GIP ligand and receptor. Markers of endocrine cells and their progenitors were studied by immunohistochemistry and RT-PCR.RESULTS-GIP and GIP receptor mRNA were both detected in the embryonic pancreas by embryonic day 9.5 and then persisted throughout gestation. GIP was generally coexpressed with glucagon by immunostaining. The GIP receptor was typically coexpressed with insulin. Morpholine-ring antisense or siRNA against either GIP ligand or GIP receptor both inhibited the differentiation of insulin-positive cells. Inhibition of GIP or its receptor also led to a decrease in the number of Pdx-1-positive and sox9-positive cells in the cultured embryonic pancreas. The number of Pax6-and Nkx2.2-positive cells, representative of developing pancreatic endocrine cells and b-cells, respectively, was also decreased.CONCLUSIONS-GIP signaling may play a role in early embryonic pancreas differentiation to form insulin-positive cells or b-cells. Diabetes 60:548-554, 2011 G lucose-dependent insulinotropic polypeptide (GIP) is an incretin. Incretins are hormones released from the gut in response to nutrient ingestion that potentiate glucose-stimulated insulin secretion (1). GIP and glucagon-like peptide 1 (GLP-1) are the two main incretins, identified as mediators of the process by which administration of oral glucose provokes a greater stimulation of insulin release than does an intravenous glucose challenge (2). This connection between gut and the pancreatic islets has been termed the "enteroinsular axis" (3) and appears to be responsible for 50% of postprandial insulin release (2,4). GIP is released from enteroendocrine K-cells in the duodenum, primarily in response to the ingestion of glucose or fat, and potentiates insulin secretion in a glucose-dependent manner (5). A recent study now reports the presence of a bioactive form of GIP in the a-cells that promotes insulin secretion in the adult islet b-cells (6). GLP-1 is a proglucagon-derived peptide hormone that is synthesized and secreted by the enteroendocrine L-cells in the distal ileum and the colon. Preproglucagon can be alternatively processed to produce glicentin or oxyntomodulin and GLP-1 (7).Th...

G Protein-Coupled Receptor Signaling and Sphingosine-1-Phosphate Play a Phylogenetically Conserved Role in Endocrine Pancreas Morphogenesis

“…RGS proteins are exclusive components of G protein-coupled receptor (GPCR) signaling and exert their effects by enhancing the intrinsic GTPase activity of activated GTP-bound G␣ subunits, thereby decreasing the duration of GPCR signaling in diverse processes (47). In the mature pancreas, GPCR signaling plays an important role in the regulation of normal ␤-cell function (43,48), and there is some evidence implicating it in cell fate specification during pancreas development (40,41).…”

Association of genetic variants of the incretin-related genes with quantitative traits and occurrence of type 2 diabetes in Japanese

“…These two patients showed insulin secretory defects, suggesting a relationship of GIPR to insulin secretion and β-cell mass as previously reported [4], [14], but we could not investigate the details due to insufficient clinical information. Further study is required to find low frequency functional variations residing in coding regions.…”

“…They potentiate glucose-induced insulin secretion from pancreatic β-cells as well as play a role in β-cell differentiation and growth [3], [4] through structurally related G protein-coupled receptors, the GIP receptor (GIPR) and GLP-1 receptor (GLP1R); however, they are rapidly degraded by the enzyme dipeptidyl peptidase 4 (DPP4). In addition, GIP promotes lipid accretion and resistin secretion from adipocytes, leading to progressive impairment of insulin action following long-term GIP administration in rodents fed a high-fat diet [5].…”

A synopsis of factors regulating beta cell development and beta cell mass

“…In vitro inhibition of proglucagon signaling in the embryonic pancreas (E11–13) [54], loss of alpha cells in a Pax6 null mutant mice [12]), or absence of glucagon function due to absence of prohormone convertase-2 (PC2/pcsk2) [116] or absence of functional glucagon receptor all led to a lack of formation of early insulin-positive cells [56, 70]. Other related members of the glucagon family of proteins such as GIP [87, 88, 90] and GLP-1 [77] have also been shown to have a similar role in endocrine differentiation.…”

“…The prohormone Pro-GIP is expressed in mouse alpha cells, and PC2 activity yields the bioactive form that has a possible role in islet development and survival [86]. Blocking either GIP receptor or GIP ligand in the embryonic pancreas in vitro using antisense led to inhibition of insulin-positive differentiation, as well as a significant decrease in pdx-1 and sox9-positive cells [87]. Transgenic mice expressing a dominant negative form of GIPr (GIPR dn ) in beta cells developed severe diabetes with significantly higher blood glucose and insulin, and accompanied by a reduction in beta cell mass [88].…”