Elevated fasting blood glucose (FBG) is associated with increased risk for the development of type 2 diabetes and cardiovascular-associated mortality. Genome-wide association studies (GWAS) have linked polymorphisms in G6PC2 with variations in FBG and body fat, although not insulin sensitivity or glucose tolerance. G6PC2 encodes an islet-specific, endoplasmic reticulum-resident glucose-6-phosphatase catalytic subunit. A combination of in situ perfused pancreas, in vitro isolated islet, and in vivo analyses were used to explore the function of G6pc2 in mice. G6pc2 deletion had little effect on insulin sensitivity and glucose tolerance, whereas body fat was reduced in female G6pc2 knockout (KO) mice on both a chow and high-fat diet, observations that are all consistent with human GWAS data. G6pc2 deletion resulted in a leftward shift in the dose-response curve for glucose-stimulated insulin secretion (GSIS). As a consequence, under fasting conditions in which plasma insulin levels were identical, blood glucose levels were reduced in G6pc2 KO mice, again consistent with human GWAS data. Glucose-6-phosphatase activity was reduced, whereas basal cytoplasmic calcium levels were elevated in islets isolated from G6pc2 KO mice. These data suggest that G6pc2 represents a novel, negative regulator of basal GSIS that acts by hydrolyzing glucose-6-phosphate, thereby reducing glycolytic flux.
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http://dx.doi.org/10.2337/db12-1067 | DOI Listing |
Front Immunol
November 2024
Université Paris Cité, Institut National de la Santé et Recherche Médicale (INSERM), Centre National de La Recherche Scientifique (CNRS), Institut Necker Enfants Malades, Paris, France.
Type 1 diabetes results from the destruction of pancreatic beta cells by autoreactive T cells. As an autoantigen with extremely high expression in beta cells, insulin triggers and sustains the autoimmune CD4 and CD8 T cell responses and islet inflammation. We have previously shown that deficiency for insulin-degrading enzyme (IDE), a ubiquitous cytosolic protease with very high affinity for insulin, induces endoplasmic reticulum (ER) stress and proliferation in islet cells and protects non-obese diabetic mice (NOD) from diabetes.
View Article and Find Full Text PDFJ Mol Endocrinol
October 2024
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
G6PC2 encodes a glucose-6-phosphatase catalytic subunit that opposes the action of glucokinase in pancreatic islets, thereby modulating the sensitivity of insulin and glucagon secretion to glucose. In mice, G6pc2 is expressed at ~20-fold higher levels in β-cells than in α-cells, whereas in humans G6PC2 is expressed at only ~5-fold higher levels in β-cells. We therefore hypothesize that G6PC2 likely influences glucagon secretion to a greater degree in humans.
View Article and Find Full Text PDFJ Immunotoxicol
December 2024
Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
Molecular mimicry has been proposed to be a possible mechanism of induction of autoimmunity. In some cases, it is believed that such events could lead to a disease such as Type 1 diabetes (T1D). One of the primary MHC-I epitopes in the non-obese diabetic (NOD) mouse model of T1D has been identified as a peptide from the islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) protein.
View Article and Find Full Text PDFFood Funct
July 2024
College of Food Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China.
In this study, we investigated the effects of glycoprotein (PG)-mediated regulation of on liver glucose metabolism in hyperglycemic mouse models, and sought to establish the underlying mechanism, as determined by the changes in liver gene expression and metabolic profiles. The results showed that 30-300 mg kg PG upregulated the expression of the liver genes , , , , , , and downregulated the expression of , , and , in a concentration-dependent manner. 300 mg kg PG downregulated the concentrations of glucose-related metabolites in the liver, but upregulated lactic acid, 2-aminoacetic acid, and glucose-1-phosphate concentrations.
View Article and Find Full Text PDFMol Med Rep
July 2024
College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju 61186, Republic of Korea.
Although there are several types of radiation exposure, it is debated whether low‑dose‑rate (LDR) irradiation (IR) affects the body. Since the small intestine is a radiation‑sensitive organ, the present study aimed to evaluate how it changes when exposed to LDR IR and identify the genes sensitive to these doses. After undergoing LDR (6.
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