G6PC2: A Negative Regulator of Basal Glucose-Stimulated Insulin Secretion

Abstract

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.

Sorcin Links Pancreatic β-Cell Lipotoxicity to ER Ca2+ Stores

“…GSE72719) (Ingenuity Pathway Analysis presented in Supplementary Table 4). Interestingly, G6pc2, one of the most highly expressed genes in β-cells (9), was strongly repressed in islets from SRI-tg10 mice. Subsequent qRT-PCR analysis in isolated islets from SRI-tg10, SRI-tg1, and Sri −/− mice confirmed the inverse relationship between Sri and G6pc2 expression levels (Fig.…”

Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets

“…In contrast, key metabolic genes that are either considered 'disallowed' or contribute to their regulation (Dhawan et al, 2015;MartinezSanchez et al, 2016;Piccand et al, 2014;Pullen and Rutter, 2013) were enriched in immature beta cells ( Figure 3E). Islets were also co-stained for insulin, Ucn3, and 8 G6pc2, which hydrolyzes glucose-6-phosphate (Pound et al, 2013) or the oxidoreductase Ero1lb, which is required for disulfide bond formation in pro-insulin (Zito et al, 2010). Both markers co-labeled Ucn3-positive mature beta cells, and the majority of Ucn3 negative beta cells did not express G6pc2 or Ero1lb ( Figure 3F-I).…”

Genetic and phenotypic correlations between surrogate measures of insulin release obtained from OGTT data

“…This variant has in previous studies been found to be associated with elevated fasting glucose [15] and it likely regulates the expression of G6PC2 encoding the catalytic subunit of glucose-6-phosphatase, a regulator of glycolytic flux in the beta cell. The major allele is proposed to cause a rightward shift of the dose-response curve for the glucosestimulated insulin secretion [16], which explains the association with HOMA-B and insulinogenic index in opposite directions.…”