Effects of G6pc2 deletion on body weight and cholesterol in mice

Abstract

Genome wide association study (GWAS) data have linked the G6PC2 gene to variations in fasting blood glucose (FBG). G6PC2 encodes an islet-specific glucose-6-phosphatase catalytic subunit that forms a substrate cycle with the beta cell glucose sensor glucokinase. This cycle modulates the glucose sensitivity of insulin secretion and hence FBG. GWAS data have not linked G6PC2 to variations in body weight but we previously reported that female C57BL/6J G6pc2 knockout (KO) mice were lighter than wild-type littermates on both a chow and high fat diet. The purpose of this study was to compare the effects of G6pc2 deletion on FBG and body weight in both chow fed and high fat fed mice on two other genetic backgrounds. FBG was reduced in G6pc2 KO mice largely independently of gender, genetic background or diet. In contrast, the effect of G6pc2 deletion on body weight was markedly influenced by these variables. Deletion of G6pc2 conferred a marked protection against diet-induced obesity in male mixed genetic background mice whereas in 129SvEv mice deletion of G6pc2 had no effect on body weight. G6pc2 deletion also reduced plasma cholesterol levels in a manner dependent on gender, genetic background and diet. An association between G6PC2 and plasma cholesterol was also observed in humans through electronic health record-derived phenotype analyses. These observations suggest that the action of G6PC2 on FBG is largely independent of the influences of environment, modifier genes or epigenetic events whereas the action of G6PC2 on body weight and cholesterol are influenced by unknown variables.

G6PC2 confers protection against hypoglycemia upon ketogenic diet feeding and prolonged fasting

“…Plasma cholesterol ( Figure 4 B), FPI ( Figure 4 C) and FBG ( Figure 4 D) were all significantly elevated following high fat diet feeding. The elevation in plasma cholesterol was greater in WT than KO mice after 84 days on the diet ( Figure 4 B), as previously reported [ 23 ]. The elevation in FBG in WT and KO mice was apparent after 28 days of high fat diet feeding and the significant difference in FBG between WT and G6pc2 KO mice remained after 84 days ( Figure 4 D).…”

G6PC2 controls glucagon secretion by defining the setpoint for glucose in pancreatic α-cells

“…Animal studies investigating G6PC2 function in vivo and ex vivo have demonstrated its role in regulating fasting blood glucose and glucose stimulated insulin secretion (GSIS). Thus, germline G6pc2 null mice and mice with β-cell-specific ablation of G6pc2 display significantly reduced fasting blood glucose levels, in support of the notion that G6PC2 encodes the effector transcript identified by the aforementioned GWAS studies (12,13,(20)(21)(22). Moreover, pancreatic islets from G6pc2 null mice exhibit higher insulin secretion at submaximal glucose concentrations, consistent with a leftward shift of the dose response curve for GSIS (13).…”

Nonsynonymous single-nucleotide polymorphisms in the G6PC2 gene affect protein expression, enzyme activity, and fasting blood glucose

“…Instead, we think the explanation for the lack of an association lies in the fact that G6PC2 regulates the glucose sensitivity of GSIS. This creates a situation in which reduced G6PC2 protein expression lowers FBG without affecting fasting plasma insulin ( 8 , 9 , 11 , 12 ). Because this reduced FBG would be associated with unchanged glycolytic flux, we previously speculated ( 9 ) that it would therefore also be associated with no change in generation of damaging reactive oxygen species (ROS) that appear sufficient to drive beta cell failure ( 46 , 47 ), explaining the lack of association with T2D risk.…”

“…Key evidence in support of this model are the observations that, in isolated G6pc2 knockout (KO) islets, glucose-6-phosphatase activity ( 8 ) and glucose cycling ( 10 ) are both reduced, whereas glycolysis is elevated ( 9 ). Deletion of G6pc2 results in a leftward shift in the dose–response curve for GSIS ( 8 ) such that under fasting conditions, insulin levels are the same in wild-type (WT) and G6pc2 KO mice, but FBG is reduced in KO mice ( 8 , 9 , 11 , 12 ). These observations are consistent with genome-wide association studies (GWAS) and molecular studies that have linked the rs560887 “A” allele to reduced G6PC2 expression and reduced FBG ( 13 , 14 , 15 , 16 ).…”