G6PC2 Modulates Fasting Blood Glucose In Male Mice in Response to Stress

Abstract

The glucose-6-phosphatase catalytic 2 (G6PC2) gene is expressed specifically in pancreatic islet beta cells. Genome-wide association studies have shown that single nucleotide polymorphisms in the G6PC2 gene are associated with variations in fasting blood glucose (FBG) but not fasting plasma insulin. Molecular analyses examining the functional effects of these single nucleotide polymorphisms demonstrate that elevated G6PC2 expression is associated with elevated FBG. Studies in mice complement these genome-wide association data and show that deletion of the G6pc2 gene lowers FBG without affecting fasting plasma insulin. This suggests that, together with glucokinase, G6PC2 forms a substrate cycle that determines the glucose sensitivity of insulin secretion. Because genome-wide association studies and mouse studies demonstrate that elevated G6PC2 expression raises FBG and because chronically elevated FBG is detrimental to human health, increasing the risk of type 2 diabetes, it is unclear why G6PC2 evolved. We show here that the synthetic glucocorticoid dexamethasone strongly induces human G6PC2 promoter activity and endogenous G6PC2 expression in isolated human islets. Acute treatment with dexamethasone selectively induces endogenous G6pc2 expression in 129SvEv but not C57BL/6J mouse pancreas and isolated islets. The difference is due to a single nucleotide polymorphism in the C57BL/6J G6pc2 promoter that abolishes glucocorticoid receptor binding. In 6-hour fasted, nonstressed 129SvEv mice, deletion of G6pc2 lowers FBG. In response to the stress of repeated physical restraint, which is associated with elevated plasma glucocorticoid levels, G6pc2 gene expression is induced and the difference in FBG between wild-type and knockout mice is enhanced. These data suggest that G6PC2 may have evolved to modulate FBG in response to stress.

Effects of G6pc2 deletion on body weight and cholesterol in mice

“…We have previously shown that male 129SvEv G6pc2 KO mice have reduced FBG but no change in FPI relative to WT littermates (Boortz et al 2016a). When this analysis was repeated using female 129SvEv chow fed mice this same reduction in FBG was observed in G6pc2 KO mice (Fig.…”

“…Despite 13 weeks of high fat feeding a comparison between female (Fig. 1D) and male (Boortz et al 2016a) chow fed with female (Fig. 1F) and male (Fig.…”

“…Previous studies have described the generation of G6pc2 KO mice on a mixed 129/SvEv × C57BL/6J (Wang et al 2007), C57BL/6J (Pound et al 2013) and 129SvEv (Boortz et al 2016a) genetic background. The targeting vector used to generate the KO allele replaced exons 1–3 of the G6pc2 gene with a LacZ/Neo cassette leaving exons 4 and 5 intact (Wang et al 2007).…”

“…Pancreatic gene expression was analyzed as previously described (Boortz et al 2016a). The following mouse primer pairs were used for the analysis of gene expression:…”

“…This results in leftward shift in the dose response curve for glucose-stimulated insulin secretion (GSIS) (Pound et al 2013). Under fasting conditions, where insulin levels are the same in WT and G6pc2 KO mice, this shift results in reduced fasting blood glucose (FBG) in KO mice (Boortz, et al 2016a; Pound et al 2013; Wang, et al 2007). In contrast, under stimulatory conditions using a sub-maximal concentration of glucose this shift results in increased GSIS from G6pc2 KO relative to WT mouse islets (Pound et al 2013).…”