Pancreatic islet beta cell-specific deletion of G6pc2 reduces fasting blood glucose

Abstract

The G6PC1, G6PC2 and G6PC3 genes encode distinct glucose-6-phosphatase catalytic subunit (G6PC) isoforms. In mice, germline deletion of G6pc2 lowers fasting blood glucose (FBG) without affecting fasting plasma insulin (FPI) while, in isolated islets, glucose-6-phosphatase activity and glucose cycling are abolished and glucose-stimulated insulin secretion (GSIS) is enhanced at submaximal but not high glucose. These observations are all consistent with a model in which G6PC2 regulates the sensitivity of GSIS to glucose by opposing the action of glucokinase. G6PC2 is highly expressed in human and mouse islet beta cells however, various studies have shown trace G6PC2 expression in multiple tissues raising the possibility that G6PC2 also affects FBG through non-islet cell actions. Using real-time PCR we show here that expression of G6pc1 and/or G6pc3 are much greater than G6pc2 in peripheral tissues, whereas G6pc2 expression is much higher than G6pc3 in both pancreas and islets with G6pc1 expression not detected. In adult mice, beta cell-specific deletion of G6pc2 was sufficient to reduce FBG without changing FPI. In addition, electronic health record-derived phenotype analyses showed no association between G6PC2 expression and phenotypes clearly unrelated to islet function in humans. Finally, we show that germline G6pc2 deletion enhances glycolysis in mouse islets and that glucose cycling can also be detected in human islets. These observations are all consistent with a mechanism by which G6PC2 action in islets is sufficient to regulate the sensitivity of GSIS to glucose and hence influence FBG without affecting FPI.

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

“…This same shift in glucose sensitivity results in increased insulin secretion from isolated G6pc2 KO islets in response to sub-maximal glucose [ 7 ]. The same results are observed in both germline [ 7 ] and beta cell-specific [ 10 ] G6pc2 KO mice, consistent with the predominant expression of G6pc2 in beta cells and suggesting that trace G6pc2 expression in peripheral tissues is not biologically important. This model is also consistent with genome-wide association and molecular studies that have linked the rs560887 ‘A’ allele to reduced G6PC2 expression and reduced FBG [ [11] , [12] , [13] ].…”

“…In contrast to G6pc2 , which is not expressed in the liver [ 10 ] and is not regulated by insulin (data not shown), hepatic G6pc1 expression increases significantly with fasting ( Figure 3 F). Because insulin represses [ 1 ] whereas glucose stimulates [ 21 ] G6pc1 expression, this suggests that the effect of reduced repression of G6pc1 expression by insulin associated with the reduction in FPI ( Figure 3 C) is dominant over the effect of reduced stimulation by glucose associated with the reduction in FBG ( Figure 3 B).…”

“…Fold induction of gene expression was calculated using the 2 (-ΔΔC(T)) method [ 18 ]. PCR primer sequences have been previously described [ 10 ]. The efficiency of primer amplification was tested in cDNA dilution analyses.…”

Random glucose GWAS in 493,036 individuals provides insights into diabetes pathophysiology, complications and treatment stratification

“…Among established glycaemic trait signals, the well-known FG loci G6PC2 ( P <5.86×10 −754 ) and GCK ( P <6.93×10 −301 ), with key roles in gluconeogenesis 12 and glucose sensing 13 , respectively, showed the strongest associations with RG ( Supplementary Table 3 ). We also observed two thirds of RG signals overlapping with T2D-risk loci ( Supplementary Figure 1e ), including SLC30A8, DGKB, TCF7L2, GRB10 and THADA .…”

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

“…Experiments in mice suggest that the nature of the physiological benefits associated with G6PC2 are that it confers a transient, beneficial elevation in FBG during periods of stress (17,18) and that it protects against hypoglycemia in response to a ketogenic diet or prolonged fasting (19). Previous biobank analyses have confirmed the association between G6PC2 and FBG and have also linked G6PC2 to an altered risk for acute pancreatitis (9). However, a caveat with these studies is that they were performed using the rs560887 G6PC2 SNP that has a mild effect on G6PC2 RNA splicing (16) such that other deleterious consequences of altered G6PC2 expression might have been missed.…”