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

Abstract

Objective G6PC2 is predominantly expressed in pancreatic islet beta cells. G6PC2 hydrolyzes glucose-6-phosphate to glucose and inorganic phosphate, thereby creating a futile substrate cycle that opposes the action of glucokinase. This substrate cycle determines the sensitivity of glucose-stimulated insulin secretion to glucose and hence regulates fasting blood glucose (FBG) but not fasting plasma insulin (FPI) levels. Our objective was to explore the physiological benefit this cycle confers. Methods We investigated the response of wild type (WT) and G6pc2 knockout (KO) mice to changes in nutrition. Results Pancreatic G6pc2 expression was little changed by ketogenic diet feeding but was inhibited by 24 hr fasting and strongly induced by high fat feeding. When challenged with either a ketogenic diet or 24 hr fasting, blood glucose fell to 70 mg/dl or less in G6pc2 KO but not WT mice, suggesting that G6PC2 may have evolved, in part, to prevent hypoglycemia. Prolonged ketogenic diet feeding reduced the effect of G6pc2 deletion on FBG. The hyperglycemia associated with high fat feeding was partially blunted in G6pc2 KO mice, suggesting that under these conditions the presence of G6PC2 is detrimental. As expected, FPI changed but did not differ between WT and KO mice in response to fasting, ketogenic and high fat feeding. Conclusions Since elevated FBG levels are associated with increased risk for cardiovascular-associated mortality (CAM), these studies suggest that, while G6PC2 inhibitors would be useful for lowering FBG and the risk of CAM, partial inhibition will be important to avoid the risk of hypoglycemia.

Glucose-6-phosphatase catalytic subunit 2 negatively regulates glucose oxidation and insulin secretion in pancreatic β-cells

“…We also verified that glucose cycling (Fig. 1B, S1A, S1C, S1E), a functional readout of G6PC2 activity, was present at levels comparable to those previously measured in primary islets at 5 mM (~10%) and 11 mM (~20%) glucose concentrations (8,10). In contrast, glucose cycling studies in INS1-832/13 cells (Fig.…”

“…Since elevated G6PC2 expression is associated with increased FBG levels and thus heightened risk for cardiovascular-associated mortality (CAM) in vivo ( 40 , 48 ), our study also suggests that G6PC2 inhibitors would be useful for lowering FBG and thereby the risk of CAM. However, one needs to be judicious in interpreting these findings as recent studies suggest that under specific physiological conditions, such as prolonged fasting and ketogenic feeding, G6PC2 offers protection against hypoglycemia ( 10 ). Future studies will involve understanding the direct and/or indirect signals that result in the metabolic changes brought about by the deletion of G6pc2 .…”

Maturation of beta cells: lessons from in vivo and in vitro models

“…One example of the latter is the higher expression of glucose-6-phosphatase catalytic subunit 2 (G6PC2) and 6-phosphofructo-2-kinase/fructose-2,6biphosphatase 2 (PFKFB2) within healthy beta cell samples [111][112][113][114][115][116] and the upregulation of these genes during maturation of SC-islet beta cells [35,61]. Both genes encode glycolytically linked enzymes that have been shown to have direct regulatory control over the glucokinase-mediated step of glycolysis [117][118][119][120]. The functional maturation of beta cells therefore correlates with heightened control over this initial step of glycolysis, which may regulate the pattern of downstream metabolism and glucose trafficking.…”

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 ).…”