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.

中文翻译：

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G6PC2 在生酮饮食喂养和长期禁食时提供防止低血糖的保护。

客观的

G6PC2主要在胰岛 β 细胞中表达。G6PC2 将 6-磷酸葡萄糖水解为葡萄糖和无机磷酸盐，从而产生一个无效的底物循环，对抗葡萄糖激酶的作用。这种底物循环决定了葡萄糖刺激的胰岛素分泌对葡萄糖的敏感性，因此调节空腹血糖 (FBG) 但不调节空腹血浆胰岛素 (FPI) 水平。我们的目标是探索这个循环带来的生理益处。

方法

我们研究了野生型 (WT) 和G6pc2敲除 (KO) 小鼠对营养变化的反应。

结果

生酮饮食喂养对胰腺G6pc2表达的影响很小，但受到 24 小时禁食的抑制和高脂肪喂养的强烈诱导。当接受生酮饮食或 24 小时禁食挑战时，G6pc2 KO 而非 WT 小鼠的血糖降至 70 mg/dl 或更低，这表明 G6PC2 可能已经进化，部分是为了防止低血糖。长期生酮饮食降低了G6pc2缺失对 FBG 的影响。与高脂肪喂养相关的高血糖在G6pc2 KO 小鼠中部分减弱，表明在这些条件下 G6PC2 的存在是有害的。正如预期的那样，响应禁食、生酮和高脂肪喂养，WT 和 KO 小鼠的 FPI 发生了变化但没有差异。

结论

由于 FBG 水平升高与心血管相关死亡率 (CAM) 风险增加有关，这些研究表明，虽然 G6PC2 抑制剂可用于降低 FBG 和 CAM 风险，但部分抑制对于避免低血糖风险很重要。