On Nov. 14, 2022, in a study published in Nature Communications, researchers discovered the pathway by which chronic hyperglycaemia reduces β-cell function. Their data also revealed that restricting glucose metabolism during hyperglycaemia prevented these changes and thus may be of therapeutic benefit.

Chronic hyperglycaemia causes a dramatic decrease in mitochondrial metabolism and insulin content in pancreatic β-cells. This underlies the progressive decline in β-cell function in diabetes. However, the molecular mechanisms by which hyperglycaemia produces these effects remain unresolved.

Using isolated islets and INS-1 cells, the research team show that one or more glycolytic metabolites downstream of phosphofructokinase and upstream of GAPDH mediates the effects of chronic hyperglycemia. This metabolite stimulates marked upregulation of mTORC1 and concomitant downregulation of AMPK.

Increased mTORC1 activity causes inhibition of pyruvate dehydrogenase which reduces pyruvate entry into the tricarboxylic acid cycle and partially accounts for the hyperglycaemia-induced reduction in oxidative phosphorylation and insulin secretion. In addition, hyperglycaemia (or diabetes) dramatically inhibits GAPDH activity, thereby impairing glucose metabolism.

The team propose that inhibition of β-cell metabolism in diabetes is mediated by accumulation of one or more glycolytic metabolites lying between PFK and GAPDH (i.e., F1,6BP, DHAP or GA3P). Their accumulation leads to the simultaneous activation of mTORC1 and inhibition of AMPK. mTORC1 activation leads to upregulation of PDK1, which results in reduced entry of pyruvate to the TCA cycle and thus a failure to generate sufficient ATP to support K_ATP channel closure and insulin secretion. In addition, GAPDH is profoundly inhibited, impairing glycolytic flux and leading to further accumulation of upstream metabolites, and greater mTORC1 activation. This limits β-cell metabolism in diabetes