Oxford scientists discover key cause of type 2 diabetes

Good news! It is actually surprising why it took so long to discover that metabolites of glucose are the cause!

"Glucose metabolites (chemicals produced when glucose is broken down by cells), rather than glucose itself, have been discovered to be key to the progression of type 2 diabetes. In diabetes, the pancreatic beta-cells do not release enough of the hormone insulin, which lowers blood glucose levels. This is because a glucose metabolite damages pancreatic beta-cell function. ...
they also demonstrated that beta-cell failure caused by chronic hyperglycaemia can be prevented by slowing the rate of glucose metabolism. ..."

From the abstract:

"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, we show here 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. Our data also reveal that restricting glucose metabolism during hyperglycaemia prevents these changes and thus may be of therapeutic benefit. In summary, we have identified a pathway by which chronic hyperglycaemia reduces β-cell function."

Oxford scientists discover key cause of type 2 diabetes

Key cause of type 2 diabetes uncovered Oxford Research reveals high blood glucose reprograms the metabolism of pancreatic beta-cells in diabetes.

Altered glycolysis triggers impaired mitochondrial metabolism and mTORC1 activation in diabetic β-cells (open access)

Fig. 10: Effects of chronic hyperglycaemia on β-cell metabolism.