Fig. 10: Effects of chronic hyperglycaemia on β-cell metabolism.
a, b Cartoons illustrating metabolism in normoglycaemic/non-diabetic (a) and chronic hyperglycaemic/diabetic (b) conditions. a In non-diabetic cells glucose is metabolised via glycolysis and oxidative phosphorylation to produce an increase in the ATP/ADP ratio which closes KATP channels and initiates electrical activity, calcium influx and insulin secretion. b In diabetic β-cells glucose uptake is markedly increased due to the elevated extracellular glucose concentration. However, the activity of GAPDH and PDH are inhibited leading to the accumulation of metabolites upstream of GAPDH which cause changes in gene expression that downregulate PDH and GAPDH activity further. Because metabolism is reduced, glucose-dependent changes in the ATP/ADP ratio, KATP channel activity and insulin secretion are impaired. The enhanced activity of glucokinase also leads to a build-up of G6P which is channelled into glycogen. c Schematic of glycolysis showing the metabolic steps (highlighted) implicated in mTORC1 activation and consequent changes in metabolic gene expression. Metabolic steps that are inhibited are also indicated.
