Diabetes and Cholesterol Metabolism

The maintenance of blood glucose in a limit run requires tight coupling among circulating insulin secretion, proinsulin biosynthesis and nutrients. Glucose, the most physiological stimulus for insulin secretion, controls insulin release through activities on so-called triggering and amplifying pathways in the β-cell. The ATP-sensitive K+ (K+-ATP) channels are key players within the activating pathway. Their activity is directed by the mitochondrial oxidative phosphorylation of glucose metabolites, which comes about in an increased cytosolic ATP to ADP ratio, hence restraining potassium efflux through the channel, depolarizing the plasma membrane, and opening voltage-dependent L-type calcium channels, which increments cytosolic calcium and leads to exocytosis of insulin. In addition to the triggering pathway, the β-cell displays pathways downstream to the K⁺-ATP channel, which increases insulin secretion to abdicate physiological levels of the hormone in response to glucose.

The islet redox state is connected with its secretory function, but the causal relationship remains undetermined. As of late it was appeared that diminished nicotinamide adenine dinucleotide phosphate (NADPH) directly stimulates insulin secretion, probably via the thioredoxin and glutaredoxin signaling pathways. A few anaplerotic shuttles, thought to be critical for glucose-stimulated insulin secretion, produce NADPH.

The support of glucose homeostasis in the face of chronic and acute changes in insulin demand depends on tight coupling between insulin secretion and proinsulin biosynthesis. Succinate is an important mediator of glucose-stimulated proinsulin biosynthesis in rat pancreatic islets. However, the downstream metabolic signals that mediate succinate intercede on proinsulin biosynthesis are not known.

The expanded glucose of diabetes would be metabolized to pyruvate that can at that point enter the mitochondria. Transformation to acetyl-CoA and oxaloacetate by pyruvate dehydrogenase and pyruvate carboxylase would lead to expanded generation of acetyl-CoA and succinate that may result in expanded generation of HMG-CoA, mevalonate, and, probably, cholesterol. Succinate metabolism would moreover enhance insulin release as a result of increased NADPH production by malic enzyme. This, in turn, would increment the production of mevalonate by HMG-CoA reductase.