Molecular mechanism for pancreatic β-cell dysfunction and atherosclerosis.

It is well known in clinical practice that when pancreatic β-cells are chronically exposed to hyperglycemia, β-cell function is gradually deteriorated. It has been revealed that under diabetic conditions oxidative stress is provoked and expression levels of insulin gene transcription factors and incretin receptors are down-regulated which are closely associated with β-cell glucose toxicity. We showed that expression levels of these factors were preserved by reducing glucose toxicity with SGLT2 inhibitor. In addition, we showed that it was more beneficial to use incretin-based drugs at an early stage of diabetes when incretin receptor expression was preserved in β-cells. Similarly, we showed that expression levels of incretin receptors in arterial cells were down-regulated which seemed to be associated with the progression of atherosclerosis. Imeglimin is a relatively new anti-diabetic drug and has been used in clinical practice. Recently we have reported that imeglimin exerts beneficial effects on mitochondria morphology in β-cells and/or number and quality of insulin granules. In addition, we have reported that imeglimin shows favorable effects against the development of atherosclerosis independently of glycemic and lipid control. Taken together, it is likely that augmentation of oxidative stress and decreased expression levels of insulin gene transcription factors and incretin receptors are closely associated with pancreatic β-cell glucose toxicity. In addition, incretin-based drugs and imeglimin are expected to exert favorable effects against β-cell glucose toxicity and the development of atherosclerosis when they are appropriately introduced.