Molecular mechanism for pancreatic β-cell dysfunction and atherosclerosis and its therapeutic application: Importance of translational research bridging clinical practice and basic research.

introductionIt is well-known that when pancreatic β-cells are chronically exposed to hyperglycemia under diabetic conditions, β-cell function is gradually deteriorating. Although such phenomena were well-known as β-cell glucose toxicity in clinical practice, its molecular mechanism remained unknown.

resultsIt has been revealed that expression levels of insulin gene transcription factors and incretin receptors are downregulated, which is closely associated with β-cell glucose toxicity. In addition, we have reported that it is more beneficial to use incretin-based drugs at an early stage of diabetes when incretin receptor expression in β-cells is preserved. Furthermore, we have reported that it is more beneficial for the prevention of atherosclerosis to use incretin-based drugs at an early stage when incretin receptor expression in arterial cells is preserved. On the other hand, although clinical trials with imeglimin in human subjects clearly indicated its efficacy and safety, its precise mechanism on β-cells remained unknown. However, to address this clinical question, we performed some basic experiments and confirmed the beneficial effects of imeglimin on mitochondrial morphology in β-cells and/or the number and quality of insulin granules, which can explain the effects of imeglimin on β-cells observed in clinical practice. In addition, we demonstrated that imeglimin exerted favorable effects on the development of atherosclerosis.

conclusionIn this review article, we would like to show the importance of translational research bridging clinical practice and basic research, especially focusing on the molecular mechanism for pancreatic β-cell dysfunction and atherosclerosis and on the protective effects of imeglimin against β-cell dysfunction and atherosclerosis.