Exploring the molecular mechanisms underlying α- and β-cell dysfunction in diabetes.

Abstract

Pancreatic islet dysfunction, including impaired insulin secretion in β cells and dysregulated glucagon secretion in α cells, is the chief pathology of diabetes. In β cells, oxidative stress, evoked by chronic hyperglycemia, was found to induce dysfunction of a critical transcription factor, PDX1, caused by its nucleocytoplasmic translocation via interactions with the insulin and JNK signaling pathways and another transcription factor, FOXO1. The significance of α-cell insulin signaling in the physiological and pathological regulation of α-cell biology was demonstrated in α-cell-specific insulin receptor knockout mice, which exhibited dysregulated glucagon secretion. Moreover, a high-glucose load directly induced excessive glucagon secretion in a glucagon-secreting cell line and isolated islets, together with impairment of insulin signaling. These findings indicate that disordered insulin signaling is central to the pathophysiology of islet dysfunction in both α and β cells. On the other hand, certain beneficial effects of GLP-1 on dysfunctional α and β cells indicate that it has therapeutic potential for diabetes patients who exhibit insulin resistance in islets. These studies, involving basic medical research approaches, have-at least in part-clarified the molecular mechanisms underlying α- and β-cell dysfunction in diabetes, and offer important clues that should aid the development of future therapeutic approaches to the disease.