TRANSCRIPTION FACTOR ABNORMALITIES AS A CAUSE OF BETA-CELL DYSFUNCTION IN DIABETES - A HYPOTHESIS

Well-characterized defects in insulin secretion, most notably a loss o f glucose-induced insulin secretion, are found in virtually all forms of NIDDM, as well as in early IDDM. Similar abnormalities have been fo und in all animal models of diabetes in which they have been studied. A novel hypothesis is being proposed to explain the mechanisms respons ible for these alterations. Many abnormalities in the various steps of glucose-induced insulin secretion have been identified in rodent mode ls of diabetes, but none by itself seems sufficient to explain the def ects. These include a loss of GLUT2, glycogen accumulation, glucose re cycling, abnormal glucokinase or hexokinase, altered mitochondrial gly cerol phosphate dehydrogenase (mGPDH) activity, abnormal ion channel f unction and beta cell degranulation. We propose that optimal secretory function is dependent upon the unique differentiation of beta cells t hat is maintained by a set of transcription factors and that this cont rol is disrupted by the diabetic state. Therefore, we propose that key transcription factors are affected even when beta cells are stressed by insulin resistance in very earliest stages of diabetes and that the abnormality becomes more severe as full-blown diabetes develops, whic h leads to loss of beta cell differentiation and a resultant derangeme nt of insulin secretion.