Appropriate therapy for type 2 diabetes mellitus in view of pancreatic ß-cell glucose toxicity: "the earlier, the better".

ABSTRACT

Pancreatic ß-cells secrete insulin when blood glucose levels become high; however, when ß-cells are chronically exposed to hyperglycemia, ß-cell function gradually deteriorates, which is known as ß-cell glucose toxicity. In the diabetic state, nuclear expression of the pancreatic transcription factors pancreatic and duodenal homeobox 1 (PDX-1) and v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA) is decreased. In addition, incretin receptor expression in ß-cells is decreased, which is likely involved in the impairment of incretin effects in diabetes. Clinically, it is important to select appropriate therapy for type 2 diabetes mellitus (T2DM) so that ß-cell function can be preserved. In addition, when appropriate pharmacological interventions against ß-cell glucose toxicity are started at the early stages of diabetes, ß-cell function is substantially restored, which is not observed if treatment is started at advanced stages. These observations indicate that it is likely that downregulation of pancreatic transcription factors and/or incretin receptors is involved in ß-cell dysfunction observed in T2DM and it is very important to start appropriate pharmacological intervention against ß-cell glucose toxicity in the early stages of diabetes.