Dysfunctional insulin secretion in type 2 diabetes: role of metabolic abnormalities

Insulin secretion is finely tuned to the requirements of tissues by tight c oupling to prevailing blood glucose levels. The normal regulation of insuli n secretion is coupled to glucose metabolism in the pancreatic B cell, a ma jor but not exclusive signal for secretion being closure of K(+)ATP (adenos ine triphosphate)-dependent channels in the cell membrane through an increa se in cytosolic ATP/adenosine diphosphate. Insulin secretion in type 2 diab etes is abnormal in several respects due to genetic causes but also due to the metabolic environment of the pancreatic B cells. This environment may b e particularly important for the deterioration of insulin secretion which o ccurs with increasing duration of diabetes. Factors in the environment with potential importance include overstimulation, a negative effect of hypergl ycemia per se ('glucotoxicity') as well as adverse effects of elevated fatt y acids ('lipotoxicity'). Elucidating the mechanisms behind these factors a s well as their clinical importance will pave the way for treatment which c ould preserve B-cell function in type 2 diabetic patients.