the Progression of Diabetes

Abstract

Inadequate -cell function is an essential component ofall forms of diabetes. The most obvious problem is a fail-ure to maintain sufficient -cell mass and function tocope with whatever insulin resistance is present. Themost striking functional defect is a loss of acute glu-cose-induced insulin secretion (GIIS). This review dis-cusses the ways in which -cells successfully adapt toincreased demand and then decompensate as diabetesdevelops. Successful adaptation is achieved throughincreased -cell mass and increased insulin secretion.The hypothesis is explored that -cells exposed to thediabetic milieu lose their differentiation, which leads toloss of specialized functions such as GIIS. This concepthas been strengthened by the finding of dedifferentia-tion of -cells in a rat model of partial pancreatectomythat includes a reduction of insulin gene expression,which may further contribute to decreased insulin pro-duction. Another finding was increased expression ofc-Myc, which probably contributes to an increase in theexpression of lactate dehydrogenase and the develop-ment of -cell hypertrophy. Arguments are developedthat the -cell changes found in diabetes are bettercorrelated with increased glucose levels than with non-esterified fatty acid levels, thus supporting the impor-tance of glucose toxicity. Diabetes50 (Suppl. 1):S154–S159, 2001