β-cell adaptation and decompensation during the progression of diabetes

Abstract

Inadequate β-cell function is an essential component of all forms of diabetes. The most obvious problem is a failure to maintain sufficient β-cell mass and function to cope with whatever insulin resistance is present. The most striking functional defect is a loss of acute glucose-induced insulin secretion (GIIS). This review discusses the ways in which β-cells successfully adapt to increased demand and then decompensate as diabetes develops. Successful adaptation is achieved through increased β-cell mass and increased insulin secretion. The hypothesis is explored that β-cells exposed to the diabetic milieu lose their differentiation, which leads to loss of specialized functions such as GIIS. This concept has been strengthened by the finding of dedifferentiation of β-cells in a rat model of partial pancreatectomy that includes a reduction of insulin gene expression, which may further contribute to decreased insulin production. Another finding was increased expression of c-Myc, which probably contributes to an increase in the expression of lactate dehydrogenase and the development of β-cell hypertrophy. Arguments are developed that the β-cell changes found in diabetes are better correlated with increased glucose levels than with non-esterified fatty acid levels, thus supporting the importance of glucose toxicity.