beta-cell adaptation and decompensation during the progression of diabetes

Inadequate beta -cell function is an essential component of all forms of di abetes. The most obvious problem is a failure to maintain sufficient beta - cell mass and function to cope with whatever insulin resistance is present. The most striking functional defect is a loss of acute glucose-induced ins ulin secretion (GIIS). This review discusses the ways in which beta -cells successfully adapt to increased demand and then decompensate as diabetes de velops. Successful adaptation is achieved through increased beta -cell mass and increased insulin secretion. The hypothesis is explored that beta -cel ls exposed to the diabetic milieu lose their differentiation, which leads t o loss of specialized functions such as GIIS. This concept has been strengt hened by the finding of dedifferentiation of beta -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 fin ding was increased expression of c-Myc, which probably contributes to an in crease in the expression of lactate dehydrogenase and the development of be ta -cell hypertrophy. Arguments are developed that the beta -cell changes f ound in diabetes are better correlated with increased glucose levels than w ith nonesterified fatty acid levels, thus supporting the importance of gluc ose toxicity.