Adaptation of beta-cell mass to substrate oversupply: enhanced function with normal gene expression

Although type 2 diabetes mellitus is associated with insulin resistance, ma ny individuals compensate by increasing insulin secretion. Putative mechani sms underlying this compensation were assessed in the present study by use of 4-day glucose (GLC; 35% Glc, 2 ml/h) and lipid (LIH; 10% Intralipid + 20 U/ml heparin; 2 ml/h) infusions to rats. Within 2 days of beginning the in fusion of either lipid or glucose, plasma glucose profiles were normalized (relative to saline-infused control rats; SAL; 0.45% 2 ml/h). During glucos e infusion, plasma glucose was maintained in the normal range by an approxi mately twofold increase in plasma insulin and an similar to 80% increase in beta -cell mass. During LIH infusion, glucose profiles were also maintaine d in the normal range. Plasma insulin responses during feeding were doubled , and beta -cell mass increased 54%. For both groups, the increase in beta -cell mass was associated with increased beta -cell proliferation (98% incr ease during GLC and 125% increase during LIH). At the end of the 4-day infu sions, no significant changes were observed in islet-specific gene transcri ption (i.e., the expression of islet hormone genes, glucose metabolism gene s, and insulin transcription factors were unaffected). Two days after termi nation of the infusions, the glucose-stimulated plasma insulin response was increased similar to 67% in glucose-infused animals. No sustained effect o n insulin secretory capacity was observed in the LIH animals. The increase in plasma insulin response after glucose infusion was achieved in the absen ce of any change in insulin clearance. We conclude that, in rats, an increa se in insulin demand after an increase in glucose appearance or free fatty acid leads to an increase in beta -cell mass, mediated in part by an increa se in beta -cell proliferation, and that these compensatory changes lead to increased insulin secretion, normal plasma glucose levels, and the mainten ance of normal islet gene expression.