Cyclic ADP-ribose-mediated insulin secretion and Reg, regenerating gene

Abstract

Glucose is the primary stimulus of insulin secretion in pancreatic β-cells of the islets of Langerhans. CD38 has both ADP-ribosyl cyclase, which catalyzes the formation of cyclic ADP-ribose from NAD⁺, and cyclic ADP-ribose hydrolase, which converts cyclic ADP-ribose to ADP-ribose. ATP, produced by glucose metabolism, inhibits the cyclic ADP-ribose hydrolase of CD38 and therefore causes cyclic ADP-ribose accumulation in β-cells. Then, cyclic ADP-ribose acts as a second messenger for Ca²⁺ mobilization from the endoplasmic reticulum to secrete insulin. The mechanism of insulin secretion as described above is completely different from the conventional hypothesis in which Ca²⁺ influx from extracellular sources was assumed to play a role in insulin secretion by glucose. On the other hand, strategies for influencing the replication of islet β-cells and the growth of the β-cell mass may be more important for ameliorating diabetes. Reg, regenerating gene, is involved in the growth of the β-cell mass, and Reg protein has been shown to increase the β-cell mass in a 90% depancreatized diabetic rat model, thereby ameliorating the diabetes. CD38 is involved in the formation of cyclic ADP-ribose and is essential for the glucose sensitivity of β-cells for insulin secretion. Therefore, CD38 gene and Reg gene will become targets for genetic engineering for diabetic β-cells.