Control of pancreatic ß cell regeneration by glucose metabolism.

Recent studies revealed a surprising regenerative capacity of insulin-producing ß cells in mice, suggesting that regenerative therapy for human diabetes could in principle be achieved. Physiologic ß cell regeneration under stressed conditions relies on accelerated proliferation of surviving ß cells, but the factors that trigger and control this response remain unclear. Using islet transplantation experiments, we show that ß cell mass is controlled systemically rather than by local factors such as tissue damage. Chronic changes in ß cell glucose metabolism, rather than blood glucose levels per se, are the main positive regulator of basal and compensatory ß cell proliferation in vivo. Intracellularly, genetic and pharmacologic manipulations reveal that glucose induces ß cell replication via metabolism by glucokinase, the first step of glycolysis, followed by closure of K(ATP) channels and membrane depolarization. Our data provide a molecular mechanism for homeostatic control of ß cell mass by metabolic demand.

Novel de novo mutation in sulfonylurea receptor 1 presenting as hyperinsulinism in infancy followed by overt diabetes in early adolescence.

OBJECTIVE: Congenital hyperinsulinism, usually associated with severe neonatal hypoglycemia, may progress to diabetes, typically during the 4th decade of life in nonpancreatectomized patients. We aimed to genotype the ATP-sensitive K(+) channel in a 10.5-year-old girl presenting with overt diabetes following hyperinsulinism in infancy. RESEARCH DESIGN AND METHODS: A female aged 10.5 years presented with new-onset, antibody-negative diabetes (A1C 10.6%). She was born large for gestational age (5 kg) to a nondiabetic mother and developed frequent hypoglycemic episodes, which persisted until age 3 years and responded initially to intravenous glucose and later to oral sweets. Currently, she is fully pubertal and obese (BMI 30.2 kg/m(2)), with a partially controlled convulsive disorder (since age 1 year) and poor school performance. Glucose levels were >11.1 mmol/l throughout 72 h of continuous glucose monitoring, with low insulin secretion during intravenous glucose tolerance testing. KCNJ11 and ABCC8 mutation analysis was performed, and the mutation identified was characterized in COSm6 cells. RESULTS: A novel, de novo heterozygous ABCC8 sulfonylurea receptor (SUR)1 mutation (R370S) was identified in the patient's DNA but not in that of either parent. Cotransfection of Kir6.2 and mutant SUR1 demonstrate that the mutated protein is expressed efficiently at the cell surface but fails to respond to MgADP, resulting in minimal channel activity. Interestingly, the heterozygous channel (WT:R370S) responded well to glibenclamide, a finding that lead to the successful initiation of sulfonylurea therapy. CONCLUSIONS: This new ABCC8 mutation is associated with neonatal hyperinsulinism progressing within 10 years to insulinopenic diabetes. Consistent with in vitro findings, the patient responded to sulfonylurea treatment. The mechanism causing the relatively rapid loss in beta-cell function is not clear, but it may involve mutation-induced increased beta-cell apoptosis related to increased metabolic demand.