The Pancreatic β Cell Heats Up UCP2 and Insulin Secretion in Diabetes

including the pancreatic cell. UCP3 is expressed priThe pancreatic cell is a highly specialized cell that marily in muscle. Adenoviral overexpression of UCP2 in normally responds to small changes in the blood gluinsulin secreting cells and rat islets leads to the precose concentration by regulating insulin secretion to dicted uncoupling of oxidative phosphorylation and an maintain blood glucose within a narrow physiological impairment of glucose-induced insulin secretion (Chan range (Matschinsky et al., 1998). When glucose concenet al., 1999). trations increase, as they do after ingestion of a meal, In this issue of Cell, Zhang and coworkers (Zhang et insulin secretion increases. With fasting, insulin secreal., 2001) extend these observations to the physiological tion is suppressed. Insulin gene transcription plays an situation in an elegant and important series of studies. important role in maintaining sufficient insulin stores in Gene targeting in embryonic stem cells was used to secretory granules. However, the release of insulin from generate UCP2-deficient mice. Homozygous ( / ) anisecretory granules in response to the minute-to-minute mals failed to express intact UCP2 mRNA in all tissues fluctuations in blood glucose depends on a complex tested, including pancreatic islets. UCP2 mRNA was signal transduction pathway linked to glucose metaboreduced in islets isolated from heterozygous ( / ) anilism (Ashcroft and Gribble, 1999). mals compared with controls. Deficiency of UCP2 had Like other cells, pancreatic cells metabolize glucose no effects on body weight or cold-induced thermogeneto yield ATP. The metabolism of glucose generates elecsis in the mutant mice. The mice lacking UCP2 had tron carriers (such as NADH) that shuttle to the inner significantly lower glucose levels and higher insulin semembrane of the mitochondrion, where they donate cretion rates under basal conditions and following intraelectrons to the electron transport chain. As electrons peritoneal and intravenous glucose administration. Panmove down this chain, protons are pumped out of the creatic islets isolated from the homozygous ( / ) mitochondrial matrix by complexes I, III, and IV, creating animals secreted more insulin and demonstrated higher a proton electrochemical gradient (Scheffler, 1999). The levels of ATP than control animals. These results sugpotential energy in this gradient is used by ATP synthase gest that the level of Ucp2 gene expression in the panto produce ATP from ADP. In the cell, the increase in creatic cell is an important determinant of the sensitivthe ATP/ADP ratio that results from glucose metabolism ity of insulin secretion to changes in glucose. closes a membrane ATP-sensitive potassium channel, On the basis of additional studies performed in ob/ causing membrane depolarization, calcium influx, and ob mice, a model of type 2 diabetes, the authors suggest insulin secretion. Normally, the generation of ATP is that UCP2 is a major link between obesity, cell dystightly coupled to the metabolism of glucose and the function, and type 2 diabetes. UCP2 mRNA and protein two processes proceed in parallel. Thus, the secretion were upregulated in pancreatic islets from ob/ob mice. of insulin is linked to the rate of glucose metabolism Although serum insulin levels were elevated 33-fold in through oxidative phosphorylation. Defects in oxidative these animals, even this marked degree of hyperinsulinphosphorylation would be expected to impair insulin emia was insufficient to compensate for the profound secretion. Consistent with this notion, mitochondrial insulin resistance, resulting in significant hyperglycemia, mutations cause maternally inherited type 2 diabetes particularly following glucose administration. When due to defects in insulin secretion (Guillausseau et al., mice lacking UCP2 were crossed with ob/ob mice, the 2001; Velho et al., 1996). Uncoupling glucose metaboresulting reduction in UCP2 expression in the ob/ob lism from ATP generation would also be expected to animals was associated with a marked improvement in impair the ability of the cell to secrete insulin in reglucose tolerance. This genetically induced reduction sponse to glucose. Reducing the extent of uncoupling of UCP2 levels in ob/ob mice had effects on insulin