UCP2 Regulates the Glucagon Response to Fasting and Starvation

Abstract

Glucagon is important for maintaining euglycemia during fasting/starvation, and abnormal glucagon secretion is associated with type 1 and type 2 diabetes; however, the mechanisms of hypoglycemia-induced glucagon secretion are poorly understood. We previously demonstrated that global deletion of mitochondrial uncoupling protein 2 (UCP2−/−) in mice impaired glucagon secretion from isolated islets. Therefore, UCP2 may contribute to the regulation of hypoglycemia-induced glucagon secretion, which is supported by our current finding that UCP2 expression is increased in nutrient-deprived murine and human islets. Further to this, we created α-cell–specific UCP2 knockout (UCP2AKO) mice, which we used to demonstrate that blood glucose recovery in response to hypoglycemia is impaired owing to attenuated glucagon secretion. UCP2-deleted α-cells have higher levels of intracellular reactive oxygen species (ROS) due to enhanced mitochondrial coupling, which translated into defective stimulus/secretion coupling. The effects of UCP2 deletion were mimicked by the UCP2 inhibitor genipin on both murine and human islets and also by application of exogenous ROS, confirming that changes in oxidative status and electrical activity directly reduce glucagon secretion. Therefore, α-cell UCP2 deletion perturbs the fasting/hypoglycemic glucagon response and shows that UCP2 is necessary for normal α-cell glucose sensing and the maintenance of euglycemia.

PTEN Deletion in Pancreatic α-Cells Protects Against High-Fat Diet–Induced Hyperglucagonemia and Insulin Resistance

“…1F). Consistent with the lack of hypothalamic genetic deletion in this model as shown here and previously by others (7,11), centrally regulated metabolic parameters, such as body weight and food intake, were not significantly different between genotypes (Fig. 1C and D).…”

“…GLUcre + Pten fl/fl mice were born in a Mendelian ratio without any apparent postnatal abnormalities. Previous studies by others and our group using the same GLUcre + mice reported an efficient recombination rate (.85% a-cells) (7,11,18). To confirm the efficacy of the gene disruption, we coimmunostained glucagon with cre recombinase and then PTEN in dispersed islet cells.…”

“…After 48-h culture in RPMI medium, cells were harvested for hormone secretion or protein extraction studies. Transfected cells were incubated in glucose or L-arginine at concentrations reported in previous studies, and media were extracted for glucagon measurements after incubation (7,11,15). Cell count was done after 48-h culture.…”

“…fl/fl mice (exons 4 and 5 of Pten flanked by loxP sites by homologous recombination) were mated with GLUcre mice (cre transgene under the control of the glucagon promoter) (10 (11). Only male mice were used for experiments, and only littermates were used as controls.…”

LKB1 couples glucose metabolism to insulin secretion in mice

“…Membrane potential recordings and whole cell patchclamp Plasma membrane potential and voltage-dependent K channel activity was measured using a perforated patch technique in whole cell configuration as described previously [31,32] (ESM Methods). 13 C 5 ]glutamine for the indicated times and compared with starved and unlabelled carbon source samples.…”