BAD modulates counterregulatory responses to hypoglycemia and protective glucoprivic feeding.

Hypoglycemia or glucoprivation triggers protective hormonal counterregulatory and feeding responses to aid the restoration of normoglycemia. Increasing evidence suggests pertinent roles for the brain in sensing glucoprivation and mediating counterregulation, however, the precise nature of the metabolic signals and molecular mediators linking central glucose sensing to effector functions are not fully understood. Here, we demonstrate that protective hormonal and feeding responses to hypoglycemia are regulated by BAD, a BCL-2 family protein with dual functions in apoptosis and metabolism. BAD-deficient mice display impaired glycemic and hormonal counterregulatory responses to systemic glucoprivation induced by 2-deoxy-D-glucose. BAD is also required for proper counterregulatory responses to insulin-induced hypoglycemia as evident from significantly higher glucose infusion rates and lower plasma epinephrine levels during hyperinsulinemic hypoglycemic clamps. Importantly, RNA interference-mediated acute knockdown of Bad in the brain provided independent genetic evidence for its relevance in central glucose sensing and proper neurohumoral responses to glucoprivation. Moreover, BAD deficiency is associated with impaired glucoprivic feeding, suggesting that its role in adaptive responses to hypoglycemia extends beyond hormonal responses to regulation of feeding behavior. Together, these data indicate a previously unappreciated role for BAD in the control of central glucose sensing

Brain glucose sensors play a significant role in the regulation of pancreatic glucose-stimulated insulin secretion.

As patients decline from health to type 2 diabetes, glucose-stimulated insulin secretion (GSIS) typically becomes impaired. Although GSIS is driven predominantly by direct sensing of a rise in blood glucose by pancreatic β-cells, there is growing evidence that hypothalamic neurons control other aspects of peripheral glucose metabolism. Here we investigated the role of the brain in the modulation of GSIS. To examine the effects of increasing or decreasing hypothalamic glucose sensing on glucose tolerance and insulin secretion, glucose or inhibitors of glucokinase, respectively, were infused into the third ventricle during intravenous glucose tolerance tests (IVGTTs). Glucose-infused rats displayed improved glucose handling, particularly within the first few minutes of the IVGTT, with a significantly lower area under the excursion curve within the first 10 min (AUC0-10). This was explained by increased insulin secretion. In contrast, infusion of the glucokinase inhibitors glucosamine or mannoheptulose worsened glucose tolerance and decreased GSIS in the first few minutes of IVGTT. Our data suggest a role for brain glucose sensors in the regulation of GSIS, particularly during the early phase. We propose that pharmacological agents targeting hypothalamic glucose-sensing pathways may represent novel therapeutic strategies for enhancing early phase insulin secretion in type 2 diabetes

Glucagon secretion in response to glucose and arginine.

<p>(A) Glucagon secretion in primary <i>Bad </i>^−/− and <i>Bad </i>^+/+ islets. Data are mean ± s.e.m and represent cumulative values from 3 independent islet isolations. Glc, glucose. *p<0.05; **p<0.01, unpaired two tailed <i>t</i>-test (B) Glucagon secretion during L-arginine stimulation of <i>Bad </i>^−/− and <i>Bad </i>^+/+ mice (n = 4–7 per group). ***p<0.001, unpaired two tailed <i>t</i>-test.</p

Genetic requirement of BAD in the glucoprivic feeding response.

<p>Glucoprivic feeding response 4 hrs after i.p. administration of 2DG (150 mg/kg) or saline to <i>Bad </i>^−/−and <i>Bad </i>^+/+ mice (n = 11–12 per group). *p<0.05; **p<0.01, unpaired two tailed <i>t</i>-test.</p

Impaired counterregulatory responses to insulin-induced hypoglycemia in BAD-deficient mice.

<p>Plasma glucose levels (A) and glucose infusion rate (GIR) (B) in <i>Bad </i>^−/− and <i>Bad </i>^+/+ mice subjected to hyperinsulinemic hypoglycemic clamp analysis. Plasma glucagon (C) and epinephrine (D) levels at 30 min during the clamp period. *p<0.05; **p<0.01, <i>Bad </i>^−/− vs <i>Bad </i>^+/+ mice (n = 9 per group), unpaired two tailed <i>t</i>-test.</p

Glucokinase inhibitor glucosamine stimulates feeding and activates hypothalamic neuropeptide Y and orexin neurons

► Antagonism of brain glucokinase by glucosamine (GSN) stimulates feeding. ► GSN-stimulated feeding is associated with increased hypothalamic neuronal activity. ► Activity in arcuate and lateral hypothalamus is strongly correlated with GSN-feeding. ► GSN activates orexigenic arcuate neuropeptide Y and lateral hypothalamus orexin cells