Brain Glucose Sensors Play a Significant Role in the Regulation of Pancreatic Glucose-Stimulated Insulin Secretion
- Mayowa A. Osundiji1,
- Daniel D. Lam2,
- Jill Shaw1,2,
- Chen-Yu Yueh1,3,
- S. Pauliina Markkula1,
- Paul Hurst1,
- Carolina Colliva4,
- Aldo Roda4,
- Lora K. Heisler2 and
- Mark L. Evans1⇓
- 1Department of Medicine, University of Cambridge Metabolic Research Laboratories, and National Institute for Health Research, Cambridge Biomedical Research Centre, Cambridge, U.K.
- 2Department of Pharmacology, University of Cambridge, Cambridge, U.K.
- 3Department of Family Medicine, Chang Gung Memorial Hospital at Chiayi, Chang Gung Institute of Technology, Chiayi, Taiwan
- 4Department of Pharmaceutical Sciences, University of Bologna, Bologna, Italy
- Corresponding authors: Mark L. Evans, , and Lora K. Heisler, .
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.
- Received July 28, 2011.
- Accepted November 10, 2011.
- © 2012 by the American Diabetes Association.
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