Brain Glucose Sensors Play a Significant Role in the Regulation of Pancreatic Glucose-Stimulated Insulin Secretion

Department of Medicine, University of Cambridge Metabolic Research Laboratories, and National Institute for Health Research, Cambridge Biomedical Research Centre, Cambridge, UK
Diabetes (Impact Factor: 8.1). 12/2011; 61(2):321-8. DOI: 10.2337/db11-1050
Source: PubMed


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.

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    • "Disrupting brain sensing of macronutrients such as glucose leads to metabolic disturbances, including defects in pancreatic glucose-stimulated insulin secretion (e.g. [18] [19] [20]). For hormones, the effects of deletion of receptors for insulin and leptin from specific populations of hypothalamic neurons demonstrate that hormone sensing by brain circuits is essential for peripheral glucose homeostasis and normal body weight [21] [22] [23]. "
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