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.
Department of Medicine, University of Cambridge Metabolic Research Laboratories, and National Institute for Health Research, Cambridge Biomedical Research Centre, Cambridge, UK
Mayowa A
MA
Osundiji
Daniel D
DD
Lam
Jill
J
Shaw
Chen-Yu
CY
Yueh
S Pauliina
SP
Markkula
Paul
P
Hurst
Carolina
C
Colliva
Aldo
A
Roda
Lora K
LK
Heisler
Mark L
ML
Evans
D000818:Animals; D005941:Glucokinase / Q000502:physiology; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D005951:Glucose Tolerance Test; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology*; D007276:Injections, Intraventricular; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D008356:Mannoheptulose / Q000494:pharmacology; D010179:Pancreas / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007328:Insulin; D008356:Mannoheptulose; D005941:Glucokinase; D005947:Glucose