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

Abstract

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.

Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice

“…In support of our study, two recent reports (11,26) showed that hypothalamic glucose sensors play an important role in the control of insulin secretion (26) and that specific reduction of insulin receptor levels in the VMH produces glucose intolerance and islet dysfunction (11). Similar to this latter work, we found that Prep gt/gt mice have impaired glucose sensing and activation of insulin receptors in the VMH.…”

Increased Glucose-induced Secretion of Glucagon-like Peptide-1 in Mice Lacking the Carcinoembryonic Antigen-related Cell Adhesion Molecule 2 (CEACAM2)

“…In light of CEACAM2 expression in the ventromedial hypothalamus (1), the glucose-sensing center in (30), it is possible that hypothalamic CEACAM2 regulates insulin secretion centrally (31,32) and independently of GLP-1 release (33). Disturbance in this neuronally mediated mechanism may contribute to the higher excursion of insulin during hyperglycemic clamp analysis in Cc2 Ϫ/Ϫ mice.…”

Boric Acid-Based Dual Modulation Photoluminescent Glucose Sensor Using Thioglycolic Acid-Capped CdTe Quantum Dots

“…Similarly, many amino acids including tyrosine, tryptophan, proline, histidine, glycine, phenylalanine, cysteine, and arginine interfere non-significantly with glucose determination. Experimental results also show that ions SO 4 2-, acetate (Ac -), NO 3 -, ClO 4 -, PO 4 3-, Cl -, NH 4 ? , NO 2 -, and F -have negligible interference with determination of glucose.…”

“…related to many diseases including diabetes, cancers, and physiological aging and neurodegenerative diseases [4][5][6]. Therefore, a large number of methods have been developed to detect glucose using organic probes functionalized with borates/boronic acids [7], such as phenylboronic acid [8], anthrylboronic acid [9], ferrocenylboronic acids [10], cyanine dye possessing boronic acid [11], boronic acid gel [12], boronic acid functionalized benzyl viologen derivative, and/or boronate-functionalized polymeric monoliths over past few decades [2,13].…”