Journal Article

Glucagon-Like Peptide-1 Decreases Intracerebral Glucose Content by Activating Hexokinase and Changing Glucose Clearance during Hyperglycemia

Gejl, Michael, Møller, Niels, Gjedde, Albert, Lerche, Susanne, Bibby, Bo Martin, Mengel, Annette, Holst, Jens Juul, Rungby, Jørgen, Egefjord, Lærke, Vang, Kim, Brock, Birgitte

2012

Overview

Type 2 diabetes and hyperglycemia with the resulting increase of glucose concentrations in the brain impair the outcome of ischemic stroke, and may increase the risk of developing Alzheimer's disease (AD). Reports indicate that glucagon-like peptide-1 (GLP-1) may be neuroprotective in models of AD and stroke: Although the mechanism is unclear, glucose homeostasis appears to be important. We conducted a randomized, double-blinded, placebo-controlled crossover study in nine healthy males. Positron emission tomography was used to determine the effect of GLP-1 on cerebral glucose transport and metabolism during a hyperglycemic clamp with 18fluoro-deoxy-glucose as tracer. Glucagon-like peptide-1 lowered brain glucose (P = 0.023) in all regions. The cerebral metabolic rate for glucose was increased everywhere (P = 0.039) but not to the same extent in all regions (P = 0.022). The unidirectional glucose transfer across the blood-brain barrier remained unchanged (P = 0.099) in all regions, while the unidirectional clearance and the phosphorylation rate increased (P = 0.013 and 0.017), leading to increased net clearance of the glucose tracer (P = 0.006). We show that GLP-1 plays a role in a regulatory mechanism involved in the actions of GLUT1 and glucose metabolism: GLP-1 ensures less fluctuation of brain glucose levels in response to alterations in plasma glucose, which may prove to be neuroprotective during hyperglycemia.

• Publisher: SAGE Publications,Nature Publishing Group,Sage Publications Ltd
• Subject: Adult / Alzheimer Disease - diagnostic imaging / Alzheimer Disease - metabolism / Alzheimer Disease - physiopathology / Alzheimer's disease / Anticonvulsants. Antiepileptics. Antiparkinson agents / Biological and medical sciences / Biological Transport / Blood-brain barrier / Blood-Brain Barrier - diagnostic imaging / Blood-Brain Barrier - metabolism / Blood-Brain Barrier - physiopathology / Brain / Brain Chemistry / Brain Ischemia - diagnostic imaging / Brain Ischemia - metabolism / Brain Ischemia - physiopathology / Cerebral blood flow / Cross-Over Studies / Diabetes mellitus / Diabetes Mellitus, Type 2 - diagnostic imaging / Diabetes Mellitus, Type 2 - metabolism / Diabetes Mellitus, Type 2 - physiopathology / Double-Blind Method / Fluorodeoxyglucose F18 - administration & dosage / Glucagon-like peptide 1 / Glucagon-Like Peptide 1 - metabolism / Glucose - metabolism / Glucose Clamp Technique / Glucose transport / Glucose Transporter Type 1 - metabolism / Hexokinase / Hexokinase - metabolism / Homeostasis / Humans / Hyperglycemia / Hyperglycemia - diagnostic imaging / Hyperglycemia - metabolism / Hyperglycemia - physiopathology / Ischemia / Male / Medical sciences / Metabolic rate / Neurodegenerative diseases / Neurology / Neuropharmacology / Neuroprotection / Original / Pharmacology. Drug treatments / Phosphorylation / Positron emission tomography / Radiography / Radiopharmaceuticals - administration & dosage / Stroke / Stroke - diagnostic imaging / Stroke - metabolism / Stroke - physiopathology / Tracers / Vascular diseases and vascular malformations of the nervous system