Glucagon-like peptide-1 decreases intracerebral glucose content by activating hexokinase and changing glucose clearance during hyperglycemia

TY - JOUR

T1 - Glucagon-like peptide-1 decreases intracerebral glucose content by activating hexokinase and changing glucose clearance during hyperglycemia

AU - Gejl, Michael

AU - Egefjord, Lærke

AU - Lerche, Susanne

AU - Vang, Kim

AU - Bibby, Bo Martin

AU - Holst, Jens Juul

AU - Mengel, Annette

AU - Møller, Niels

AU - Rungby, Jørgen

AU - Brock, Birgitte

AU - Gjedde, Albert

PY - 2012/12

Y1 - 2012/12

N2 - 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 (18)fluoro-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.

AB - 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 (18)fluoro-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.

KW - Adult

KW - Alzheimer Disease

KW - Biological Transport

KW - Blood-Brain Barrier

KW - Brain Chemistry

KW - Brain Ischemia

KW - Cross-Over Studies

KW - Diabetes Mellitus, Type 2

KW - Double-Blind Method

KW - Fluorodeoxyglucose F18

KW - Glucagon-Like Peptide 1

KW - Glucose

KW - Glucose Clamp Technique

KW - Glucose Transporter Type 1

KW - Hexokinase

KW - Humans

KW - Hyperglycemia

KW - Male

KW - Positron-Emission Tomography

KW - Radiopharmaceuticals

KW - Stroke

U2 - 10.1038/jcbfm.2012.118

DO - 10.1038/jcbfm.2012.118

M3 - Journal article

C2 - 22929437

SN - 0271-678X

VL - 32

SP - 2146

EP - 2152

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

IS - 12

ER -