Glucagon-Like Peptide-1 Inhibits Blood-Brain Glucose Transfer in Humans

Abstract

OBJECTIVE-Glucagon-like peptide-1 (GLP-1) has many effects on glucose homeostasis, and GLP-1 receptors are broadly represented in many tissues including the brain. Recent research in rodents suggests a protective effect of GLP-1 on brain tissue. The mechanism is unknown. We therefore tested whether these neuroprotective effects could relate to changes of glucose transport and consumption.RESEARCH DESIGN AND METHODS-We studied 10 healthy men in a randomized, double-blinded, placebo-controlled cross-over experiment. We used positron emission tomography to determine the acute insulin-independent effect of GLP-1 on unidirectional glucose transport into the brain during a pituitarypancreatic normoglycemic (plasma glucose ϳ4.5 mmol/l) clamp with 18-fluoro-deoxy-glucose as tracer.RESULTS-On average, GLP-1 reduced cerebral glucose transport by 27% in total cerebral gray matter (P ϭ 0.05) and by 25-30% in individual gray matter regions (P ϭ 0.02-0.06). The same regions revealed a uniform trend toward similarly reduced cerebral glucose metabolism. Consequently, the intracerebral glucose concentration remained constant in all regions, with and without GLP-1. CONCLUSIONS-We have demonstrated that a hormone involved in postprandial glucose regulation also limits glucose delivery to brain tissue and hence provides a possible regulatory mechanism for the link between plasma glucose and brain glucose. Because GLP-1 reduces glucose uptake across the intact blood-brain barrier at normal glycemia, GLP-1 may also protect the brain by limiting intracerebral glucose fluctuation when plasma glucose is increased. Diabetes 57:325-331, 2008 G lucagon-like peptide-1 (GLP-1) is an incretin hormone with several beneficial effects on glucose homeostasis. GLP-1 is not solely produced by the entero-endocrine L-cells in the gut but also in the brain by neurons in the nucleus of the tractus solitarius and thus functions as a neuropeptide (1). It stimulates insulin secretion and inhibits glucagon secretion in the presence of glucose, inhibits gastric emptying, and reduces appetite and food intake (2,3). Furthermore, it acts as a ␤-cell growth factor by stimulating ␤-cell proliferation and islet neogenesis and by reducing ␤-cell apoptosis (4). The glucose dependency of GLP-1 action on insulin and glucagon secretion results in a low risk of hypoglycemic episodes (5). These effects make GLP-1 attractive as an anti-diabetes medication, and several studies prove the beneficial effect on glucose homeostasis in the type 2 diabetic patient (6,7).Although GLP-1 receptors (GLP-1Rs) are predominantly located on the ␤-, ␦-, and presumably ␣-cells of the pancreas, receptors in other tissues may mediate GLP-1's effects outside the pancreas (8,9), where gastric emptying and appetite are well-known targets, as are other tissues including heart, kidney, and lungs (8). GLP-1R expression has been demonstrated in human brain (10), where receptors are particularly abundant in the paraventricular nucleus and the arcuate nucleus in the hypothalamus (11). Infusion of GL...

Exenatide Regulates Cerebral Glucose Metabolism in Brain Areas Associated With Glucose Homeostasis and Reward System

“…In contrast to previous studies that infused GLP-1 during pancreatic euglycemic (12) and hyperglycemic clamps (13), our study evaluated the effect of GLP-1 under physiologic conditions by combining 18 F-FDG with stable isotope tracer infusion during OGTT and quantitated CMR glu , RaO, and RaT. We found that RaO and RaT were inversely correlated with CMR glu but only after EX and not after PLC.…”

“…The protocol reflects the effect of normal route of subcutaneous EX administration on the normal route of glucose administration (oral). Previous studies used intravenous infusion of glucose, GLP-1, and somatostatin, and found a trend to decrease in CMR glu during normoglycemia (12) and an increase in CMR glu during hyperglycemia (13). However, in the Gejl et al (13) study, insulin concentrations were three times those observed during PLC, and thus a separate effect of insulin could not be excluded.…”

Brain Activation by Visual Food-Related Stimuli and Correlations with Metabolic and Hormonal Parameters: A fMRI Study

“…Also, recently published data have implicated adiponectin in regulating food intake and energy expenditure [48,49]. Moreover, glucagon-like peptide-1 (GLP-1), which is synthesized in the brain as well [50,51], may also be involved. Therefore, future research should attempt to investigate the correlations between these hormones/adipokines and regional brain activation using a similar fMRI paradigm.…”

GLP-1 Receptor Activation Modulates Appetite- and Reward-Related Brain Areas in Humans

“…Sulfonylureas were discontinued 3 days prior to examination, and metformin was discontinued on the day of examination. In order to study the effects of GLP-1 receptor activation per se, i.e., independent of hormonal or metabolic changes induced by GLP-1 receptor activation, all measurements were performed during a somatostatin pancreatic-pituitary clamp according to principles previously described (20). In short, somatostatin (Somatostatin; Eumedica) was infused at a rate of 60 ng/kg/min to suppress endogenous insulin, glucagon, growth hormone, and GLP-1 production.…”