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.

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...

In hyperglycemia, glucagon-like peptide-1 (GLP-1) lowers brain glucose concentration together with increased net blood-brain clearance and brain metabolism, but it is not known whether this effect depends on the prevailing plasma glucose (PG) concentration. In hypoglycemia, glucose depletion potentially impairs brain function. Here, we test the hypothesis that GLP-1 exacerbates the effect of hypoglycemia. To test the hypothesis, we determined glucose transport and consumption rates in seven healthy men in a randomized, double-blinded placebo-controlled cross-over experimental design. The acute effect of GLP-1 on glucose transfer in the brain was measured by positron emission tomography (PET) during a hypoglycemic clamp (3 mM plasma glucose) with 18F-fluoro-2-deoxy-glucose (FDG) as tracer of glucose. In addition, we jointly analyzed cerebrometabolic effects of GLP-1 from the present hypoglycemia study and our previous hyperglycemia study to estimate the Michaelis-Menten constants of glucose transport and metabolism. The GLP-1 treatment lowered the vascular volume of brain tissue. Loading data from hypo- to hyperglycemia into the Michaelis-Menten equation, we found increased maximum phosphorylation velocity (Vmax) in the gray matter regions of cerebral cortex, thalamus, and cerebellum, as well as increased blood-brain glucose transport capacity (Tmax) in gray matter, white matter, cortex, thalamus, and cerebellum. In hypoglycemia, GLP-1 had no effects on net glucose metabolism, brain glucose concentration, or blood-brain glucose transport. Neither hexokinase nor transporter affinities varied significantly with treatment in any region. We conclude that GLP-1 changes blood-brain glucose transfer and brain glucose metabolic rates in a PG concentration-dependent manner. One consequence is that hypoglycemia eliminates these effects of GLP-1 on brain glucose homeostasis.

The counter-regulatory response during 48 h of subcutaneous GLP-1 infusion was preserved despite long-term fasting with no apparent increased risk of hypoglycaemic episodes. No reactive hypoglycaemia was observed when the fast was followed by an OGTT. Thus use of long-acting GLP-1 analogues may not increase the risk of hypoglycaemia.

Background Hypoglycaemia, especially nocturnal, remains the main limiting factor of achieving good glycaemic control in type 1 diabetes. The effect of first generation long-acting insulin analogues in reducing nocturnal hypoglycaemia is well documented in patient with type 1 diabetes. The effect of the newer long-acting insulin degludec on risk of nocturnal hypoglycaemia remains undocumented in patients with type 1 diabetes and recurrent severe nocturnal hypoglycaemia. The HypoDeg trial is designed to investigate whether insulin degludec in comparison with insulin glargine U100 is superior in limiting the occurrence of nocturnal hypoglycaemia in patients with recurrent nocturnal severe hypoglycaemia. This paper reports the study design of the HypoDeg trial. Methods/design A Danish investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, two-year cross-over study investigating the effect of insulin degludec versus insulin glargine U100 on frequency of nocturnal hypoglycaemia in patients with type 1 diabetes and one or more episodes of nocturnal severe hypoglycaemia during the preceding two years as the major inclusion criteria. Patients are randomised (1:1) to basal therapy with insulin degludec or insulin glargine. Insulin aspart is used as bolus therapy in both treatment arms. Discussion In contrast to most other insulin studies the HypoDeg trial includes only patients at high risk of hypoglycaemia. The HypoDeg trial will compare treatment with insulin degludec to insulin glargine U100 in terms of risk of nocturnal hypoglycaemic episodes in patients with type 1 diabetes with the greatest potential to benefit from near-physiological insulin replacement therapy. www.clinicaltrials.gov : NCT02192450.