Glucagon-like peptide-1 (GLP-1) raises blood-brain glucose transfer capacity and hexokinase activity in human brain

Abstract

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.

Cerebral Blood Flow and Aβ-Amyloid Estimates by WARM Analysis of [11C]PiB Uptake Distinguish among and between Neurodegenerative Disorders and Aging

“…The binding in the AD patients was the more significant measure, but the group as a whole had marked decrease of the sCBF estimates, particularly in FL and PL, as previously reported by Johannsen et al (2000). This finding is of considerable interest because a matching decline of glucose metabolism generally is not present (Edison et al, 2007), although lowered metabolism generally is evident also in FL in addition to the pathognomonic decline in parietal lobe (Gejl et al, 2012, 2013, 2014, 2016). The low flow may be a physiological reaction to the functional decline of the diseased brain, as oxygen delivery is commensurate with the reduced consumption of oxygen (Rodell et al, 2012).…”

At the Centennial of Michaelis and Menten, Competing Michaelis–Menten Steps Explain Effect of GLP‐1 on Blood–Brain Transfer and Metabolism of Glucose

“…The hypoglycaemia condition revealed that effects of native GLP‐1 on glucose metabolism in brain depend on the plasma glucose concentration , as in other tissues, notably beta cells in pancreas . Thus, GLP‐1 does not alter brain glucose metabolism or transport during hypoglycaemia.…”

“…Thus, GLP‐1 does not alter brain glucose metabolism or transport during hypoglycaemia. However, the GLP‐1 treatment led to a lower estimate of vascular volume in the brain . We did not determine cerebral blood flow in that study, but the glucose unidirectional and net clearances are measures that in principle incorporate effects of blood flow, expressed by the changes of extraction fractions (unidirectional and net).…”

Regulation of Glucose Homeostasis by GLP-1

“…For example, under conditions of hyperglycemia, peripherally administered GLP-1 increases the phosphorylation velocity ( V max ) of neuronal hexokinase while also increasing blood–brain glucose transport capacity ( T max ). 157,158 …”