title: BDNF action in the brain attenuates diabetic hyperglycemia via insulin-independent inhibition of hepatic glucose production.
abstract: Recent evidence suggests that central leptin administration fully normalizes hyperglycemia in a rodent model of uncontrolled insulin-deficient diabetes by reducing hepatic glucose production (HGP) and by increasing glucose uptake. The current studies were undertaken to determine whether brain-derived neurotrophic factor (BDNF) action in the brain lowers blood glucose in uncontrolled insulin-deficient diabetes and to investigate the mechanisms mediating this effect. Adult male rats implanted with cannulas to either the lateral cerebral ventricle or the ventromedial hypothalamic nucleus (VMN) received either vehicle or streptozotocin to induce uncontrolled insulin-deficient diabetes. Three days later, animals received daily intracerebroventricular or intra-VMN injections of either BDNF or its vehicle. We found that repeated daily intracerebroventricular administration of BDNF attenuated diabetic hyperglycemia independent of changes in food intake. Instead, using tracer dilution techniques during a basal clamp, we found that BDNF lowered blood glucose levels by potently suppressing HGP, without affecting tissue glucose uptake, an effect associated with normalization of both plasma glucagon levels and hepatic expression of gluconeogenic genes. Moreover, BDNF microinjection directly into the VMN also lowered fasting blood glucose levels in uncontrolled insulin-deficient diabetes, but this effect was modest compared with intracerebroventricular administration. We conclude that central nervous system BDNF attenuates diabetic hyperglycemia via an insulin-independent mechanism. This action of BDNF likely involves the VMN and is associated with inhibition of glucagon secretion and a decrease in the rate of HGP.
authors.affiliation: Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Meek
authors.forename: Brent E
authors.initials: BE
authors.lastname: Wisse
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Thaler
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Guyenet
authors.forename: Miles E
authors.initials: ME
authors.lastname: Matsen
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Fischer
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Taborsky
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schwartz
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Morton
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001692:Biological Transport / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D005247:Feeding Behavior / Q000187:drug effects; D005934:Glucagon / Q000097:blood / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007276:Injections, Intraventricular; D007328:Insulin / Q000627:therapeutic use; D020547:Lateral Ventricles / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014697:Ventromedial Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D007004:Hypoglycemic Agents; D007328:Insulin; D005934:Glucagon; D005947:Glucose