Brain glucosamine boosts protective glucoprivic feeding.
The risk of iatrogenic hypoglycemia is increased in diabetic patients who lose defensive glucoregulatory responses, including the important warning symptom of hunger. Protective hunger symptoms during hypoglycemia may be triggered by hypothalamic glucose-sensing neurons by monitoring changes downstream of glucose phosphorylation by the specialized glucose-sensing hexokinase, glucokinase (GK), during metabolism. Here we investigated the effects of intracerebroventricular (ICV) infusion of glucosamine (GSN), a GK inhibitor, on food intake at normoglycemia and protective feeding responses during glucoprivation and hypoglycemia in chronically catheterized rats. ICV infusion of either GSN or mannoheptulose, a structurally different GK inhibitor, dose-dependently stimulated feeding at normoglycemia. Consistent with an effect of GSN to inhibit competitively glucose metabolism, ICV coinfusion of d-glucose but not l-glucose abrogated the orexigenic effect of ICV GSN at normoglycemia. Importantly, ICV infusion of a low GSN dose (15 nmol/min) that was nonorexigenic at normoglycemia boosted feeding responses to glucoprivation in rats with impaired glucose counterregulation. ICV infusion of 15 nmol/min GSN also boosted feeding responses to threatened hypoglycemia in rats with defective glucose counterregulation. Altogether our findings suggest that GSN may be a potential therapeutic candidate for enhancing defensive hunger symptoms during hypoglycemia.
Osundiji
Mayowa A
MA
University of Cambridge, Institute of Metabolic Science, IMS-MRL, Box 289 Addenbrookes Hospital, Hills Road, Cambridge CB2 0QQ United Kingdom.
Zhou
Ligang
L
Shaw
Jill
J
Moore
Stephen P
SP
Yueh
Chen-Yu
CY
Sherwin
Robert
R
Heisler
Lora K
LK
Evans
Mark L
ML
D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001923:Brain Chemistry; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004435:Eating / Q000187:drug effects*; D005941:Glucokinase / Q000378:metabolism; D005944:Glucosamine / Q000008:administration & dosage* / Q000032:analysis / Q000378:metabolism; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006815:Hunger / Q000187:drug effects*; D007003:Hypoglycemia / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008356:Mannoheptulose / Q000008:administration & dosage; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley
D001786:Blood Glucose; D016760:Proto-Oncogene Proteins c-fos; D008356:Mannoheptulose; D005941:Glucokinase; D005947:Glucose; D005944:Glucosamine