title: Hepatic glycogen can regulate hypoglycemic counterregulation via a liver-brain axis.
abstract: Liver glycogen is important for the counterregulation of hypoglycemia and is reduced in individuals with type 1 diabetes (T1D). Here, we examined the effect of varying hepatic glycogen content on the counterregulatory response to low blood sugar in dogs. During the first 4 hours of each study, hepatic glycogen was increased by augmenting hepatic glucose uptake using hyperglycemia and a low-dose intraportal fructose infusion. After hepatic glycogen levels were increased, animals underwent a 2-hour control period with no fructose infusion followed by a 2-hour hyperinsulinemic/hypoglycemic clamp. Compared with control treatment, fructose infusion caused a large increase in liver glycogen that markedly elevated the response of epinephrine and glucagon to a given hypoglycemia and increased net hepatic glucose output (NHGO). Moreover, prior denervation of the liver abolished the improved counterregulatory responses that resulted from increased liver glycogen content. When hepatic glycogen content was lowered, glucagon and NHGO responses to insulin-induced hypoglycemia were reduced. We conclude that there is a liver-brain counterregulatory axis that is responsive to liver glycogen content. It remains to be determined whether the risk of iatrogenic hypoglycemia in T1D humans could be lessened by targeting metabolic pathway(s) associated with hepatic glycogen repletion.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Winnick
authors.forename: Guillaume
authors.initials: G
authors.lastname: Kraft
authors.forename: Justin M
authors.initials: JM
authors.lastname: Gregory
authors.forename: Dale S
authors.initials: DS
authors.lastname: Edgerton
authors.forename: Phillip
authors.initials: P
authors.lastname: Williams
authors.forename: Ian A
authors.initials: IA
authors.lastname: Hajizadeh
authors.forename: Maahum Z
authors.initials: MZ
authors.lastname: Kamal
authors.forename: Marta
authors.initials: M
authors.lastname: Smith
authors.forename: Ben
authors.initials: B
authors.lastname: Farmer
authors.forename: Melanie
authors.initials: M
authors.lastname: Scott
authors.forename: Doss
authors.initials: D
authors.lastname: Neal
authors.forename: E Patrick
authors.initials: EP
authors.lastname: Donahue
authors.forename: Eric
authors.initials: E
authors.lastname: Allen
authors.forename: Alan D
authors.initials: AD
authors.lastname: Cherrington
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D005632:Fructose / Q000008:administration & dosage; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006801:Humans; D007003:Hypoglycemia / Q000097:blood / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism*; D008297:Male; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; D007328:Insulin; D008112:Liver Glycogen; D005632:Fructose; D019344:Lactic Acid; D005947:Glucose