title: Insulin-induced hypoglycemia increases hepatic sensitivity to glucagon in dogs.
abstract: In individuals with type 1 diabetes, hypoglycemia is a common consequence of overinsulinization. Under conditions of insulin-induced hypoglycemia, glucagon is the most important stimulus for hepatic glucose production. In contrast, during euglycemia, insulin potently inhibits glucagon's effect on the liver. The first aim of the present study was to determine whether low blood sugar augments glucagon's ability to increase glucose production. Using a conscious catheterized dog model, we found that hypoglycemia increased glucagon's ability to overcome the inhibitory effect of insulin on hepatic glucose production by almost 3-fold, an effect exclusively attributable to marked enhancement of the effect of glucagon on net glycogen breakdown. To investigate the molecular mechanism by which this effect comes about, we analyzed hepatic biopsies from the same animals, and found that hypoglycemia resulted in a decrease in insulin signaling. Furthermore, hypoglycemia and glucagon had an additive effect on the activation of AMPK, which was associated with altered activity of the enzymes of glycogen metabolism.
authors.affiliation: Department of Molecular Physiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Noelia
authors.initials: N
authors.lastname: Rivera
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ramnanan
authors.forename: Zhibo
authors.initials: Z
authors.lastname: An
authors.forename: Tiffany
authors.initials: T
authors.lastname: Farmer
authors.forename: Marta
authors.initials: M
authors.lastname: Smith
authors.forename: Ben
authors.initials: B
authors.lastname: Farmer
authors.forename: Jose M
authors.initials: JM
authors.lastname: Irimia
authors.forename: Wanda
authors.initials: W
authors.lastname: Snead
authors.forename: Margaret
authors.initials: M
authors.lastname: Lautz
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Roach
authors.forename: Alan D
authors.initials: AD
authors.lastname: Cherrington
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000097:blood; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005934:Glucagon / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000187:drug effects; D050261:Glycogenolysis / Q000187:drug effects; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced / Q000378:metabolism*; D007328:Insulin / Q000009:adverse effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D015398:Signal Transduction
chemical_list: D005230:Fatty Acids, Nonesterified; D007328:Insulin; D008112:Liver Glycogen; D005934:Glucagon; D055372:AMP-Activated Protein Kinases; D020155:3-Hydroxybutyric Acid