title: Impact of a glycogen phosphorylase inhibitor and metformin on basal and glucagon-stimulated hepatic glucose flux in conscious dogs.
abstract: The effects of a glycogen phosphorylase inhibitor (GPI) and metformin (MT) on hepatic glucose fluxes (μmol · kg(-1) · min(-1)) in the presence of basal and 4-fold basal levels of plasma glucagon were investigated in 18-h fasted conscious dogs. Compared with the vehicle treatment, GPI infusion suppressed net hepatic glucose output (NHGO) completely (-3.8 ± 1.3 versus 9.9 ± 2.8) despite increased glucose 6-phosphate (G-6-P) neogenesis from gluconeogenic precursors (8.1 ± 1.1 versus 5.5 ± 1.1). MT infusion did not alter those parameters. In response to a 4-fold rise in plasma glucagon levels, in the vehicle group, plasma glucose levels were increased 2-fold, and NHGO was increased (43.9 ± 5.7 at 10 min and 22.7 ± 3.4 at steady state) without altering G-6-P neogenesis (3.7 ± 1.5 and 5.5 ± 0.5, respectively). In the GPI group, there was no increase in NHGO due to decreased glucose-6-phosphatase flux associated with reduced G-6-P concentration. A lower G-6-P concentration was the result of increased net glycogenesis without altering G-6-P neogenesis. In the MT group, the increment in NHGO (22.2 ± 4.4 at 10 min and 12.1 ± 3.6 at steady state) was approximately half of that of the vehicle group. The lesser NHGO was associated with reduced glucose-6-phosphatase flux but a rise in G-6-P concentration and only a small incorporation of plasma glucose into glycogen. In conclusion, the inhibition of glycogen phosphorylase a activity decreases basal and glucagon-induced NHGO via redirecting glucose 6-phosphate flux from glucose toward glycogen, and MT decreases glucagon-induced NHGO by inhibiting glucose-6-phosphatase flux and thereby reducing glycogen breakdown.
authors.affiliation: Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2215 Garland Ave., Nashville, TN 37232-0615, USA.
authors.forename: Tracy P
authors.initials: TP
authors.lastname: Torres
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Sasaki
authors.forename: E Patrick
authors.initials: EP
authors.lastname: Donahue
authors.forename: Brooks
authors.initials: B
authors.lastname: Lacy
authors.forename: Richard L
authors.initials: RL
authors.lastname: Printz
authors.forename: Alan D
authors.initials: AD
authors.lastname: Cherrington
authors.forename: Judith L
authors.initials: JL
authors.lastname: Treadway
authors.forename: Masakazu
authors.initials: M
authors.lastname: Shiota
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005215:Fasting; D005230:Fatty Acids, Nonesterified / Q000097:blood / Q000378:metabolism; D005260:Female; D005934:Glucagon / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D005943:Gluconeogenesis / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000187:drug effects / Q000502:physiology; D005990:Glycerol / Q000097:blood / Q000378:metabolism; D025001:Glycogen Phosphorylase, Liver Form / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006400:Hematocrit; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000378:metabolism; D019344:Lactic Acid / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008112:Liver Glycogen / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D010654:Phenylbutyrates / Q000494:pharmacology
chemical_list: C504712:3-(5-chloroindole-2-carbonyl)amino-2-hydroxy-4-phenylbutyric acid N-methyl-N-methoxyamide; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007211:Indoles; D007328:Insulin; D008112:Liver Glycogen; D010654:Phenylbutyrates; D019344:Lactic Acid; D005934:Glucagon; D008687:Metformin; D025001:Glycogen Phosphorylase, Liver Form; D005952:Glucose-6-Phosphatase; D005947:Glucose; D005990:Glycerol