Impact of a glycogen phosphorylase inhibitor and metformin on basal and glucagon-stimulated hepatic glucose flux in conscious dogs

• Published in: The Journal of pharmacology and experimental therapeutics 2011-06, Vol.337 (3), p.610-620
• Main Authors: Torres, Tracy P, Sasaki, Noriyasu, Donahue, E Patrick, Lacy, Brooks, Printz, Richard L, Cherrington, Alan D, Treadway, Judith L, Shiota, Masakazu
• Format: Article
• Language: English
• Subjects: Animals; Blood Glucose - metabolism; Dogs; Enzyme Inhibitors - pharmacology; Fasting; Fatty Acids, Nonesterified - blood; Fatty Acids, Nonesterified - metabolism; Female; Gastrointestinal, Hepatic, Pulmonary, and Renal; Glucagon - blood; Glucagon - metabolism; Glucagon - pharmacology; Gluconeogenesis - drug effects; Gluconeogenesis - physiology; Glucose - metabolism; Glucose-6-Phosphatase - drug effects; Glucose-6-Phosphatase - physiology; Glycerol - blood; Glycerol - metabolism; Glycogen Phosphorylase, Liver Form - antagonists & inhibitors; Glycogen Phosphorylase, Liver Form - metabolism; Hematocrit; Hypoglycemic Agents - pharmacology; Indoles - pharmacology; Insulin - blood; Insulin - metabolism; Lactic Acid - blood; Lactic Acid - metabolism; Liver - drug effects; Liver - metabolism; Liver Glycogen - metabolism; Male; Metformin - pharmacology; Phenylbutyrates - pharmacology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.110.177899

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.