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 (mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) 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 (Ϫ3.8 Ϯ 1.3 versus 9.9 Ϯ 2.8) despite increased glucose 6-phosphate (G-6-P) neogenesis from gluconeogenic precursors (8.1 Ϯ 1.1 versus 5.5 Ϯ 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 Ϯ 5.7 at 10 min and 22.7 Ϯ 3.4 at steady state) without altering G-6-P neogenesis (3.7 Ϯ 1.5 and 5.5 Ϯ 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 Ϯ 4.4 at 10 min and 12.1 Ϯ 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-phospatase flux and thereby reducing glycogen breakdown.

Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

“…This compound significantly decreased plasma glucose levels and increased hepatic glycogen levels in db/db and streptozocin-induced diabetic mouse models 31 , but long-term effects or actions in other tissues were not studied. CP-316,819, is an indole carboxamide compound 32 that decreased hepatic glucose output in fasted dogs with basal or elevated glucagon levels 33 , although thorough analysis of potential effects on other tissues was not performed. Another commercially available glycogen phosphorylase inhibitor, BAY R 3401, which acts by a similar mechanism as indole carboxamides, also successfully decreased hepatic glucose output and plasma glucose levels in fasted dogs 34 .…”

Glucagon and Cyclic AMP: Time to Turn the Page?

“…The collective evidence has established beyond doubt ( Fig. 1) that activation of *Address correspondence to this author at the Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, 02881, USA; Tel: 401-874-5033; Fax: 401-874-2646; E-mail: rrodgers@uri.edu AC -and production of cAMP -by glucagon stimulates lipolysis in adipose tissue, inotropy and chronotropy in heart, and glucose output in liver [10][11][12][13][14][15][16][17][18][19].…”

Hypoglycemia and severe lactic acidosis in a dog following metformin exposure

“…Antagonism of glucagon activity may be the primary mechanism by which metformin causes hypoglycemia; however, increased glucose consumption during aerobic metabolism may be a concurrent factor . In both diabetic and nondiabetic patients, metformin has been shown to independently increase glucagon‐like peptide 1 (GLP‐1) .…”

“…There is research suggesting that there may be genetic variations that affect the pharmacodynamics, pharmacokinetics, and metabolism of metformin, which may be a contributing factor to the development of hypoglycemia [29]. Antagonism of glucagon activity may be the primary mechanism by which metformin causes hypoglycemia; however, increased glucose consumption during aerobic metabolism may be a concurrent factor [21,22,[30][31][32]. In both diabetic and nondiabetic patients, metformin has been shown to independently increase glucagon-like peptide 1 (GLP-1) [22,33].…”