Lack of hepatic "interregulation" during inhibition of glycogenolysis in a canine model.
It has been proposed that the glycogenolytic and gluconeogenic pathways contributing to endogenous glucose production are interrelated. Thus a change in one source of glucose 6-phosphate might be compensated for by an inverse change in the other pathway. We therefore investigated the effects of 1,4-dideoxy-1,4-imino-D-arabinitol (DAB), a potent glycogen phosphorylase inhibitor, on glucose production in fasted conscious dogs. When dogs were treated acutely with high glucagon, glucose production rose from 1.93 +/- 0.14 to 3.07 +/- 0.37 mg x kg(-1) x min(-1) (P < 0.01). When dogs were treated acutely with DAB in addition to high glucagon infusion, the stimulation of the glycogenolytic rate was completely suppressed. Glucose production rose from 1.85 +/- 0.20 to 2.41 +/- 0.17 mg x kg(-1) x min(-1) (P < 0.05), which was due to the increase in gluconeogenesis from 0.93 +/- 0.09 to 1.54 +/- 0.08 mg x kg(-1) x min(-1) (P < 0.001). In conclusion, infusion of DAB inhibited glycogenolysis; however, the absolute contribution of gluconeogenesis to glucose production was not affected. These results suggest that inhibition of glycogenolysis could be an effective antidiabetic treatment.
Fosgerau
K
K
Department of Diabetes Biochemistry and Metabolism, Novo Nordisk, DK-2760 Maaloev, Denmark. kf@novonordisk.com
Mittelman
S D
SD
Sunehag
A
A
Dea
M K
MK
Lundgren
K
K
Bergman
R N
RN
D000818:Animals; D001089:Arabinose; D001786:Blood Glucose / Q000187:drug effects; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005934:Glucagon / Q000008:administration & dosage; D005943:Gluconeogenesis / Q000187:drug effects; D015309:Glucose Clamp Technique; D006003:Glycogen / Q000378:metabolism*; D006868:Hydrolysis / Q000187:drug effects; D050113:Imino Furanoses; D007262:Infusions, Intravenous; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D006005:Phosphorylases / Q000037:antagonists & inhibitors; D011169:Portal Vein; D013402:Sugar Alcohols / Q000008:administration & dosage
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D050113:Imino Furanoses; D013402:Sugar Alcohols; C058137:1,4-dideoxy-1,4-iminoarabinitol; D006003:Glycogen; D005934:Glucagon; D001089:Arabinose; D006005:Phosphorylases