Relative contribution of Ca2+-dependent mechanism in glucagon-induced glucose output from the liver.
Divalent cations are known to affect the activity of the cAMP-generating system. By observing the effects of the addition of cobalt (Co2+) and the depletion of calcium (Ca2+), this study tried to determine the relative contribution of Ca2+-dependent mechanism in glucagon-induced glucose output from the isolated perfused rat liver. Co2+ (1 mM) completely suppressed glucose and cAMP output induced by 0.1 nM glucagon and partly suppressed those induced by 1 to 10 nM glucagon. Co2+ (1-5 mM) did not inhibit 125I-labeled glucagon binding to hepatic cell membrane. Phenylephrine- or angiotensin II-induced glucose output was not affected by 1 mM Co2+. Co2+ (1 mM) inhibited a glucagon-induced increase in [Ca2+]i in isolated rat hepatocytes but did not inhibit a phenylephrine-induced increase in [Ca2+]i. The removal of Ca2+ from the perfusion medium impaired phenylephrine- or angiotensin II-induced glucose output, but did not impair glucagon-induced glucose output. When glucagon-induced cAMP production was inhibited by Co2+, the glucose output produced by 1 to 10 nM glucagon was impaired further in the Ca2+-free perfusion. Addition of 0.1 mM IBMX increased the glucose output produced by 1 nM glucagon but did not increase that produced by 10 nM glucagon in the Co2+-containing Ca2+-free perfusion. These results suggest that Co2+ inhibits the glucagon-responsive adenylyl cyclase system directly, resulting in impaired glucose output. Glucagon increases [Ca2+]i through a mechanism different from that of phenylephrine. Glucagon (0.01-10 nM)-induced glucose output from the liver is derived mainly through a cAMP-dependent mechanism. Only when glucagon-induced cAMP production was inhibited by Co2+ was the Ca2+ dependency observed in high concentrations (>/=1 nM) of glucagon-induced glucose output, and it approximated 30% of the glucose output produced by 10 nM glucagon.
Yamatani
K
K
The Third Department of Internal Medicine, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan.
Saito
K
K
Ikezawa
Y
Y
Ohnuma
H
H
Sugiyama
K
K
Manaka
H
H
Takahashi
K
K
Sasaki
H
H
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D003035:Cobalt / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D005934:Glucagon / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D008099:Liver / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D007457:Iodine Radioisotopes; D000804:Angiotensin II; D010656:Phenylephrine; D003035:Cobalt; D005934:Glucagon; D000242:Cyclic AMP; D005947:Glucose; D002118:Calcium