(Des-Histidine1) (Nϵ-phenylthiocarbamoyllysine12)-glucagon: Effects on glycogenolysis in perfused rat liver

Khan, Bijay; Bregman, Marvin D.; Nugent, Charles A.; Hruby, Victor J.; Brendel, Klaus

doi:10.1016/0006-291x(80)91138-9

Cited by 20 publications

(8 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar concentrations also inhibit PK activity by 30 -65% [175,178]. Correspondingly, increases in gluconeogenesis and glucose output reach approximately 60 -65% of the maximum attainable by higher, AC-activating hormone concentrations [94][95][96] (Fig. 7A).…”

Section: Post-translational Regulation Of Pyruvate Kinasementioning

confidence: 92%

See 1 more Smart Citation

Glucagon and Cyclic AMP: Time to Turn the Page?

Rodgers

2012

CDR

View full text Add to dashboard Cite

It is well established that glucagon can stimulate adipose lipolysis, myocardial contractility, and hepatic glucose output by activating a GPCR and adenylate cyclase (AC) and increasing cAMP production. It is also widely reported that activation of AC in all three tissues requires pharmacological levels of the hormone, exceeding 0.1 nM. Extensive evidence is presented here supporting the view that cAMP does not mediate metabolic actions of glucagon on adipose, heart, or liver in vivo. Only pharmacological levels stimulate AC, adipose lipolysis, or cardiac contractility. Physiological concentrations of glucagon (below 0.1 nM) duplicate metabolic effects of insulin on the heart by activating a PI3K-dependent signal without stimulating AC. In the liver, glucagon can enhance gluconeogenesis and glucose output -by increasing the expression of PEPCK or inhibiting the activity of PK -at pharmacological concentrations by activating AC coupled to a low-affinity GPCR, but also at physiological concentrations by activating a high affinity receptor without generating cAMP. Plausible AC/cAMP-independent signals mediating the increase in gluconeogenesis include p38 MAPK (PEPCK expression) and IP3/DAG/Ca 2+ (PK activity). None of glucagon's physiological effects can be explained by activation of spare receptors or amplification of the AC/cAMP signal. In a new model proposed here, glucagon antagonizes insulin on the liver but mimics insulin on the heart without activating AC. Confirmation of the model would have broad implications, applicable not only to the general field of metabolic endocrinology but also to the specific role of glucagon in the pathogenesis and treatment of diabetes.

show abstract

Section: Post-translational Regulation Of Pyruvate Kinasementioning

confidence: 92%

“…All curves are composites compiled from multiple reports: A) [13,[23][24][25][26][27]; B) [63][64][65][66][67][68][69][70][71][72]; and C) [24,69,[88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103]. The shaded area is the average glucagon blood range in the rat, from references [30][31][32][33][34][35][36][37][38][39].…”

Section: Fig (2)mentioning

confidence: 99%

Glucagon and Cyclic AMP: Time to Turn the Page?

Rodgers

2012

CDR

View full text Add to dashboard Cite

show abstract

“…In other words, in the presence of phorbol esters, a clear dissociation between glucagon-mediated cyclic AMP accumulation and glucagon-mediated metabolic effects is observed. We (Cairdenas-Tanu(s et al, 1982; and other authors (Okajima & Ui, 1976;Birnbaum & Fain, 1977;Fain & Shepherd, 1977;Khan et al, 1980), using different experimental approaches, have been able to observe dissociation between cyclic AMP accumulation and the physiological responses produced by glucagon action. These data suggest that cyclic AMP might be the main, but not the sole, factor involved in the metabolic actions of glucagon on liver cells.…”

Section: Discussionmentioning

confidence: 75%

Effects of phorbol esters on α1-adrenergic-mediated and glucagon-mediated actions in isolated rat hepatocytes

García‐Sáinz¹,

Mendlovic²,

Martínez-Olmedo³

1985

Biochemical Journal

View full text Add to dashboard Cite

Phorbol 12-myristate 13-acetate (PMA) inhibited the stimulation of ureogenesis produced by adrenaline, but produced a minimal displacement to the right of the dose-response curve for glucagon. However, PMA diminished the accumulation of cyclic AMP induced by glucagon. Dissociation between the cyclic AMP concentrations and the metabolic effects induced by glucagon is evidenced in the presence of phorbol esters.

show abstract

“…On the other hand, [/V"-CAR-His']glucagon demonstrates partial agonist activity with respect to adenylate cyclase but is devoid of any lipolytic and glycogenolytic activities in vivo (Grande et al, 1972). In addition, antagonists of glucagon such as des-His1, [TV'-PTC-Lys12]glucagon and [A"-TNP-His!,HArg12]glucagon, which bind to liver plasma membrane receptors, are inactive in the adenylate cyclase bioassay system, and can antagonize the stimulation of adenylate cyclase by glucagon (Bregman et al, 1980), were found to be weak but full agonists when tested for glycogenolytic activity in the perfused rat liver (Khan et al, 1980) and isolated hepatocyte systems (Corvera et al, 1984). It is possible that the apparent contradictions described above may be explained by a differential interaction of these analogues with the proposed high-and low-affinity receptor sites for glucagon (Musso et al, 1984).…”

Section: Discussionmentioning

confidence: 99%

“…It is possible that the apparent contradictions described above may be explained by a differential interaction of these analogues with the proposed high-and low-affinity receptor sites for glucagon (Musso et al, 1984). It has also been suggested that under some conditions glucagon may mediate its activity by a cAMP-independent mechanism (Exton et al, 1971; Okajima & Ui, 1976; Birnbaum & Fain, 1977; Fain & Shephard, 1977; Cote & Epand, 1979;Khan et al, 1980;Corvera et al, 1984).…”

Section: Discussionmentioning

confidence: 99%

Receptor binding and adenylate cyclase activities of glucagon analogs modified in the N-terminal region

et al. 1986

Self Cite

View full text Add to dashboard Cite

In this study, we determined the ability of four N-terminally modified derivatives of glucagon, [3-Me-His1,Arg12]-, [Phe1,Arg12]-, [D-Ala4,Arg12]-, and [D-Phe4]glucagon, to compete with 125I-glucagon for binding sites specific for glucagon in hepatic plasma membranes and to activate the hepatic adenylate cyclase system, the second step involved in producing many of the physiological effects of glucagon. Relative to the native hormone, [3-Me-His1,Arg12]glucagon binds approximately twofold greater to hepatic plasma membranes but is fivefold less potent in the adenylate cyclase assay. [Phe1,Arg12]glucagon binds threefold weaker and is also approximately fivefold less potent in adenylate cyclase activity. In addition, both analogues are partial agonists with respect to adenylate cyclase. These results support the critical role of the N-terminal histidine residue in eliciting maximal transduction of the hormonal message. [D-Ala4,Arg12]glucagon and [D-Phe4]glucagon, analogues designed to examine the possible importance of a beta-bend conformation in the N-terminal region of glucagon for binding and biological activities, have binding potencies relative to glucagon of 31% and 69%, respectively. [D-Ala4,Arg12]glucagon is a partial agonist in the adenylate cyclase assay system having a fourfold reduction in potency, while the [D-Phe4] derivative is a full agonist essentially equipotent with the native hormone. These results do not necessarily support the role of an N-terminal beta-bend in glucagon receptor recognition. With respect to in vivo glycogenolysis activities, all of the analogues have previously been reported to be full agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

show abstract

(Des-Histidine1) (Nϵ-phenylthiocarbamoyllysine12)-glucagon: Effects on glycogenolysis in perfused rat liver

Cited by 20 publications

References 30 publications

Glucagon and Cyclic AMP: Time to Turn the Page?

Glucagon and Cyclic AMP: Time to Turn the Page?

Effects of phorbol esters on α1-adrenergic-mediated and glucagon-mediated actions in isolated rat hepatocytes

Receptor binding and adenylate cyclase activities of glucagon analogs modified in the N-terminal region

Contact Info

Product

Resources

About