Effects of skyrin, a receptor-selective glucagon antagonist, in rat and human hepatocytes.

Parker, Janice C.; McPherson, R. Kirk; Andrews, Kim; Levy, Carolyn B.; Dubins, Jeffrey S.; Chin, Je; Perry, Pia; Hulin, Bernard; Perry, David A.; Inagaki, Taisuke; Dekker, K.; Tachikawa, Kazushige; Sugie, Yoko; Treadway, Judith L.

doi:10.2337/diabetes.49.12.2079

Cited by 60 publications

(30 citation statements)

References 18 publications

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“…Such maneuvers also improved the metabolic state in insulin deficiency (76)(77)(78)(79)(80). These results strongly suggest that the catabolic actions heretofore considered the direct consequences of insulin lack are actually mediated by a relative or absolute excess of glucagon to insulin.…”

Section: Glucagonocentrism: Insulin Actions Are Mediated By Glucagonssupporting

confidence: 50%

Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

2012

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The hormone glucagon has long been dismissed as a minor contributor to metabolic disease. Here we propose that glucagon excess, rather than insulin deficiency, is the sine qua non of diabetes. We base this on the following evidence: (a) glucagon increases hepatic glucose and ketone production, catabolic features present in insulin deficiency; (b) hyperglucagonemia is present in every form of poorly controlled diabetes; (c) the glucagon suppressors leptin and somatostatin suppress all catabolic manifestations of diabetes during total insulin deficiency; (d) total β cell destruction in glucagon receptor-null mice does not cause diabetes; and (e) perfusion of normal pancreas with anti-insulin serum causes marked hyperglucagonemia. From this and other evidence, we conclude that glucose-responsive β cells normally regulate juxtaposed α cells and that without intraislet insulin, unregulated α cells hypersecrete glucagon, which directly causes the symptoms of diabetes. This indicates that glucagon suppression or inactivation may provide therapeutic advantages over insulin monotherapy.Conflict of interest: Alan D.

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Section: Glucagonocentrism: Insulin Actions Are Mediated By Glucagonssupporting

confidence: 50%

Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

2012

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“…The published antagonists appear to act via distinct receptor mechanisms. Skyrin, one of the earlier antagonists, appeared to functionally inhibit glucagon-stimulated cAMP production and glycogenolysis without affecting glucagon binding (36). Other antagonists inhibit both the binding and the function of glucagon in competitive or noncompetitive fashion.…”

Section: Discussionmentioning

confidence: 99%

A Novel Glucagon Receptor Antagonist Inhibits Glucagon-Mediated Biological Effects

et al. 2004

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Glucagon maintains glucose homeostasis during the fasting state by promoting hepatic gluconeogenesis and glycogenolysis. Hyperglucagonemia and/or an elevated glucagon-to-insulin ratio have been reported in diabetic patients and animals. Antagonizing the glucagon receptor is expected to result in reduced hepatic glucose overproduction, leading to overall glycemic control. Here we report the discovery and characterization of compound 1 (Cpd 1), a compound that inhibits binding of 125 I-labeled glucagon to the human glucagon receptor with a half-maximal inhibitory concentration value of 181 ؎ 10 nmol/l. In CHO cells overexpressing the human glucagon receptor, Cpd 1 increased the half-maximal effect for glucagon stimulation of adenylyl cyclase with a K DB of 81 ؎ 11 nmol/l. In addition, Cpd 1 blocked glucagon-mediated glycogenolysis in primary human hepatocytes. In contrast, a structurally related analog (Cpd 2) was not effective in blocking glucagon-mediated biological effects. Real-time measurement of glycogen synthesis and breakdown in perfused mouse liver showed that Cpd 1 is capable of blocking glucagoninduced glycogenolysis in a dosage-dependent manner. Finally, when dosed in humanized mice, Cpd 1 blocked the rise of glucose levels observed after intraperitoneal administration of exogenous glucagon. Taken together, these data suggest that Cpd 1 is a potent glucagon receptor antagonist that has the capability to block the effects of glucagon in vivo. Diabetes 53

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“…These include studies of the impacts of suppression of endogenous glucagon secretion in experimental animals (5) and humans (40), immunoneutralization of glucagon (3), defective synthesis of biologically active glucagon (12, 49), diverse mutations (1, 17, 25, 26), and absent (13, 32) or reduced (21, 45) glucagon receptors in experimental animals and of glucagon antagonists in experimental animals (19), cells (33), and humans (35).…”

Section: Evidence For the Prevalent Viewmentioning

confidence: 99%

“…A peptide glucagon antagonist has been reported to lower blood glucose concentrations in anesthetized streptozotocin-diabetic rats (19), a nonpeptide antagonist to reduce glucagon actions on cells in vitro (33), and another nonpeptide antagonist to reduce glycemic responses to infused glucagon in healthy humans (35). Notably, however, the last glucagon antagonist had no effect on postabsorptive rates of endogenous glucose production or plasma glucose concentrations over the 120-min interval between drug administration and initiation of glucagon infusion, the time frame that included maximum plasma concentrations of the antagonist (35).…”

Section: Evidence For the Prevalent Viewmentioning

confidence: 99%

Maintenance of the postabsorptive plasma glucose concentration: insulin or insulin plus glucagon?

Raju

Cryer

2005

American Journal of Physiology-Endocrinology and Metabolism

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The prevalent view is that the postabsorptive plasma glucose concentration is maintained within the physiological range by the interplay of the glucose-lowering action of insulin and the glucose-raising action of glucagon. It is supported by a body of evidence derived from studies of suppression of glucagon (and insulin, among other effects) with somatostatin in animals and humans, immunoneutralization of glucagon, defective glucagon synthesis, diverse mutations, and absent or reduced glucagon receptors in animals and glucagon antagonists in cells, animals, and humans. Many of these studies are open to alternative interpretations, and some lead to seemingly contradictory conclusions. For example, immunoneutralization of glucagon lowered plasma glucose concentrations in rabbits, but administration of a glucagon antagonist did not lower plasma glucose concentrations in healthy humans. Evidence that the glycemic threshold for glucagon secretion, unlike that for insulin secretion, lies below the physiological range, and the finding that selective suppression of insulin secretion without stimulation of glucagon secretion raises fasting plasma glucose concentrations in humans underscore the primacy of insulin in the regulation of the postabsorptive plasma glucose concentration and challenge the prevalent view. The alternative view is that the postabsorptive plasma glucose concentration is maintained within the physiological range by insulin alone, specifically regulated increments and decrements in insulin, and the resulting decrements and increments in endogenous glucose production, respectively, and glucagon becomes relevant only when glucose levels drift below the physiological range. Although the balance of evidence suggests that glucagon is involved in the maintenance of euglycemia, more definitive evidence is needed, particularly in humans. glucose metabolism; hypoglycemia; diabetes GIVEN EVIDENCE of absolute or relative hyperglucagonemia in patients with type 1 and type 2 diabetes (27,29,37,38), Unger and Orci (48) first proposed that glucagon, in the setting of absolute or relative insulin deficiency, plays a role in the pathogenesis of diabetes. Their bihormonal hypothesis was based on three lines of evidence: 1) endogenous hyperglycemia had never been observed in the absence of glucagon; 2) when both insulin and glucagon were suppressed with somatostatin, hyperglycemia did not occur; and 3) somatostatin-induced suppression of glucagon reduced glycemia in humans with diabetes. With respect to the last, somatostatin has been shown to reduce, but not normalize, fasting and postprandial hyperglycemia (15) and to delay increments in plasma glucose (as well as in plasma nonesterified fatty acids, glycerol, and ␤-hydroxybutyrate) concentrations following withdrawal of insulin in patients with type 1 diabetes (14). Although these findings are entirely consistent with a role of glucagon in the pathogenesis of hyperglycemia (and ketosis) in type 1 diabetes, control studies with somatostatin administration and replacem...

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Effects of skyrin, a receptor-selective glucagon antagonist, in rat and human hepatocytes.

Cited by 60 publications

References 18 publications

Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

A Novel Glucagon Receptor Antagonist Inhibits Glucagon-Mediated Biological Effects

Maintenance of the postabsorptive plasma glucose concentration: insulin or insulin plus glucagon?

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