A Novel Glucagon Receptor Antagonist Inhibits Glucagon-Mediated Biological Effects

Qureshi, Sajjad A.; Candelore, Mari R.; Xie, Dan; Yang, Xiaodong; Tota, Laurie; Ding, Victor D.-H.; Li, Zhihua; Bansal, Alka; Miller, Corin; Cohen, Steven L.; Jiang, Guoqiang; Brady, Edward J.; Saperstein, Richard; Duffy, Joseph; Tata, James R.; Chapman, Kevin T.; Moller, David E.; Zhang, Bei B.

doi:10.2337/diabetes.53.12.3267

Cited by 99 publications

(71 citation statements)

References 44 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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“…19 This technology appears to possess sufficient sensitivity to detect this phenomenon as well, as evident from the higher k pyr->bic exchange rate. Treatment with a glucagon-receptor antagonist appears to alleviate HGP in the diabetic liver, 20 and reducing glucagon signaling is being explored as a potential therapy for diabetes. 21 It will be interesting to measure corresponding changes in hepatic metabolism upon therapeutic intervention with a glucagon-receptor antagonist in diabetic animals, and that forms the next phase of our research.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Hyperpolarized Carbon-13 Magnetic Resonance Spectroscopy Reveals Increased Pyruvate Carboxylase Flux in an Insulin-Resistant Mouse Model

et al. 2013

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The pathogenesis of type 2 diabetes is characterized by impaired insulin action and increased hepatic glucose production (HGP). Despite the importance of hepatic metabolic aberrations in diabetes development, there is currently no molecular probe that allows measurement of hepatic gluconeogenic pathways in vivo and in a noninvasive manner. In this study, we used hyperpolarized carbon 13 ( 13 C)-labeled pyruvate magnetic resonance spectroscopy (MRS) to determine changes in hepatic gluconeogenesis in a high-fat diet (HFD)-induced mouse model of type 2 diabetes. Compared with mice on chow diet, HFD-fed mice displayed higher levels of oxaloacetate, aspartate, and malate, along with increased 13 C label exchange rates between hyperpolarized [1-13 C]pyruvate and its downstream metabolites, [1-13 C]malate and [1-13 C]aspartate. Biochemical assays using liver extract revealed up-regulated malate dehydrogenase activity, but not aspartate transaminase activity, in HFD-fed mice. Moreover, the 13 C label exchange rate between [1-13 C]pyruvate and [1-13 C]aspartate (k pyr->asp ) exhibited apparent correlation with gluconeogenic pyruvate carboxylase (PC) activity in hepatocytes. Finally, up-regulated HGP by glucagon stimulation was detected by an increase in aspartate signal and k pyr->asp , whereas HFD mice treated with metformin for 2 weeks displayed lower production of aspartate and malate, as well as reduced k pyr->asp and 13 C-label exchange rate between pyruvate and malate, consistent with down-regulated gluconeogenesis. Conclusion: Taken together, we demonstrate that increased PC flux is an important pathway responsible for increased HGP in diabetes development, and that pharmacologically induced metabolic changes specific to the liver can be detected in vivo with a hyperpolarized 13 C-biomolecular probe. Hyperpolarized 13 C MRS and the determination of metabolite exchange rates may allow longitudinal monitoring of liver function in disease development. (HEPATOLOGY 2013;57:515-524) T he coordinated actions of insulin and glucagon ensure that glucose homeostasis is maintained across a wide range of physiological conditions. In obesity-associated type 2 diabetes, control of glucose metabolism by these two regulatory hormones is impaired, resulting in hepatic insulin resistance and excessive endogenous glucose production. 1 To date, it has not been possible to evaluate this metabolic dysfunction in the liver by a noninvasive in vivo method.Carbon-13 ( 13 C) magnetic resonance spectroscopy (MRS) has been used to study hepatic gluconeogenesis since the 1980s. However, its inherent low sensitivity has largely limited its application to the study of steady-state metabolism in perfused livers with long Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; 13 C, carbon-13; ChREBP, carbohydrate response element-binding protein; FAS, fatty acid synthase; G-6-Pase, glucose-6-phosphatase; HFD, high-fat diet; HGP, hepatic glucose production; IHTG, intrahepatic triglyceride; IPGTT, intraperitoneal glucose toleranc...

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“…Reduction of glucagon activity using glucagon antagonists, immunoneutralizing antisera, or antisense oligonucleotides (ASOs) directed against Gcgr attenuates hyperglycemia in experimental models of diabetes (16)(17)(18)(19)(20)(21)(22)(23). The importance of glucagon action has also been examined via generation and characterization of the Gcgr -/-mouse.…”

Section: Introductionmentioning

confidence: 99%

Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis

Ali

Lamont

Charron³

et al. 2011

J. Clin. Invest.

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Disordered glucagon secretion contributes to the symptoms of diabetes, and reduced glucagon action is known to improve glucose homeostasis. In mice, genetic deletion of the glucagon receptor (Gcgr) results in increased levels of the insulinotropic hormone glucagon-like peptide 1 (GLP-1), which may contribute to the alterations in glucose homeostasis observed in Gcgr -/-mice. Here, we assessed the contribution of GLP-1 receptor (GLP-1R) signaling to the phenotype of Gcgr -/-mice by generating Gcgr -/-Glp1r -/-mice. Although insulin sensitivity was similar in all genotypes, fasting glucose was increased in Gcgr -/-Glp1r -/-mice. Elimination of the Glp1r normalized gastric emptying and impaired intraperitoneal glucose tolerance in Gcgr -/-mice. Unexpectedly, deletion of Glp1r in Gcgr -/-mice did not alter the improved oral glucose tolerance and increased insulin secretion characteristic of that genotype. Although Gcgr -/-Glp1r -/-islets exhibited increased sensitivity to the incretin glucose-dependent insulinotropic polypeptide (GIP), mice lacking both Glp1r and the GIP receptor (Gipr) maintained preservation of the enteroinsular axis following reduction of Gcgr signaling. Moreover, Gcgr -/-Glp1r -/-islets expressed increased levels of the cholecystokinin A receptor (Cckar) and G protein-coupled receptor 119 (Gpr119) mRNA transcripts, and Gcgr -/-Glp1r -/-mice exhibited increased sensitivity to exogenous CCK and the GPR119 agonist AR231453. Our data reveal extensive functional plasticity in the enteroinsular axis via induction of compensatory mechanisms that control nutrient-dependent regulation of insulin secretion.

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A Novel Glucagon Receptor Antagonist Inhibits Glucagon-Mediated Biological Effects

Cited by 99 publications

References 44 publications

Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

In Vivo Hyperpolarized Carbon-13 Magnetic Resonance Spectroscopy Reveals Increased Pyruvate Carboxylase Flux in an Insulin-Resistant Mouse Model

Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis

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