Hepatic and glucagon-like peptide-1–mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors

Sloop, Kyle W.; Cao, Julia Xiao-Chun; Siesky, Angela M.; Zhang, Hong Yan; Bodenmiller, Diane; Cox, Amy L.; Jacobs, Steven J.; Moyers, Julie S.; Owens, Rebecca A.; Showalter, Aaron D.; Brenner, Martin; Raap, Achim; Gromada, Jesper; Berridge, Brian R.; Monteith, David K.; Pørksen, Niels; McKay, Robert A.; Monia, Brett P.; Bhanot, Sanjay; Watts, Lynnetta M.; Michael, M. Dodson

doi:10.1172/jci200420911

Cited by 81 publications

(138 citation statements)

References 32 publications

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“…Hyperglucagonemia, accompanied by hypertrophy and hyperplasia of the pancreatic a-cells, has been observed in glucagon receptor knock-out mice (34) and mice treated with glucagon receptor antisense oligonucleotides (35). In contrast, in our study ZDF rats treated with NaCh blockers for 8 weeks had no change in lipid levels (Supplementary Table 2), had lower circulating glucagon levels, and had fewer a-cells than vehicle-treated rats (Fig.…”

Section: Glucagon As a Target For Diabetescontrasting

confidence: 53%

“…Therefore, the suppression of glucagon secretion or the inhibition of its action in the liver constitutes potential therapeutic targets for diabetes (30)(31)(32). The results of studies with glucagon receptor antagonists (peptide and small molecule), antisense oligonucleotides, and glucagon receptor knock-out mice show that elimination or inhibition of glucagon receptor signaling has strong anti-hyperglycemic effects in various animal models of diabetes (31,(33)(34)(35). Significant dose-dependent reductions in HbA 1c levels have been reported (33,36) with glucagon receptor antagonists MK-0893 (0.6-1.5 6 0.5%, compared with placebo) and LY-2409021 (0.7-1%) in patients with T2DM.…”

Section: Glucagon As a Target For Diabetesmentioning

confidence: 99%

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Blockade of Na+ Channels in Pancreatic α-Cells Has Antidiabetic Effects

et al. 2014

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Pancreatic a-cells express voltage-gated Na + channels (NaChs), which support the generation of electrical activity leading to an increase in intracellular calcium, and cause exocytosis of glucagon. Ranolazine, a NaCh blocker, is approved for treatment of angina. In addition to its antianginal effects, ranolazine has been shown to reduce HbA 1c levels in patients with type 2 diabetes mellitus and coronary artery disease; however, the mechanism behind its antidiabetic effect has been unclear. We tested the hypothesis that ranolazine exerts its antidiabetic effects by inhibiting glucagon release via blockade of NaChs in the pancreatic a-cells. Our data show that ranolazine, via blockade of NaChs in pancreatic a-cells, inhibits their electrical activity and reduces glucagon release. We found that glucagon release in human pancreatic islets is mediated by the Na v 1.3 isoform. In animal models of diabetes, ranolazine and a more selective NaCh blocker (GS-458967) lowered postprandial and basal glucagon levels, which were associated with a reduction in hyperglycemia, confirming that glucose-lowering effects of ranolazine are due to the blockade of NaChs. This mechanism of action is unique in that no other approved antidiabetic drugs act via this mechanism, and raises the prospect that selective Na v 1.3 blockers may constitute a novel approach for the treatment of diabetes.

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Section: Glucagon As a Target For Diabetescontrasting

confidence: 53%

Section: Glucagon As a Target For Diabetesmentioning

confidence: 99%

Blockade of Na+ Channels in Pancreatic α-Cells Has Antidiabetic Effects

et al. 2014

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“…Diabetic db/db mice treated with these oligonucleotides had lower glucose, triglyceride and free fatty acids blood levels, as well as improved glucose tolerance, and they developed hyperglucagonaemia without apparent effects on a-cell size or number (Liang et al 2004). This approach is also accompanied by an increase in GLP1 and insulin levels in Zucker diabetic fatty rats and db/db and ob/ ob mice (Sloop et al 2004). Furthermore, the use of high affinity, neutralizing glucagon monoclonal antibodies improved glycaemic control and reduced hepatic glucose production in diabetic ob/ob mice (Sorensen et al 2006).…”

Section: Molecular Pharmacology Of Glucagon Release and Action: Theramentioning

confidence: 99%

Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes

Quesada¹,

Tudurí²,

Ripoll³

et al. 2008

Journal of Endocrinology

337

330

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The secretion of glucagon by pancreatic a-cells plays a critical role in the regulation of glycaemia. This hormone counteracts hypoglycaemia and opposes insulin actions by stimulating hepatic glucose synthesis and mobilization, thereby increasing blood glucose concentrations. During the last decade, knowledge of a-cell physiology has greatly improved, especially concerning molecular and cellular mechanisms. In this review, we have addressed recent findings on a-cell physiology and the regulation of ion channels, electrical activity, calcium signals and glucagon release. Our focus in this review has been the multiple control levels that modulate glucagon secretion from glucose and nutrients to paracrine and neural inputs. Additionally, we have described the glucagon actions on glycaemia and energy metabolism, and discussed their involvement in the pathophysiology of diabetes. Finally, some of the present approaches for diabetes therapy related to a-cell function are also discussed in this review. A better understanding of the a-cell physiology is necessary for an integral comprehension of the regulation of glucose homeostasis and the development of diabetes.

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“…Several GCGR antagonists that improve glycemic control in animal models of diabetes and diabetic patients have been described (3)(4)(5)(6)(7)(8). Although biochemical studies of glucagon and GCGR mutants have facilitated the mapping of some elements that contribute to glucagon binding (4,(9)(10)(11)(12), the molecular mechanisms of GCGR activation and inhibition remain largely unknown because there are currently no high-resolution structures of GCGR.…”

mentioning

confidence: 99%

Molecular basis for negative regulation of the glucagon receptor

Koth¹,

Murray²,

Mukund³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

123

179

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Members of the class B family of G protein-coupled receptors (GPCRs) bind peptide hormones and have causal roles in many diseases, ranging from diabetes and osteoporosis to anxiety. Although peptide, small-molecule, and antibody inhibitors of these GPCRs have been identified, structure-based descriptions of receptor antagonism are scarce. Here we report the mechanisms of glucagon receptor inhibition by blocking antibodies targeting the receptor's extracellular domain (ECD). These studies uncovered a role for the ECD as an intrinsic negative regulator of receptor activity. The crystal structure of the ECD in complex with the Fab fragment of one antibody, mAb1, reveals that this antibody inhibits glucagon receptor by occluding a surface extending across the entire hormone-binding cleft. A second antibody, mAb23, blocks glucagon binding and inhibits basal receptor activity, indicating that it is an inverse agonist and that the ECD can negatively regulate receptor activity independent of ligand binding. Biochemical analyses of receptor mutants in the context of a high-resolution ECD structure show that this previously unrecognized inhibitory activity of the ECD involves an interaction with the third extracellular loop of the receptor and suggest that glucagon-mediated structural changes in the ECD accompany receptor activation. These studies have implications for the design of drugs to treat class B GPCR-related diseases, including the potential for developing novel allosteric regulators that target the ECDs of these receptors.T he glucagon receptor (GCGR) is a member of the class B G protein-coupled receptor (GPCR) family (1) that mediates the activity of glucagon, a pancreatic islet-derived peptide hormone that plays a central role in the pathophysiology of diabetes (2). Several GCGR antagonists that improve glycemic control in animal models of diabetes and diabetic patients have been described (3-8). Although biochemical studies of glucagon and GCGR mutants have facilitated the mapping of some elements that contribute to glucagon binding (4, 9-12), the molecular mechanisms of GCGR activation and inhibition remain largely unknown because there are currently no high-resolution structures of GCGR. The current model for activation class B GPCRs proposes a tethering mechanism whereby the C-terminal half of the peptide ligand first binds a large extracellular domain (ECD), thereby enabling a high-affinity interaction of the N-terminal half of the ligand with a cleft formed by the transmembrane α-helical bundle (13,14), termed the juxtamembrane (JM) domain. This interaction induces a structural change in the transmembrane and intracellular face of the receptor that enables G protein coupling, likely similar to that described for the activated form of the β-adrenergic receptor (15). Recent structural studies of several class B GPCR ECDs and ECD-ligand complexes support this model (16)(17)(18)(19)(20)(21). Glucagon likely interacts with GCGR in a similar fashion to the interaction of other peptide ligands with class B GPC...

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Hepatic and glucagon-like peptide-1–mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors

Cited by 81 publications

References 32 publications

Blockade of Na+ Channels in Pancreatic α-Cells Has Antidiabetic Effects

Blockade of Na+ Channels in Pancreatic α-Cells Has Antidiabetic Effects

Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes

Molecular basis for negative regulation of the glucagon receptor

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