Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

Unger, Roger H; Cherrington, Alan D.

doi:10.1172/jci60016

Cited by 594 publications

(567 citation statements)

References 100 publications

(103 reference statements)

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“…Indeed, glucagon is known as a counterregulatory hormone that exerts a potent hyperglycaemic effect by increasing hepatic glucose output through the stimulation of both glycogenolysis and gluconeogenesis 9 . Some experimental data suggested that glucagon suppression or inactivation may provide therapeutic advantages over insulin monotherapy 10 . Many attempts have been developed to inhibit glucagon secretion and/or action, with the aim of improving glucose control in T2DM, however without obvious success so far except the success story of incretin-based therapies 11 .…”

Section: Wordsmentioning

confidence: 99%

A new paradigm for treating obesity and diabetes mellitus

Scheen

Paquot

2015

Nat Rev Endocrinol

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Standfirst :An innovative unimolecular, polypharmaceutical strategy using a well-balanced monomeric peptide triagonist targeting three metabolically-related hormone receptors (glucagon-like peptide-1, glucose-dependent insulinotropic poplypeptide and glucagon) appears the most effective pharmacological approach to reversing obesity and metabolic comorbidities in rodents and could open new perspective to tackle the dual obesity-diabetes burden in humans.

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Section: Wordsmentioning

confidence: 99%

A new paradigm for treating obesity and diabetes mellitus

Scheen

Paquot

2015

Nat Rev Endocrinol

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“…Insulin counteracts ketogenesis by stimulating the use of glucose as primary energy source and by decreasing the release of FFA in the circulation (21). In contrast, glucagon stimulates ketogenesis, hepatic glucose production, and lipolysis (1,40). Changes in glucose metabolism are associated with adaptation of the number and/or function of ␤-cells to produce and secrete an adequate amount of insulin (6,34).…”

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confidence: 99%

Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice

Ellenbroek

Dijck

Töns

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

124

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Ellenbroek JH, van Dijck L, Töns HA, Rabelink TJ, Carlotti F, Ballieux BE, de Koning EJ. Long-term ketogenic diet causes glucose intolerance and reduced ␤-and ␣-cell mass but no weight loss in mice. Am J Physiol Endocrinol Metab 306: E552-E558, 2014. First published January 7, 2014 doi:10.1152/ajpendo.00453.2013.-High-fat, low-carbohydrate ketogenic diets (KD) are used for weight loss and for treatment of refractory epilepsy. Recently, short-time studies in rodents have shown that, besides their beneficial effect on body weight, KD lead to glucose intolerance and insulin resistance. However, the long-term effects on pancreatic endocrine cells are unknown. In this study we investigate the effects of long-term KD on glucose tolerance and ␤-and ␣-cell mass in mice. Despite an initial weight loss, KD did not result in weight loss after 22 wk. Plasma markers associated with dyslipidemia and inflammation (cholesterol, triglycerides, leptin, monocyte chemotactic protein-1, IL-1␤, and IL-6) were increased, and KD-fed mice showed signs of hepatic steatosis after 22 wk of diet. Long-term KD resulted in glucose intolerance that was associated with insufficient insulin secretion from ␤-cells. After 22 wk, insulin-stimulated glucose uptake was reduced. A reduction in ␤-cell mass was observed in KD-fed mice together with an increased number of smaller islets. Also ␣-cell mass was markedly decreased, resulting in a lower ␣-to ␤-cell ratio. Our data show that long-term KD causes dyslipidemia, a proinflammatory state, signs of hepatic steatosis, glucose intolerance, and a reduction in ␤-and ␣-cell mass, but no weight loss. This indicates that long-term high-fat, lowcarbohydrate KD lead to features that are also associated with the metabolic syndrome and an increased risk for type 2 diabetes in humans. pancreatic islet; ketogenic diet; glucose intolerance; ␤-cell; ␣-cell

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“…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)(4)(5)(6)(7)(8).…”

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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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Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

Cited by 594 publications

References 100 publications

A new paradigm for treating obesity and diabetes mellitus

A new paradigm for treating obesity and diabetes mellitus

Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice

Molecular basis for negative regulation of the glucagon receptor

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