Liraglutide

Drucker, Daniel J.; Dritselis, Argyris; Kirkpatrick, Peter

doi:10.1038/nrd3148

Cited by 161 publications

(127 citation statements)

References 13 publications

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“…Clinical studies revealed that replacement therapies with metabolically stable GLP-1 mimetics, or treatment with dipeptidyl peptidase-IV inhibitors, can improve the management of hyperglycemia for some patients. Both exenatide (Byetta; Amylin Pharmaceuticals, Inc., San Diego, CA) and liraglutide (Victoza; Novo Nordisk A/S, Bagsvaerd, Denmark) have been approved by the U.S. Food and Drug Administration for the treatment of type II diabetes (Kolterman et al, 2003;Drucker et al, 2010). However, as peptide analogs of GLP-1, these require administration by intravenous or subcutaneous injection and have been associated with significant adverse side effects, including pan-creatitis (Olansky, 2010).…”

Section: Introductionmentioning

confidence: 99%

Modulation of the Glucagon-Like Peptide-1 Receptor Signaling by Naturally Occurring and Synthetic Flavonoids

Wootten

Simms

Koole

et al. 2010

J Pharmacol Exp Ther

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The glucagon-like peptide 1 receptor (GLP-1R) is a promising target for the treatment of type II diabetes mellitus because of its role in metabolic homeostasis. In recent years, difficulties with peptide therapies have driven the search for small-molecule compounds to modulate the activity of this receptor. We recently identified quercetin, a naturally occurring flavonoid, as a probe-dependent, pathway-selective allosteric modulator of GLP-1R-mediated signaling. Using Chinese hamster ovary cells expressing the human GLP-1R, we have now extended this work to identify the structural requirements of flavonoids to modify GLP-1R binding and signaling (cAMP formation and intracellular Ca 2ϩ mobilization) of each of the GLP-1R endogenous agonists, as well as the clinically used exogenous peptide mimetic exendin-4. This study identified a chemical series of hydroxyl flavonols with the ability to selectively augment calcium (Ca 2ϩ ) signaling in a peptide agonist-specific manner, with effects only on truncated GLP-1 peptides [GLP-1(7-36)NH 2 and GLP-1(7-37)] and exendin-4, but not on oxyntomodulin or full-length GLP-1 peptides [GLP-1(1-36)NH 2 and GLP-1(1-37)]. In addition, the 3-hydroxyl group on the flavone backbone (i.e., a flavonol) was essential for this activity, however insufficient on its own, to produce the allosteric effects. In contrast to hydroxyl flavonols, catechin had no effect on peptide-mediated Ca 2ϩ signaling but negatively modulated peptide-mediated cAMP formation in a probe-dependent manner. These data represent a detailed examination of the action of different flavonoids on peptide agonists at the GLP-1R and may aid in the development of future small molecule compounds targeted at this receptor.

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Section: Introductionmentioning

confidence: 99%

Modulation of the Glucagon-Like Peptide-1 Receptor Signaling by Naturally Occurring and Synthetic Flavonoids

Wootten

Simms

Koole

et al. 2010

J Pharmacol Exp Ther

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“…In addition to EX-4 (Bachem, Torrance, CA), another GLP-1 analog has been approved for the treatment of type 2 diabetes, i.e., liraglutide (Victoza; Novo Nordisk, Princeton, NJ). Liralgutide possesses an extended plasma half-life, similarly to EX-4, via a fatty acid acylation mechanism (Chapter et al, 2010;Drucker et al, 2010). Another mechanism of GLP-1 modification that has demonstrated therapeutic potential is fusion of the GLP-1 dimer with recombinant human albumin, producing albiglutide (Baggio et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Transferrin Fusion Technology: A Novel Approach to Prolonging Biological Half-Life of Insulinotropic Peptides

Kim¹,

Zhou²,

Martin³

et al. 2010

J Pharmacol Exp Ther

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Fusion proteins made up of glucagon-like peptide 1 (GLP-1) and exendin-4 (EX-4) fused to a nonglycosylated form of human transferrin (GLP-1-Tf or EX-4-Tf) were produced and characterized. GLP-1-Tf activated the GLP-1 receptor, was resistant to inactivation by peptidases, and had a half-life of approximately 2 days, compared with 1 to 2 min for native GLP-1. GLP-1-Tf retained the acute, glucose-dependent insulin-secretory properties of native GLP-1 in diabetic animals and had a profound effect on proliferation of pancreatic ␤-cells. In addition, Tf and the fusion proteins did not cross the blood-brain-barrier but still reduced food intake after peripheral administration. EX-4-Tf proved to be as effective as EX-4 but had longer lived effects on blood glucose and food intake. This novel transferrin fusion technology could improve the pharmacology of various peptides.

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“…One of the FDA-approved GLP-1R agonists is liraglutide which is used to treat type 2 diabetes (23). Liraglutide has a 97% homology with human GLP-1 including a lysine to arginine mutation at position 34 and a palmitoyl side-chain at lysine 26 (24).…”

mentioning

confidence: 99%

Regulation of Adipocyte Formation by GLP-1/GLP-1R Signaling

Challa

Beaton

Arnold

et al. 2012

Journal of Biological Chemistry

115

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Liraglutide

Abstract: In January 2010, liraglutide (Victoza; Novo Nordisk)--an injectable glucagon-like peptide 1 receptor agonist--was approved by the US FDA to improve glycaemic control in adults with type 2 diabetes mellitus.

Cited by 161 publications

References 13 publications

Modulation of the Glucagon-Like Peptide-1 Receptor Signaling by Naturally Occurring and Synthetic Flavonoids

Modulation of the Glucagon-Like Peptide-1 Receptor Signaling by Naturally Occurring and Synthetic Flavonoids

Transferrin Fusion Technology: A Novel Approach to Prolonging Biological Half-Life of Insulinotropic Peptides

Regulation of Adipocyte Formation by GLP-1/GLP-1R Signaling

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