Effects of JNJ‐38431055, a novel GPR119 receptor agonist, in randomized, double‐blind, placebo‐controlled studies in subjects with type 2 diabetes

Katz, Leonid; Gambale, Jay J.; Rothenberg, Paul; Vanapalli, Sreenivasa R.; Vaccaro, Nicole; Xi, Liuqing; Sarich, Troy C.; Stein, Peter

doi:10.1111/j.1463-1326.2012.01587.x

Cited by 89 publications

(67 citation statements)

References 20 publications

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“…Currently no specific GPR119 antagonists are commercially available however studies have shown that GLP-1 receptor antagonist exendin (9-39) reduces glucose lowering ability of AR-231453 in mice (Chu et al, 2008;Flock et al, 2011). Clinical trials with GPR119 agonists namely JNJ-38431055 have shown therapeutic potential that may be augmented with the administered DPP-IV inhibitor (Katz et al, 2011(Katz et al, , 2012.…”

Section: Introductionmentioning

confidence: 97%

Activation of GPR119 by fatty acid agonists augments insulin release from clonal β-cells and isolated pancreatic islets and improves glucose tolerance in mice

Moran

Abdel-Wahab

Flatt

et al. 2013

Biological Chemistry

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G-protein coupled receptor 119 (GPR119) is emerging as a potential target for the treatment of type 2 diabetes with beneficial effects on glucose homeostasis. This study assessed the insulin-secreting properties of various GPR119 agonists and the distribution of GPR119 in pancreatic islets. Endogenous ligands [oleoylethanolamide (OEA), palmitoylethanolamine (PEA)] and chemically synthetic analogues (AS-1269574, PSN-375963) were investigated in clonal BRIN-BD11 cells and mouse pancreatic islets. Secondary messenger assays such as intracellular Ca²⁺ and cAMP in response to agonists at normoglycaemic and hyperglycaemic conditions were assessed. Cytotoxicity was assessed by LDH release. AS-1269574 was the most potent and selective agonist tested in isolated islets, with an EC₅₀ value of 9.7×10⁻⁷ mol/l, enhancing insulin release maximally by 63.2%. Stimulation was also observed with GPR119 ligands; OEA (3.0×10⁻⁶ mol/l; 37.5%), PSN-375963 (2.4×10⁻⁶ mol/l; 28.7%) and PEA (1.2×10⁻⁶ mol/l; 22.2%). Results were corroborated by studies using BRIN-BD11 cells, which revealed augmentation of intracellular Ca²⁺ and cAMP. Both OEA and AS-1269574 enhanced insulin release and improved glucose tolerance in vivo in NIH Swiss mice. These results demonstrate the cellular localisation of GPR119 on islet cells (β and pancreatic polypeptide cells), its activation of the β-cell stimulus-secretion coupling pathway and glucose lowering effects in vivo.

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Section: Introductionmentioning

confidence: 97%

Activation of GPR119 by fatty acid agonists augments insulin release from clonal β-cells and isolated pancreatic islets and improves glucose tolerance in mice

Moran

Abdel-Wahab

Flatt

et al. 2013

Biological Chemistry

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“…Pharmacological activation of GPR119 using synthetic smallmolecule agonists increased both plasma GLP1 and GIP concentrations in mice (62). Oral administration of 2-oleoylglycerol increased plasma GLP1 and GIP levels in humans (67), however, a GPR119 agonist failed to stimulate GLP1 and PYY secretion from human colonic cultures (66), and the efficacy of GPR119 agonists in clinical trials has been underwhelming (73).…”

Section: Gut Microbiota Host Defense and Eec Signalingmentioning

confidence: 99%

Gut chemosensing mechanisms

Psichas¹,

Reimann²,

Gribble³

2015

J. Clin. Invest.

199

173

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“…In patients with T2DM, JNJ-38431055 (Johnson & Johnson), a GPR119 agonist, increased post-meal GLP-1 and glucose-dependent insulinotropic polypeptide levels, and was not associated with hypoglycemia. 48 …”

Section: Gpr119 Agonistsmentioning

confidence: 97%

Hypoglycemic Potential of Current and Emerging Pharmacotherapies in Type 2 Diabetes Mellitus

Brunton¹

2012

Postgraduate Medicine

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Intensive glycemic control can reduce the risk of microvascular complications in patients with type 2 diabetes mellitus (T2DM). However, hypoglycemia induced by diabetes medications is recognized as a major limiting factor in the attainment of glycemic goals. Mild hypoglycemia is relatively common in patients with T2DM, and the prevalence of severe hypoglycemia increases with insulin treatment and can approach the prevalence seen in patients with type 1 diabetes. Mild hypoglycemia and the fear of hypoglycemia can have a substantial impact on the physical, mental, social, and economic well-being of patients with T2DM. Severe hypoglycemia is more serious and may be associated with an increased risk of dementia, cardiovascular events, and death. Insulin and insulin secretagogue therapies (eg, sulfonylureas and meglitinides) are the major causes of hypoglycemia in patients with T2DM. Other diabetes drugs, such as metformin, when used as monotherapy, have a low risk of hypoglycemia. Emerging experimental therapies, such as activators of the free fatty acid receptor 1, G protein-coupled receptor 119 agonists, glucokinase activators, inhibitors of 11β-hydroxysteroid dehydrogenase type 1, and sodium-glucose co-transporter 2 inhibitors, some of which have mechanisms of action consistent with a potential low risk of hypoglycemia, may help patients with T2DM achieve improved glycemic control.

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Effects of JNJ‐38431055, a novel GPR119 receptor agonist, in randomized, double‐blind, placebo‐controlled studies in subjects with type 2 diabetes

Abstract: These studies provide evidence of limited glucose lowering and incretin activity for JNJ-38431055 in subjects with T2DM.

Cited by 89 publications

References 20 publications

Activation of GPR119 by fatty acid agonists augments insulin release from clonal β-cells and isolated pancreatic islets and improves glucose tolerance in mice

Activation of GPR119 by fatty acid agonists augments insulin release from clonal β-cells and isolated pancreatic islets and improves glucose tolerance in mice

Gut chemosensing mechanisms

Hypoglycemic Potential of Current and Emerging Pharmacotherapies in Type 2 Diabetes Mellitus

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