LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept

Molecular Metabolism, Journal Year: 2018, Volume and Issue: 18, P. 3 - 14

Published: Oct. 3, 2018

A novel dual GIP and GLP-1 receptor agonist, LY3298176, was developed to determine whether the metabolic action of adds established clinical benefits selective agonists in type 2 diabetes mellitus (T2DM).LY3298176 is a fatty acid modified peptide with agonist activity designed for once-weekly subcutaneous administration. LY3298176 characterised vitro, using signaling functional assays cell lines expressing recombinant or endogenous incretin receptors, vivo body weight, food intake, insulin secretion glycemic profiles mice. Phase 1, randomised, placebo-controlled, double-blind study comprised three parts: single-ascending dose (SAD; doses 0.25-8 mg) 4-week multiple-ascending (MAD; 0.5-10 studies healthy subjects (HS), followed by multiple-dose 1 b proof-of-concept (POC; 0.5-15 patients T2DM (ClinicalTrials.gov no. NCT02759107). Doses higher than 5 mg were attained titration, dulaglutide (DU) used as positive control. The primary objective investigate safety tolerability LY3298176.LY3298176 activated both vitro showed glucose-dependent improved glucose tolerance acting on receptors With chronic administration mice, potently decreased weight intake; these effects significantly greater agonist. total 142 human received at least dulaglutide, placebo. PK profile investigated over wide range (0.25-15 supports In trial diabetic subjects, 10 15 reduced fasting serum compared placebo (least square mean [LSM] difference [95% CI]: -49.12 mg/dL [-78.14, -20.12] -43.15 [-73.06, -13.21], respectively). Reductions 1.5 mg, 4.5 versus MAD HS (LSM -1.75 kg [-3.38, -0.12], -5.09 [-6.72, -3.46] -4.61 [-6.21, -3.01], respectively) had relevant effect -2.62 [-3.79, -1.45] -2.07 [-3.25, -0.88], respectively. most frequent side reported gastrointestinal (vomiting, nausea, appetite, diarrhoea, abdominal distension) T2DM; all dose-dependent considered mild moderate severity.Based results, pharmacology translates from preclinical studies. has potential deliver clinically meaningful improvement glycaemic control weight. data warrant further evaluation treatment potentially obesity.

Language: Английский

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Function and mechanisms of enteroendocrine cells and gut hormones in metabolism

Nature Reviews Endocrinology, Journal Year: 2019, Volume and Issue: 15(4), P. 226 - 237

Published: Feb. 13, 2019

Language: Английский

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Gut-liver axis: Pathophysiological concepts and clinical implications

Cell Metabolism, Journal Year: 2022, Volume and Issue: 34(11), P. 1700 - 1718

Published: Oct. 7, 2022

Language: Английский

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Gut microbiota: a new path to treat obesity

International Journal of Obesity Supplements, Journal Year: 2019, Volume and Issue: 9(1), P. 10 - 19

Published: April 1, 2019

Language: Английский

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Equol: A Bacterial Metabolite from The Daidzein Isoflavone and Its Presumed Beneficial Health Effects

Nutrients, Journal Year: 2019, Volume and Issue: 11(9), P. 2231 - 2231

Published: Sept. 16, 2019

Epidemiological data suggest that regular intake of isoflavones from soy reduces the incidence estrogen-dependent and aging-associated disorders, such as menopause symptoms in women, osteoporosis, cardiovascular diseases cancer. Equol, produced daidzein, is isoflavone-derived metabolite with greatest estrogenic antioxidant activity. Consequently, equol has been endorsed having many beneficial effects on human health. The conversion daidzein into takes place intestine via action reductase enzymes belonging to incompletely characterized members gut microbiota. While all animal species analyzed so far produce equol, only between one third half subjects (depending community) are able do so, ostensibly those harbor equol-producing microbes. Conceivably, these might be ones who can fully benefit or isoflavone consumption. This review summarizes current knowledge microorganisms involved in, genetic background to, biochemical pathways of, biosynthesis. It also outlines results recent clinical trials meta-analyses different areas health discusses briefly its presumptive mode action.

Language: Английский

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Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist

JCI Insight, Journal Year: 2020, Volume and Issue: 5(17)

Published: July 30, 2020

Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by selective agonist. Therefore, we hypothesized integrated potency signaling properties provide unique pharmacological profile tailored improving broad metabolic control. Here, establish methodology calculating occupancy each clinically efficacious doses drug. This analysis reveals greater degree engagement than receptor, corroborating an imbalanced mechanism action. Pharmacologically, studies demonstrate mimics actions native at but shows bias to favor cAMP generation over β-arrestin recruitment, coincident with weaker ability drive internalization compared GLP-1. Experiments primary islets reveal β-arrestin1 limits insulin response GLP-1, not or tirzepatide, suggesting biased agonism enhances secretion. Imbalance toward combined distinct together may account promising efficacy this investigational agent.

Language: Английский

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Impact of GPCR Structures on Drug Discovery

Cell, Journal Year: 2020, Volume and Issue: 181(1), P. 81 - 91

Published: April 1, 2020

Language: Английский

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How May GIP Enhance the Therapeutic Efficacy of GLP-1?

Trends in Endocrinology and Metabolism, Journal Year: 2020, Volume and Issue: 31(6), P. 410 - 421

Published: March 16, 2020

Glucagon-like peptide-1 (GLP-1) receptor agonists improve glucose homeostasis, reduce bodyweight, and over time benefit cardiovascular health in type 2 diabetes mellitus (T2DM). However, dose-related gastrointestinal effects limit efficacy, therefore agents possessing GLP-1 pharmacology that can also target alternative pathways may expand the therapeutic index. One approach is to engineer activity into sequence of glucose-dependent insulinotropic polypeptide (GIP). Although implications lipogenic actions GIP are debated, its ability lipid metabolism especially evident when paired with anorexigenic mechanism GLP-1. We review complexity regulating adipose tissue function energy balance context recent findings T2DM showing dual GIP/GLP-1 agonist therapy produces profound weight loss, glycemic control, lowering.

Language: Английский

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Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice

Science, Journal Year: 2022, Volume and Issue: 376(6598), P. 1192 - 1202

Published: May 5, 2022

Caloric restriction (CR) prolongs life span, yet the mechanisms by which it does so remain poorly understood. Under CR, mice self-impose chronic cycles of 2-hour feeding and 22-hour fasting, raising question if is calories, or time day that cause this increased span. We show here 30% CR was sufficient to extend span 10%; however, a daily fasting interval circadian alignment acted together 35% in male C57BL/6J mice. These effects were independent body weight. Aging induced widespread increases gene expression associated with inflammation decreases genes encoding components metabolic pathways liver from ad libitum-fed at night ameliorated these aging-related changes. Our results interventions promote longevity provide perspective further explore aging.

Language: Английский

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Insulin Resistance in Alzheimer's Disease

Frontiers in Neuroscience, Journal Year: 2018, Volume and Issue: 12

Published: Nov. 13, 2018

The epidemiological connection between diabetes, obesity and dementia represents an important public health challenge but also opportunity to further understand these conditions. key intersection among the three diseases is insulin resistance, which has been classically described occur in peripheral tissues diabetes obesity, recently shown develop Alzheimer's disease brains. Here we review encouraging preclinical clinical data indicating potential of targeting impaired signaling with antidiabetic drugs treat dementia. We discuss biological mechanisms through metabolic dysregulation may lead brain malfunction, providing possible explanations for disease. Finally, briefly how lifelong allostatic load interact aging increase risk late life.

Language: Английский

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