A5075599028- Adipose Tissue and Metabolism
- Diabetes Treatment and Management
- Metabolism, Diabetes, and Cancer
- Pharmacology and Obesity Treatment
- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Regulation of Appetite and Obesity
- Diet and metabolism studies
- Helicobacter pylori-related gastroenterology studies
- Fibroblast Growth Factor Research
- Peroxisome Proliferator-Activated Receptors
- Cancer, Hypoxia, and Metabolism
- Epigenetics and DNA Methylation
- Pancreatic function and diabetes
- Adipokines, Inflammation, and Metabolic Diseases
- Kruppel-like factors research
- Bariatric Surgery and Outcomes
- Gastrointestinal motility and disorders
- Neuroendocrine Tumor Research Advances
- Pharmacological Effects and Assays
- Exercise and Physiological Responses
- Growth Hormone and Insulin-like Growth Factors
- Inflammatory mediators and NSAID effects
- Biochemical Analysis and Sensing Techniques
- Gastroesophageal reflux and treatments
Eli Lilly (United States)
2013-2024
Indianapolis Zoo
2021-2023
With an increasing prevalence of obesity, there is a need for new therapies to improve body weight management and metabolic health. Multireceptor agonists in development may provide approaches fulfill this unmet medical need. LY3437943 novel triple agonist peptide at the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide (GIPR), glucagon-like peptide-1 (GLP-1R). In vitro, shows balanced GCGR GLP-1R activity but more GIPR activity. obese mice, administration decreased...
Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor (GLP-1R) agonist, delivered superior glycemic control weight loss compared with GLP-1R agonism in patients type 2 diabetes. However, the mechanism by which tirzepatide improves efficacy how (GIPR) contributes is not fully understood. Here, we show that an effective insulin sensitizer, improving sensitivity obese mice to greater extent than agonism. To determine whether GIPR contributes, effect of WT Glp-1r–null mice. In absence...
Tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist, has, in clinical trials, demonstrated greater reductions glucose, body weight, and triglyceride levels compared with selective GLP-1R agonists people type 2 diabetes (T2D). However, cellular mechanisms by which GIPR agonism may contribute to these improved efficacy outcomes have not been fully defined. Using human adipocyte mouse models, we investigated how long-acting regulate...
Abstract The effect of dual glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) receptor agonist (RA) tirzepatide on gastric emptying (GE) was compared to that GLP‐1RAs in non‐clinical clinical studies. GE assessed following acute chronic treatment with diet‐induced obese mice versus semaglutide or long‐acting GIP analogue alone. Participants [with without type 2 diabetes (T2DM)] from a phase 1, 4‐week multiple dose study received tirzepatide, dulaglutide...
Fibroblast growth factor 21 is an emerging metabolic regulator that was recently proposed to be a fed-state inducible in adipose tissue. As mice lacking FGF21 were refractory treatment with rosiglitazone, suggested underlie PPARγ-driven pharmacology and side effect profile (Dutchak et al., 2012 [12]). To evaluate FGF21/PPARγ cross-talk we conducted experiments control null animals found rosiglitazone equally efficacious both strains. Specifically, diverse endpoints ranging from enhanced...
Delayed gastric emptying (GE) is a well-known effect of glucagon-like peptide-1 (GLP-1).1, 2 Similarly, glucagon (GCG) has been shown to slow GE in rodents and humans,3, 4 while glucose-dependent insulinotropic polypeptide (GIP) does not appear impact GE.1, Retatrutide (LY3437943) novel GIP/GLP-1/GCG receptor agonist (RA) under investigation for chronic weight management its complications. It more potent at the human GIP less GCG GLP-1 receptors versus native hormones, with half-life...
Abstract Aim To clarify the effects of glucose‐dependent insulinotropic polypeptide (GIP) receptor agonists (GIPRAs) on feeding and body weight. Materials Methods Acute subchronic subcutaneous GIPFA‐085, a long‐acting GIPRA, blood glucose, food intake, weight, respiratory exchange ratio plasma leptin levels were measured in diet‐induced obese (DIO) mice and/or functional leptin‐deficient ob / mice. The GIPFA‐085 hypothalamic arcuate nucleus (ARC) neurons from lean DIO studied by measuring...
Fibroblast growth factor 19 (FGF19) is a postprandial hormone which plays diverse roles in the regulation of bile acid, glucose, and lipid metabolism. Administration FGF19 to obese/diabetic mice lowers body weight, improves insulin sensitivity, enhances glycemic control. The primary target organ liver, where it regulates acid homeostasis response nutrient absorption. In contrast, broader pharmacologic actions are proposed be driven, part, by recruitment thermogenic protein uncoupling 1...
Prostaglandins E1 and E2 are synthesized in the intestine mediate a range of gastrointestinal functions via activation prostanoid E type (EP) family receptors. We examined potential role EP receptors regulation gut hormone secretion from L cells. Analysis mRNA expression mouse enteroendocrine GLUTag cells demonstrated abundant EP4 receptor, whereas other was much lower. Prostaglandin E2, nonselective agonists for all receptor subtypes, triggered glucagon like peptide 1 (GLP-1) cells, as did...
Background: Chronic continuous glucose monitoring options for animal research have been very limited due to various technical and biological challenges. We provide an evaluation of a novel telemetry device temperature, activity, plasma levels in the arterial blood rats up 2 months. Methods: In vivo testing including oral tolerance tests (OGTTs) intraperitoneal (IPGTTs) ex waterbath were performed evaluate acute chronic sensor performance. Animal studies accordance with guidelines care use...
Recent studies have found that glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism can enhance the metabolic efficacy of glucagon-like peptide–1 agonist treatment by promoting both weight-dependent and -independent improvements on systemic insulin sensitivity. These findings prompted new investigations aimed at better understanding broad benefit GIPR activation. Herein, we determined whether favorably influenced pharmacologic insulin-sensitizing thiazolidinedione (TZD)...
Glucagon is a crucial regulator of glucose and lipid metabolism as well whole-body energy balance. Thus, modulation glucagon receptor (GCGR) activity in the context single-molecule multi-receptor co-agonists has become an emerging therapeutic target against obesity obesity-associated metabolic dysfunction. To better elucidate role GCGR-signaling when paired with incretin signaling or on its own, we developed, LY3324954, GCGR agonist improved potency selectivity compared to native peptide.
Orally bioavailable, synthetic nonpeptide agonists (NPAs) of the glucagon-like peptide-1 receptor (GLP-1R) may offer an effective, scalable pharmacotherapy to address metabolic disease epidemic. One first molecules in emerging class GLP-1R NPAs is orforglipron, which clinical development for treating type 2 diabetes and obesity. Here, we characterized pharmacological properties orforglipron comparison with peptide-based other NPAs. Competition binding experiments using either [ 125...
The ever-growing prevalence of obesity and its associated comorbidities (T2D, NASH/NAFLD) is driving the need to discover new therapies for improving metabolic health. Recently, multi-receptor agonists have offered promise meeting this need. Here, we characterize LY3437943, a novel single agent tri-agonist at GIP, GLP-1, glucagon (Gcg) receptors (R). Pharmacologic analysis LY3437943 in cAMP assays using recombinant cell lines expressing individual indicated potency balance favoring GIPR...
We report the novel combination of a selective beta adrenoceptor modulator and norepinephrine-serotonin uptake inhibitor (sibutramine) with potential for treatment obesity. The synthesis characterization 6-[4-[2-[[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino]-2-methylpropyl]phenoxy]pyridine-3-carboxamide (LY377604), human β3-adrenergic receptor agonist β1- β2-adrenergic antagonist no sympathomimetic activity at receptors, is reported. Some in vivo data both rats humans presented.
GIP receptor (GIPR) agonism enhances the reduction of food intake and weight loss induced by GLP-1 (GLP-1R) agonism. Recently, GLP-1R agonists have been described that exhibit biased as determined using cells engineered to facilitate measuring two canonical signaling pathways engaged upon binding GLP-1R. Such “biased agonists” retain ability activate G alpha S/cyclic AMP (cAMP) pathway a similar magnitude native but markedly weaker induce recruitment beta-arrestin. The prototype agonist...
The development of multi-agonists targeting the glucose-dependent insulinotropic polypeptide receptor (GIPR) has resulted in significant clinical improvements body weight management, however contribution GIPR agonism to this effect is incompletely understood. Using a diet induced obese (DIO) mouse model, (LAGIPRA) alone demonstrated little no efficacy whereas addition LAGIPRA long acting GLP-1R decreased food intake and increased energy expenditure resulting greater loss compared with...
<p dir="ltr">Recent studies have found that GIPR agonism can enhance the metabolic efficacy of GLP-1R agonist treatment by promoting both weight-dependent and -independent improvements on systemic insulin sensitivity. These findings prompted new investigations aimed at better understanding broad benefit activation. Herein, we determined whether favorably influenced pharmacologic sensitizing thiazolidinedione, rosiglitazone in obese resistant (IR) mice.<b> </b>Genetic...
<p dir="ltr">Recent studies have found that GIPR agonism can enhance the metabolic efficacy of GLP-1R agonist treatment by promoting both weight-dependent and -independent improvements on systemic insulin sensitivity. These findings prompted new investigations aimed at better understanding broad benefit activation. Herein, we determined whether favorably influenced pharmacologic sensitizing thiazolidinedione, rosiglitazone in obese resistant (IR) mice.<b> </b>Genetic...
Fibroblast growth factor 19 (FGF19) is a postprandial hormone reported to play diverse roles in the regulation of bile acid, glucose and lipid metabolism. The administration FGF19 obese/diabetic mice has been lower body weight, improve insulin sensitivity homeostasis. Classically, primary target organ was considered be liver, where period it shown regulate acid homeostasis response nutrient absorption. More recently, proposed that therapeutic benefits associated with are due, part, binding...