Non-canonical G protein signaling

Pharmacology & Therapeutics, Journal Year: 2024, Volume and Issue: 255, P. 108589 - 108589

Published: Jan. 29, 2024

The original paradigm of classical - also referred to as canonical cellular signal transduction heterotrimeric G proteins (G protein) is defined by a hierarchical, orthograde interaction three players: the agonist-activated protein-coupled receptor (GPCR), which activates transducing protein, that in turn regulates its intracellular effectors. This receptor-transducer-effector concept was extended identification regulators and adapters such protein signaling (RGS), kinases like βARK, or GPCR-interacting arrestin are integrated into this process at different levels enable fine-tuning. Finally, atypical mechanisms regulators, together with discovery novel modulators, added new fascinating dimension transduction. heterogeneous group accessory modulators coined "activators signaling" (AGS) plays distinct roles non-canonical pathways. AGS contribute control essential functions cell development division, transport processes, secretion, autophagy movements. As such, they involved numerous biological processes crucial for diseases, diabetes mellitus, cancer, stroke, represent major health burdens. Although large number pathways has broadened spectrum communication system, their underlying mechanisms, functions, effects poorly understood. In review, we highlight discuss protein-dependent focus on inhibitory (Gi) transduction, review recent developments open questions, address potential approaches targeted pharmacological interventions.

Language: Английский

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Unveiling the Therapeutic Potential of the Second-Generation Incretin Analogs Semaglutide and Tirzepatide in Type 1 Diabetes and Latent Autoimmune Diabetes in Adults

Journal of Clinical Medicine, Journal Year: 2025, Volume and Issue: 14(4), P. 1303 - 1303

Published: Feb. 15, 2025

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease caused by the immune-mediated destruction of insulin-producing pancreatic beta cells, resulting in lifelong need for exogenous insulin. Over last few years, overweight and obesity have recently emerged as growing health issues also afflicting patients with T1D. In this context, term "double diabetes" has been coined to indicate T1D who family history type 2 (T2D) and/or are affected insulin resistance overweight/obesity metabolic syndrome. At same time, use second-generation incretin analogs semaglutide tirzepatide substantially increased on global scale over given remarkable clinical benefits these drugs (in terms glucose control weight loss) T2D overweight/obesity. Although glucagon-like peptide-1 (GLP-1) receptor agonists novel dual GIP (glucose-dependent insulinotropic polypeptide)/GLP-1 agonist currently not approved treatment T1D, body evidence years shown that medications may serve valid add-on treatments substantial efficacy improving control, promoting loss, preserving residual beta-cell function providing other beneficial effects double latent adults (LADA). This manuscript aims comprehensively review available literature (mostly consisting real-world studies) regarding safety therapeutic (for different purposes) (at stages disease), LADA.

Language: Английский

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GLP-1 receptor agonists, are we witnessing the emergence of a paradigm shift for neuro-cardio-metabolic disorders?

Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: unknown, P. 108824 - 108824

Published: Feb. 1, 2025

Language: Английский

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Tirzepatide 10 and 15 mg versus semaglutide 2.4 mg in people with obesity or overweight with type 2 diabetes: An indirect treatment comparison

Diabetes Obesity and Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: May 5, 2025

Abstract Aims Tirzepatide and semaglutide demonstrated clinically meaningful weight reduction in people with obesity or overweight type 2 diabetes (T2D) SURMOUNT‐2 STEP clinical trials, respectively. In the absence of head‐to‐head this study compared efficacy tirzepatide 10 15 mg 2.4 using an indirect treatment comparison. Materials Methods Mean percent change from baseline, ≥5% mean glycated haemoglobin (HbA1c [%]) were between 10/15 (week 72, SURMOUNT‐2) 68, 2) applying Bucher method to estimand. Sensitivity analyses included use matching‐adjusted comparison, regimen estimand comparing outcomes at 68 weeks. Results associated significantly greater reductions versus (mean difference, mg: 2.57%; 4.79%, p < 0.01). had higher odds achieving (odds ratio 1.76, 95% CI 1.04–2.97, = 0.035; 1.24, 0.75–2.04, 0.407), both doses HbA1c (%) levels 0.47%; 0.56%, 0.001) than semaglutide. generally consistent primary analysis, exceptions including when power was reduced comparison categorical outcome. Conclusions This analysis suggested bodyweight T2D.

Language: Английский

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Reduced Efficacy of Glucagon-Like Peptide-1 Receptor Agonists Therapy in People With Type 1 Diabetes and Genetic Forms of Obesity

Journal of Diabetes Science and Technology, Journal Year: 2024, Volume and Issue: unknown

Published: April 17, 2024

Once weekly Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA) have been shown to improve glycemic outcomes and cause significant weight loss. However, 9% 27% of individuals little or no response these drugs. In this article, we investigated the efficacy GLP-1 RA therapy among adults with type 1 diabetes obesity likely related genetic mutations compared unrelated mutations.

Language: Английский

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In vivofunctional profiling and structural characterisation of the humanGlp1rA316T variant

Published: Oct. 21, 2024

Abstract Glucagon-like peptide-1 receptor (GLP-1R) agonists are a highly effective therapy class for type 2 diabetes (T2D) and obesity, yet there variable patient responses. Variation in the human Glp1r gene leading to altered structure, signal transduction, function might be directly linked therapeutic responses patients. A naturally occurring, low-frequency, gain-of-function missense variant, rs10305492 G>A (A316T), protects against T2D cardiovascular disease. Here we employ CRISPR/Cas9 technology generate humanised knock-in mouse model bearing homozygous A316T substitution. Human A316T/A316T mice displayed lower fasting blood glucose levels improved tolerance, as well increased plasma insulin secretion responses, even under metabolic stress. They also exhibited alterations islet cytoarchitecture β-cell identity indicative of compensatory mechanisms high-fat, high-sucrose (HFHS) diet challenge. Across all models investigated, variant characteristics constitutive activation but blunted incretin-induced Our results further supported by cryo-EM analysis molecular dynamics (MD) simulations GLP-1R demonstrating that governs basal activity pharmacological GLP-1R-targeting anti-diabetic therapies, highlighting importance precise characterisation variants predict individual

Language: Английский

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Incretin-Related Drugs and Nutrition

Nippon Eiyo Shokuryo Gakkaishi, Journal Year: 2024, Volume and Issue: 77(5), P. 333 - 338

Published: Jan. 1, 2024

Language: Английский

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