Trends in insulin resistance: insights into mechanisms and therapeutic strategy

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: July 6, 2022

The centenary of insulin discovery represents an important opportunity to transform diabetes from a fatal diagnosis into medically manageable chronic condition. Insulin is key peptide hormone and mediates the systemic glucose metabolism in different tissues. resistance (IR) disordered biological response for stimulation through disruption molecular pathways target Acquired conditions genetic factors have been implicated IR. Recent biochemical studies suggest that dysregulated metabolic mediators released by adipose tissue including adipokines, cytokines, chemokines, excess lipids toxic lipid metabolites promote IR other associated with several groups abnormal syndromes include obesity, diabetes, dysfunction-associated fatty liver disease (MAFLD), cardiovascular disease, polycystic ovary syndrome (PCOS), abnormalities. Although no medication specifically approved treat IR, we summarized lifestyle changes pharmacological medications used as efficient intervention improve sensitivity. Ultimately, systematic discussion complex mechanism will help identify potential new targets closely

Language: Английский

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Increased cell senescence in human metabolic disorders

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(12)

Published: June 14, 2023

Cell senescence (CS) is at the nexus between aging and associated chronic disorders, increases burden of CS in all major metabolic tissues. However, also increased adult obesity, type 2 diabetes (T2D), nonalcoholic fatty liver disease independent aging. Senescent tissues are characterized by dysfunctional cells inflammation, both progenitor mature, fully differentiated nonproliferating afflicted. Recent studies have shown that hyperinsulinemia insulin resistance (IR) promote human adipose cells. Similarly, promotes cellular IR, showing their interdependence. Furthermore, T2D age, BMI, degree hyperinsulinemia, suggesting premature These results suggest senomorphic/senolytic therapy may become important for treating these common disorders.

Language: Английский

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Cardiometabolic characteristics of people with metabolically healthy and unhealthy obesity

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(4), P. 745 - 761.e5

Published: April 1, 2024

There is considerable heterogeneity in the cardiometabolic abnormalities associated with obesity. We evaluated multi-organ system metabolic function 20 adults metabolically healthy obesity (MHO; normal fasting glucose and triglycerides, oral tolerance, intrahepatic triglyceride content, whole-body insulin sensitivity), unhealthy (MUO; prediabetes, hepatic steatosis, resistance), 15 who were lean. Compared MUO, people MHO had (1) altered skeletal muscle biology (decreased ceramide content increased expression of genes involved BCAA catabolism mitochondrial structure/function); (2) adipose tissue inflammation extracellular matrix remodeling lipogenesis); (3) lower 24-h plasma glucose, insulin, non-esterified fatty acids, triglycerides; (4) higher adiponectin PAI-1 concentrations; (5) decreased oxidative stress. These findings provide a framework potential mechanisms responsible for This study was registered at ClinicalTrials.gov (NCT02706262).

Language: Английский

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The Role of G Protein–Coupled Receptors and Receptor Kinases in Pancreaticβ-Cell Function and Diabetes

Pharmacological Reviews, Journal Year: 2024, Volume and Issue: 76(2), P. 267 - 299

Published: Jan. 30, 2024

Type 2 diabetes mellitus (T2D) has emerged as a major global health concern that accelerated in recent years due to poor diet and lifestyle. Afflicted individuals have high blood glucose levels stem from the inability of pancreas make enough insulin meet demand. While medication can help maintain normal with chronic disease, many these medicines are outdated, severe side effects, often become less efficacious over time necessitating need for therapy. G protein-coupled receptors (GPCRs) regulate physiological processes including levels. In pancreatic β-cells, GPCRs β-cell growth, apoptosis, secretion which all critical maintaining sufficient mass output ensure euglycemia. years, new insight into signaling incretin other underscored potential desirable targets treatment diabetes. The is modulated by GPCR kinases (GRKs) phosphorylate agonist activated marking receptor arrestin binding internalization. Interestingly, genome wide association studies (GWAS) using diabetic patient cohorts link GRKs arrestins T2D. Moreover, reports show expressed serve role regulation function growth both dependent independent pathways. this review, we describe importance GRK modulating physiology. Significance Statement Pancreatic β-cells contain diverse array been shown improve survival, yet only handful successfully targeted This review discusses advances our understanding pharmacology while also highlighting necessity investigating islet enriched largely unexplored unveil novel strategies.

Language: Английский

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Macrophages, Low-Grade Inflammation, Insulin Resistance and Hyperinsulinemia: A Mutual Ambiguous Relationship in the Development of Metabolic Diseases

Journal of Clinical Medicine, Journal Year: 2022, Volume and Issue: 11(15), P. 4358 - 4358

Published: July 27, 2022

Metabolic derangement with poor glycemic control accompanying overweight and obesity is associated chronic low-grade inflammation hyperinsulinemia. Macrophages, which present a very heterogeneous population of cells, play key role in the maintenance normal tissue homeostasis, but functional alterations resident macrophage pool as well newly recruited monocyte-derived macrophages are important drivers development inflammation. While metabolic dysfunction, insulin resistance damage may trigger or advance pro-inflammatory responses macrophages, itself contributes to resulting Macrophages express receptors whose downstream signaling networks share number knots pathways pattern recognition cytokine receptors, shape polarity. The shared allow enhance attenuate both anti-inflammatory responses. This supposedly physiological function be impaired by hyperinsulinemia macrophages. review discusses mutual ambiguous relationship inflammation, resistance, insulin-dependent modulation activity focus on adipose liver.

Language: Английский

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Exploring the Complex Relationship between Diabetes and Cardiovascular Complications: Understanding Diabetic Cardiomyopathy and Promising Therapies

Biomedicines, Journal Year: 2023, Volume and Issue: 11(4), P. 1126 - 1126

Published: April 7, 2023

Diabetes mellitus (DM) and cardiovascular complications are two unmet medical emergencies that can occur together. The rising incidence of heart failure in diabetic populations, addition to apparent coronary disease, ischemia, hypertension-related complications, has created a more challenging situation. Diabetes, as predominant cardio-renal metabolic syndrome, is related severe vascular risk factors, it underlies various complex pathophysiological pathways at the molecular level progress converge toward development cardiomyopathy (DCM). DCM involves several downstream cascades cause structural functional alterations heart, such diastolic dysfunction progressing into systolic dysfunction, cardiomyocyte hypertrophy, myocardial fibrosis, subsequent over time. effects glucagon-like peptide-1 (GLP-1) analogues sodium-glucose cotransporter-2 (SGLT-2) inhibitors on (CV) outcomes diabetes have shown promising results, including improved contractile bioenergetics significant benefits. purpose this article highlight pathophysiological, metabolic, contribute its cardiac morphology functioning. Additionally, will discuss potential therapies may be available future.

Language: Английский

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Glucokinase activity in diabetes: too much of a good thing?

Trends in Endocrinology and Metabolism, Journal Year: 2022, Volume and Issue: 34(2), P. 119 - 130

Published: Dec. 29, 2022

Type 2 diabetes (T2D) is a global health problem characterised by chronic hyperglycaemia due to inadequate insulin secretion. Because glucose must be metabolised stimulate release it was initially argued that drugs glucokinase (the first enzyme in metabolism) would enhance secretion diabetes. However, the long term, activators have been largely disappointing. Recent studies show hyperactivation of metabolism, not itself, underlies progressive decline beta-cell function This perspective discusses if exacerbate this (by promoting and, counterintuitively, inhibitors might better therapeutic strategy for preserving T2D.

Language: Английский

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Precision nutrition in diabetes: when population-based dietary advice gets personal

Diabetologia, Journal Year: 2022, Volume and Issue: 65(11), P. 1839 - 1848

Published: May 20, 2022

Language: Английский

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Endocrine disruptors in plastics alter β-cell physiology and increase the risk of diabetes mellitus

AJP Endocrinology and Metabolism, Journal Year: 2023, Volume and Issue: 324(6), P. E488 - E505

Published: May 3, 2023

Plastic pollution breaks a planetary boundary threatening wildlife and humans through its physical chemical effects. Of the latter, release of endocrine disrupting chemicals (EDCs) has consequences on prevalence human diseases related to system. Bisphenols (BPs) phthalates are two groups EDCs commonly found in plastics that migrate into environment make low-dose exposure ubiquitous. Here we review epidemiological, animal, cellular studies linking BPs altered glucose regulation, with emphasis role pancreatic β-cells. Epidemiological indicate is associated diabetes mellitus. Studies animal models treatment doses within range decreases insulin sensitivity tolerance, induces dyslipidemia, modifies functional β-cell mass serum levels insulin, leptin, adiponectin. These reveal disruption physiology by plays key impairing homeostasis altering mechanisms used β-cells adapt metabolic stress such as chronic nutrient excess. at level demonstrate modify same biochemical pathways involved adaptation excess fuel. include changes biosynthesis secretion, electrical activity, expression genes, mitochondrial function. The data summarized here important risk factors for mellitus support global effort decrease plastic EDCs.

Language: Английский

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Prohormone convertase 1/3 deficiency causes obesity due to impaired proinsulin processing

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Aug. 13, 2022

Abstract Defective insulin processing is associated with obesity and diabetes. Prohormone convertase 1/3 (PC1/3) an endopeptidase required for the of neurotransmitters hormones. PC1/3 deficiency genome-wide association studies relate early onset obesity. Here, we find that deletion in obesity-related neuronal cells expressing proopiomelanocortin mildly transiently change body weight fail to produce a phenotype when targeted Agouti-related peptide- or nestin-expressing tissues. In contrast, pancreatic β cell-specific ablation induces hyperphagia consecutive despite uncontrolled diabetes glucosuria. Obesity develops not due impaired pro-islet amyloid polypeptide but maturation. Proinsulin crosses blood-brain-barrier does induce central satiety. Accordingly, therapy prevents hyperphagia. Further, islet expression levels negatively correlate mass index humans. this work, show PC1/3-mediated proinsulin processing, as observed human prediabetes, promotes hyperphagic

Language: Английский

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