Mechanisms of Insulin Action and Insulin Resistance

Physiological Reviews, Год журнала: 2018, Номер 98(4), С. 2133 - 2223

Опубликована: Авг. 1, 2018

The 1921 discovery of insulin was a Big Bang from which vast and expanding universe research into action resistance has issued. In the intervening century, some discoveries have matured, coalescing solid fertile ground for clinical application; others remain incompletely investigated scientifically controversial. Here, we attempt to synthesize this work guide further mechanistic investigation inform development novel therapies type 2 diabetes (T2D). rational such necessitates detailed knowledge one key pathophysiological processes involved in T2D: resistance. Understanding resistance, turn, requires normal action. review, both physiology pathophysiology are described, focusing on three target tissues: skeletal muscle, liver, white adipose tissue. We aim develop an integrated physiological perspective, placing intricate signaling effectors that carry out cell-autonomous response context tissue-specific functions generate coordinated organismal response. First, section II, effects direct, tissue reviewed, beginning at receptor working downstream. Section III considers critical underappreciated role crosstalk whole body action, especially essential interaction between lipolysis hepatic gluconeogenesis. is then described IV. Special attention given pathways become resistant setting chronic overnutrition, alternative explanation phenomenon ‟selective resistanceˮ presented. Sections V, VI, VII critically examine evidence against several putative mediators V reviews linking bioactive lipids diacylglycerol, ceramide, acylcarnitine resistance; VI impact nutrient stresses endoplasmic reticulum mitochondria discusses non-cell autonomous factors proposed induce including inflammatory mediators, branched-chain amino acids, adipokines, hepatokines. Finally, VIII, propose model links these final common metabolite-driven gluconeogenesis ectopic lipid accumulation.

Язык: Английский

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Anti-obesity drug discovery: advances and challenges

Nature Reviews Drug Discovery, Год журнала: 2021, Номер 21(3), С. 201 - 223

Опубликована: Ноя. 23, 2021

Enormous progress has been made in the last half-century management of diseases closely integrated with excess body weight, such as hypertension, adult-onset diabetes and elevated cholesterol. However, treatment obesity itself proven largely resistant to therapy, anti-obesity medications (AOMs) often delivering insufficient efficacy dubious safety. Here, we provide an overview history AOM development, focusing on lessons learned ongoing obstacles. Recent advances, including increased understanding molecular gut–brain communication, are inspiring pursuit next-generation AOMs that appear capable safely achieving sizeable sustained weight loss. The development therapies loss proved tremendously challenging. Müller et al. drug learned, challenges recent advances field.

Язык: Английский

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The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD)

Journal of Diabetes Research, Год журнала: 2020, Номер 2020, С. 1 - 16

Опубликована: Авг. 4, 2020

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) remain as one of the most global problematic metabolic diseases with rapidly increasing prevalence incidence. Epidemiological studies noted that T2DM patients have by two-fold increase to develop NAFLD, vice versa. This complex intricate association is supported mediated insulin resistance (IR). In this review, we discuss NAFLD immunopathogenesis, connection IR T2DM, role screening noninvasive tools, mostly impact current antidiabetic drugs on steatosis new potential therapeutic targets.

Язык: Английский

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Melatonin Suppresses Ferroptosis Induced by High Glucose via Activation of the Nrf2/HO-1 Signaling Pathway in Type 2 Diabetic Osteoporosis

Oxidative Medicine and Cellular Longevity, Год журнала: 2020, Номер 2020, С. 1 - 18

Опубликована: Дек. 4, 2020

Ferroptosis is recently identified, an iron- and reactive oxygen species- (ROS-) dependent form of regulated cell death. This study was designed to determine the existence ferroptosis in pathogenesis type 2 diabetic osteoporosis confirm that melatonin can inhibit osteoblasts through activating Nrf2/HO-1 signaling pathway improve bone microstructure vivo vitro. We treated MC3T3-E1 cells with different concentrations (1, 10, or 100 μM) exposed them high glucose (25.5 mM) for 48 h Our data showed induce osteoblast cytotoxicity accumulation lipid peroxide, mitochondria show same morphology changes as erastin treatment group, expression ferroptosis-related proteins glutathione peroxidase 4 (GPX4) cystine-glutamate antiporter (SLC7A11) downregulated, but these effects were reversed by inhibitor ferrastatin-1 iron chelator deferoxamine (DFO). Furthermore, western blot real-time polymerase chain reaction used detect levels nuclear factor erythroid 2-related (Nrf2) heme oxygenase-1 (HO-1); osteogenic capacity evaluated alizarin red S staining osteoprotegerin, osteocalcin, alkaline phosphatase; results 1, μM melatonins significantly higher than after using Nrf2-SiRNA interference, therapeutic effect inhibited. also performed experiments a rat model two (10, 50 mg/kg). Dynamic histomorphometry micro-CT observe microstructure, GPX4 Nrf2 determined immunohistochemistry. Here, we first report induces via increased ROS/lipid peroxidation/glutathione depletion osteoporosis. More importantly, reduced level improved

Язык: Английский

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Obesity cardiomyopathy: evidence, mechanisms, and therapeutic implications

Physiological Reviews, Год журнала: 2021, Номер 101(4), С. 1745 - 1807

Опубликована: Май 5, 2021

The prevalence of heart failure is on the rise and imposes a major health threat, in part, due to rapidly increased overweight obesity. To this point, epidemiological, clinical, experimental evidence supports existence unique disease entity termed "obesity cardiomyopathy," which develops independent hypertension, coronary disease, other diseases. Our contemporary review evaluates for pathological condition, examines putative responsible mechanisms, discusses therapeutic options disorder. Clinical findings have consolidated presence left ventricular dysfunction Experimental investigations uncovered pathophysiological changes myocardial structure function genetically predisposed diet-induced Indeed, consolidates wide array cellular molecular mechanisms underlying etiology obesity cardiomyopathy including adipose tissue dysfunction, systemic inflammation, metabolic disturbances (insulin resistance, abnormal glucose transport, spillover free fatty acids, lipotoxicity, amino acid derangement), altered intracellular especially mitochondrial Ca2+ homeostasis, oxidative stress, autophagy/mitophagy defect, fibrosis, dampened flow reserve, microvascular (microangiopathy), endothelial impairment. Given important role risk failure, that with preserved systolic recent rises COVID-19-associated cardiovascular mortality, should provide compelling cardiomyopathy, various comorbid conditions, offer new insights into potential approaches (pharmacological lifestyle modification) clinical management cardiomyopathy.

Язык: Английский

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The Role of Leptin and Adiponectin in Obesity-Associated Cognitive Decline and Alzheimer’s Disease

Frontiers in Neuroscience, Год журнала: 2019, Номер 12

Опубликована: Янв. 13, 2019

Cross-talk between adipose tissue and central nervous system (CNS) underlies the increased risk of obese people to develop brain diseases such as cognitive mood disorders. Detailed mechanisms for how peripheral changes caused by accumulation in obesity impact CNS cause dysfunction are poorly understood. Adipokines a large group substances secreted white regulate wide range homeostatic processes including, but not limited to, energy metabolism immunity. Obesity is characterized generalized change levels circulating adipokines due abnormal tissue. Altered adipokine underlie complications well development obesity-related comorbidities type 2 diabetes, cardiovascular neurodegenerative diseases. Here, we review literature role key mediators communication periphery health disease. We will focus on actions leptin adiponectin, two most abundant studied adipokines, brain, with particular emphasis altered signaling these may lead augmented Alzheimer's A better understanding biology disorders prove major relevance diagnostic, prevention therapy.

Язык: Английский

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Simple animal models for microbiome research

Nature Reviews Microbiology, Год журнала: 2019, Номер 17(12), С. 764 - 775

Опубликована: Авг. 15, 2019

Язык: Английский

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Animal models of arrhythmia: classic electrophysiology to genetically modified large animals

Nature Reviews Cardiology, Год журнала: 2019, Номер 16(8), С. 457 - 475

Опубликована: Март 20, 2019

Язык: Английский

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Animal and translational models of SARS-CoV-2 infection and COVID-19

Mucosal Immunology, Год журнала: 2020, Номер 13(6), С. 877 - 891

Опубликована: Авг. 20, 2020

Язык: Английский

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A small molecule HIF-1α stabilizer that accelerates diabetic wound healing

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Июнь 7, 2021

Abstract Impaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design synthesis cyclometalated iridium(III) metal complex 1a as stabilizer hypoxia-inducible factor-1α (HIF-1α). vitro biophysical cellular analyses demonstrate that compound binds to Von Hippel-Lindau (VHL) inhibits VHL–HIF-1α interaction. Furthermore, accumulates HIF-1α levels cellulo activates mediated gene expression, including VEGF , GLUT1 EPO . vivo mouse models, significantly accelerates closure both normal mice, with greater effect being observed group. We also driven genes related (i.e. HSP-90 VEGFR-1 SDF-1 SCF Tie-2 ) increased tissue -treated mice (including, db / HFD/STZ STZ models). Our study demonstrates small molecule promising therapeutic agent for healing, and, more importantly, validates feasibility treating wounds by blocking VHL

Язык: Английский

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