Mechanisms of Insulin Action and Insulin Resistance

Physiological Reviews, Journal Year: 2018, Volume and Issue: 98(4), P. 2133 - 2223

Published: Aug. 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.

Language: Английский

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Type 2 diabetes mellitus

Nature Reviews Disease Primers, Journal Year: 2015, Volume and Issue: 1(1)

Published: July 22, 2015

Language: Английский

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Diabetes mellitus: The epidemic of the century

World Journal of Diabetes, Journal Year: 2015, Volume and Issue: 6(6), P. 850 - 850

Published: Jan. 1, 2015

The epidemic nature of diabetes mellitus in different regions is reviewed.The Middle East and North Africa region has the highest prevalence adults (10.9%) whereas, Western Pacific number diagnosed with countries (37.5%).Different classes mellitus, type 1, 2, gestational other types are compared terms diagnostic criteria, etiology genetics.The molecular genetics received extensive attention recent years by many prominent investigators research groups biomedical field.A large array mutations single nucleotide polymorphisms genes that play a role various steps pathways involved glucose metabolism development, control function pancreatic cells at levels major advances understanding relation to comparison previous this field briefly reviewed here.Despite accumulation data cellular levels, mechanism development complications still not fully understood.Definitely, more needed will eventually reflect on ultimate objective improve diagnoses, therapy minimize chance chronic development.

Language: Английский

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Insulin action and resistance in obesity and type 2 diabetes

Nature Medicine, Journal Year: 2017, Volume and Issue: 23(7), P. 804 - 814

Published: July 1, 2017

Language: Английский

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Insulin resistance: Review of the underlying molecular mechanisms

Journal of Cellular Physiology, Journal Year: 2018, Volume and Issue: 234(6), P. 8152 - 8161

Published: Oct. 14, 2018

Abstract Most human cells utilize glucose as the primary substrate, cellular uptake requiring insulin. Insulin signaling is therefore critical for these tissues. However, decrease in insulin sensitivity due to disruption of various molecular pathways causes resistance (IR). IR underpins many metabolic disorders such type 2 diabetes and syndrome, impairments disrupting entry into adipocytes, skeletal muscle cells. Although exact underlying cause has not been fully elucidated, a number major mechanisms, including oxidative stress, inflammation, receptor mutations, endoplasmic reticulum mitochondrial dysfunction have suggested. In this review, we consider role mechanisms play development IR.

Language: Английский

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Biochemical and cellular properties of insulin receptor signalling

Nature Reviews Molecular Cell Biology, Journal Year: 2017, Volume and Issue: 19(1), P. 31 - 44

Published: Oct. 4, 2017

Language: Английский

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Insulin signaling, resistance, and metabolic syndrome: insights from mouse models into disease mechanisms

Journal of Endocrinology, Journal Year: 2013, Volume and Issue: 220(2), P. T1 - T23

Published: Nov. 26, 2013

Insulin resistance is a major underlying mechanism responsible for the ‘metabolic syndrome’, which also known as insulin syndrome. The incidence of metabolic syndrome increasing at an alarming rate, becoming public and clinical problem worldwide. Metabolic represented by group interrelated disorders, including obesity, hyperglycemia, hyperlipidemia, hypertension. It significant risk factor cardiovascular disease increased morbidity mortality. Animal studies have demonstrated that its signaling cascade normally control cell growth, metabolism, survival through activation MAPKs phosphatidylinositide-3-kinase (PI3K), in PI3K associated with receptor substrate 1 (IRS1) IRS2 subsequent Akt→Foxo1 phosphorylation has central role nutrient homeostasis organ survival. inactivation Akt Foxo1, suppression IRS1 different organs following hyperinsulinemia, inflammation, overnutrition, may act mechanisms humans. Targeting IRS→Akt→Foxo1 will probably provide strategy therapeutic intervention treatment type 2 diabetes complications. This review discusses basis signaling, mouse models, how deficiency components contributes to features Emphasis placed on IRS1, IRS2, pathways are coupled forkhead/winged helix transcription Foxo1.

Language: Английский

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Molecular Mechanisms Linking Oxidative Stress and Diabetes Mellitus

Oxidative Medicine and Cellular Longevity, Journal Year: 2020, Volume and Issue: 2020, P. 1 - 13

Published: March 9, 2020

Type 2 diabetes mellitus (T2DM) is the most prevalent metabolic disorder characterized by chronic hyperglycemia and an inadequate response to circulatory insulin peripheral tissues resulting in resistance. Insulin resistance has a complex pathophysiology, it contributed multiple factors including oxidative stress. Oxidative stress refers imbalance between free radical production antioxidant system leading reduction of sensitivity contributing development T2DM via several molecular mechanisms. In this review, we present mechanisms which milieu contributes pathophysiology mellitus.

Language: Английский

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Metabolites as regulators of insulin sensitivity and metabolism

Nature Reviews Molecular Cell Biology, Journal Year: 2018, Volume and Issue: 19(10), P. 654 - 672

Published: Aug. 13, 2018

Language: Английский

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Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease

Journal of Neuroinflammation, Journal Year: 2018, Volume and Issue: 15(1)

Published: Sept. 24, 2018

Alzheimer’s disease (AD) is a neurodegenerative disorder, most cases of which lack clear causative event. This has made the difficult to characterize and, thus, diagnose. Although some are genetically linked, there many diseases and lifestyle factors that can lead an increased risk developing AD, including traumatic brain injury, diabetes, hypertension, obesity, other metabolic syndromes, in addition aging. Identifying common trends between these conditions could enhance our understanding AD development more effective treatments. immune system one body’s key defense mechanisms, chronic inflammation been increasingly linked with several age-related diseases. Moreover, it now well accepted important role onset progression AD. In this review, different inflammatory signals associated its will be outlined demonstrate how may influencing individual susceptibility Our goal bring attention potential shared presented by during successful

Language: Английский

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