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Molecular Mechanisms of Insulin Resistance in Peripheral Tissues

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 25942

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Dr. Eric Hajduch

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Guest Editor

INSERM U1138, Centre de Recherche des Cordeliers, Paris, France
Interests: sphingolipid metabolism; insulin resistance and type 2 diabetes

Prof. Dr. Hervé Le Stunff

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Guest Editor

Institut des Neurosciences Paris-Saclay (Neuro-PSI)-CNRS UMR 9197, Equipe Neuroendocrinologie Moléculaire de la Prise Alimentaire, Université Paris-Sud (Université Paris Saclay), Bâtiment 447, 91405 Orsay CEDEX, France
Interests: sphingolipid; ceramide; sphingosine-1-phosphate; diabetes; obesity; apoptosis; insulin resistance; pancreatic beta cell failure; elongases; insulin secretion

Special Issue Information

Dear Colleagues,

In healthy people, the balance between glucose production and its use is finely controlled. When blood glucose reaches a critical level, pancreatic ß cells secrete insulin, which has two major actions: it decreases circulating glucose levels by facilitating its storage (mainly in muscles and liver), while inhibiting hepatic glucose production. A central complication of obesity is the development of insulin resistance, a state in which insulin is incapable of eliciting postprandial nutrient storage in its primary target tissues, i.e., adipocytes, skeletal muscle, and liver. This condition predisposes individuals to type 2 diabetes and may give rise to the other diseases associated with obesity.

In recent years, the discovery of several mechanisms (lipid derivative accumulation, inflammation, endoplasmic reticulum stress, and mitochondrial dysfunction) has explained how fat overflow may affect overall insulin sensitivity throughout the body, contributing to the downregulation of insulin signaling in peripheral tissues.

This Special Issue “Molecular Mechanisms of Insulin Resistance in Peripheral Tissues” will cover a selection of recent research topics and current review articles in the field of insulin resistance and type 2 diabetes in different organs, such as heart, liver, pancreas, muscles, and fat.

Dr. Eric Hajduch
Prof. Dr. Hervé Le Stunff
Guest Editors

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Keywords

insulin
diabetes
inflammation
stress
sphingolipids
diacyl-glycerol
cardiovascular risk

Published Papers (5 papers)

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Research

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13 pages, 2601 KiB

Open AccessArticle

Short-Term Strength Exercise Reduces Hepatic Insulin Resistance in Obese Mice by Reducing PTP1B Content, Regardless of Changes in Body Weight

by Kellen Cristina da Cruz Rodrigues, Rodrigo Martins Pereira, Guilherme Francisco Peruca, Lucas Wesley Torres Barbosa, Marcella Ramos Sant’Ana, Vitor Rosetto Muñoz, Ana Paula Morelli, Fernando Moreira Simabuco, Adelino Sanchez Ramos da Silva, Dennys Esper Cintra, Eduardo Rochete Ropelle, José Rodrigo Pauli and Leandro Pereira de Moura

Int. J. Mol. Sci. 2021, 22(12), 6402; https://doi.org/10.3390/ijms22126402 - 15 Jun 2021

Cited by 9 | Viewed by 2785

Abstract

Obesity is closely related to insulin resistance and type 2 diabetes genesis. The liver is a key organ to glucose homeostasis since insulin resistance in this organ increases hepatic glucose production (HGP) and fasting hyperglycemia. The protein-tyrosine phosphatase 1B (PTP1B) may dephosphorylate the IR and IRS, contributing to insulin resistance in this organ. Aerobic exercise is a great strategy to increase insulin action in the liver by reducing the PTP1B content. In contrast, no study has shown the direct effects of strength training on the hepatic metabolism of PTP1B. Therefore, this study aims to investigate the effects of short-term strength exercise (STSE) on hepatic insulin sensitivity and PTP1B content in obese mice, regardless of body weight change. To achieve this goal, obese Swiss mice were submitted to a strength exercise protocol lasting 15 days. The results showed that STSE increased Akt phosphorylation in the liver and enhanced the control of HGP during the pyruvate tolerance test. Furthermore, sedentary obese animals increased PTP1B content and decreased IRS-1/2 tyrosine phosphorylation; however, STSE was able to reverse this scenario. Therefore, we conclude that STSE is an important strategy to improve the hepatic insulin sensitivity and HGP by reducing the PTP1B content in the liver of obese mice, regardless of changes in body weight. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Insulin Resistance in Peripheral Tissues)

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13 pages, 1763 KiB

Open AccessArticle

Short-Term Combined Exercise Improves Inflammatory Profile in the Retina of Obese Mice

by Thaís Dantis Pereira de Campos, Kellen Cristina da Cruz Rodrigues, Rodrigo Martins Pereira, Ana Paula Morelli, Alisson Luiz da Rocha, Raphael dos Santos Canciglieri, Adelino Sanchez Ramos da Silva, Eduardo Rochete Ropelle, José Rodrigo Pauli, Fernando Moreira Simabuco, Dennys Esper Cintra and Leandro Pereira de Moura

Int. J. Mol. Sci. 2020, 21(17), 6099; https://doi.org/10.3390/ijms21176099 - 24 Aug 2020

Cited by 6 | Viewed by 2440

Abstract

Excess of adipose tissue increases the concentration of proinflammatory cytokines, triggering a subclinical inflammatory condition. This inflammatory profile contributes to retina damage, which can lead to retinal dysfunction and reduced vision. Regularly practicing both aerobic and strength exercises is well known for promoting anti-inflammatory effects on different organs in the peripheral and central regions. However, the effects of combined physical exercise (CPE; strength + aerobic) on the inflammatory process in the retina tissue are not yet known. This study aimed to investigate the effects of CPE on the inflammatory profile of the retina in obese mice. Swiss mice were distributed into control, sedentary obese, and trained obese groups. The trained obese group was subjected to short-term CPE, 1 h/day, for 7 days. The CPE was composed of aerobic and strength exercises in the same exercise session. The strength exercise protocol consisted of 10 climbing series, with 12 ± 1 dynamic climbing movements at 70% of the maximum voluntary carrying capacity (MVCC), and the aerobic exercise protocol consisted of 30 min of treadmill running, with an intensity of 75% of the exhaust velocity. Subsequently, the retina was excised and analyzed by Western blot. Obese animals presented impairment on glucose homeostasis and elevated levels of proinflammatory proteins in the serum and retina; however, CPE was effective in reversing these parameters, independently of changes in body adiposity. Therefore, for the first time, we have shown that short-term CPE can be an important strategy to treat an inflammatory profile in the retina. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Insulin Resistance in Peripheral Tissues)

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Review

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27 pages, 796 KiB

Open AccessReview

Novel Insights and Mechanisms of Lipotoxicity-Driven Insulin Resistance

by Benjamin Lair, Claire Laurens, Bram Van Den Bosch and Cedric Moro

Int. J. Mol. Sci. 2020, 21(17), 6358; https://doi.org/10.3390/ijms21176358 - 2 Sep 2020

Cited by 37 | Viewed by 5122

Abstract

A large number of studies reported an association between elevated circulating and tissue lipid content and metabolic disorders in obesity, type 2 diabetes (T2D) and aging. This state of uncontrolled tissue lipid accumulation has been called lipotoxicity. It was later shown that excess lipid flux is mainly neutralized within lipid droplets as triglycerides, while several bioactive lipid species such as diacylglycerols (DAGs), ceramides and their derivatives have been mechanistically linked to the pathogenesis of insulin resistance (IR) by antagonizing insulin signaling and action in metabolic organs such as the liver and skeletal muscle. Skeletal muscle and the liver are the main sites of glucose disposal in the body and IR in these tissues plays a pivotal role in the development of T2D. In this review, we critically examine recent literature supporting a causal role of DAGs and ceramides in the development of IR. A particular emphasis is placed on transgenic mouse models with modulation of total DAG and ceramide pools, as well as on modulation of specific subspecies, in relation to insulin sensitivity. Collectively, although a wide number of studies converge towards the conclusion that both DAGs and ceramides cause IR in metabolic organs, there are still some uncertainties on their mechanisms of action. Recent studies reveal that subcellular localization and acyl chain composition are determinants in the biological activity of these lipotoxic lipids and should be further examined. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Insulin Resistance in Peripheral Tissues)

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19 pages, 810 KiB

Open AccessReview

Metabolic and Molecular Mechanisms of Macrophage Polarisation and Adipose Tissue Insulin Resistance

by Lucie Orliaguet, Tina Ejlalmanesh and Fawaz Alzaid

Int. J. Mol. Sci. 2020, 21(16), 5731; https://doi.org/10.3390/ijms21165731 - 10 Aug 2020

Cited by 23 | Viewed by 5054

Abstract

Inflammation plays a key role in the development and progression of type-2 diabetes (T2D), a disease characterised by peripheral insulin resistance and systemic glucolipotoxicity. Visceral adipose tissue (AT) is the main source of inflammation early in the disease course. Macrophages are innate immune cells that populate all peripheral tissues, including AT. Dysregulated AT macrophage (ATM) responses to microenvironmental changes are at the root of aberrant inflammation and development of insulin resistance, locally and systemically. The inflammatory activation of macrophages is regulated at multiple levels: cell surface receptor stimulation, intracellular signalling, transcriptional and metabolic levels. This review will cover the main mechanisms involved in AT inflammation and insulin resistance in T2D. First, we will describe the physiological and pathological changes in AT that lead to inflammation and insulin resistance. We will next focus on the transcriptional and metabolic mechanisms described that lead to the activation of ATMs. We will discuss more novel metabolic mechanisms that influence macrophage polarisation in other disease or tissue contexts that may be relevant to future work in insulin resistance and T2D. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Insulin Resistance in Peripheral Tissues)

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30 pages, 1560 KiB

Open AccessReview

Rewiring of Lipid Metabolism in Adipose Tissue Macrophages in Obesity: Impact on Insulin Resistance and Type 2 Diabetes

by Veronica D. Dahik, Eric Frisdal and Wilfried Le Goff

Int. J. Mol. Sci. 2020, 21(15), 5505; https://doi.org/10.3390/ijms21155505 - 31 Jul 2020

Cited by 35 | Viewed by 9684

Abstract

Obesity and its two major comorbidities, insulin resistance and type 2 diabetes, represent worldwide health issues whose incidence is predicted to steadily rise in the coming years. Obesity is characterized by an accumulation of fat in metabolic tissues resulting in chronic inflammation. It is now largely accepted that adipose tissue inflammation underlies the etiology of these disorders. Adipose tissue macrophages (ATMs) represent the most enriched immune fraction in hypertrophic, chronically inflamed adipose tissue, and these cells play a key role in diet-induced type 2 diabetes and insulin resistance. ATMs are triggered by the continuous influx of dietary lipids, among other stimuli; however, how these lipids metabolically activate ATM depends on their nature, composition and localization. This review will discuss the fate and molecular programs elicited within obese ATMs by both exogenous and endogenous lipids, as they mediate the inflammatory response and promote or hamper the development of obesity-associated insulin resistance and type 2 diabetes. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Insulin Resistance in Peripheral Tissues)

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