Roles of Diacylglycerols and Ceramides in Hepatic Insulin Resistance

Petersen, Max C.; Shulman, Gerald I.

doi:10.1016/j.tips.2017.04.004

Cited by 268 publications

(220 citation statements)

References 125 publications

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“…Insulin resistance in skeletal muscle plays a key role in Type 2 diabetes development. Various studies support the importance of specific muscle ceramides in the development of lipid-induced skeletal muscle insulin resistance [61,62]; however, the role of ceramides as mediators of hepatic insulin resistance is unclear and supported by a few [7,63,64], but not all [65] studies, as recently reviewed [66]. The degradation of ceramides both in the liver and in fat tissue improved glucose metabolism, suggesting a major contributing role for both these tissues in regulating circulating ceramide levels, and, in addition, confirming the role of these substances on glucose homeostasis [7].…”

Section: Ceramides and Glucose Metabolismmentioning

confidence: 99%

Ceramides and diabetes mellitus: an update on the potential molecular relationships

Yaribeygi

Ruscica

et al. 2019

Diabet. Med.

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Recent evidence suggests that ceramides can play an important pathophysiological role in the development of diabetes. Ceramides are primarily recognized as lipid bilayer building blocks, but recent work has shown that these endogenous molecules are important intracellular signalling mediators and may exert some diabetogenic effects via molecular pathways involved in insulin resistance, β‐cell apoptosis and inflammation. In the present review, we consider the available evidence on the possible roles of ceramides in diabetes mellitus and introduce eight different molecular mechanisms mediating the diabetogenic action of ceramides, categorized into those predominantly related to insulin resistance vs those mainly implicated in β‐cell dysfunction. Specifically, the mechanistic evidence involves β‐cell apoptosis, pancreatic inflammation, mitochondrial stress, endoplasmic reticulum stress, adipokine release, insulin receptor substrate 1 phosphorylation, oxidative stress and insulin synthesis. Collectively, the evidence suggests that therapeutic agents aimed at reducing ceramide synthesis and lowering circulating levels may be beneficial in the prevention and/or treatment of diabetes and its related complications.

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Section: Ceramides and Glucose Metabolismmentioning

confidence: 99%

Ceramides and diabetes mellitus: an update on the potential molecular relationships

Yaribeygi

Ruscica

et al. 2019

Diabet. Med.

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“…The insulin-resistant state is central to the pathophysiology of cardiometabolic disease via the following: (1) defects in glucose homeostasis, substrate oxidation, and mitochondrial function; (2) increased inflammation and oxidative stress; (3) alterations in lipids and lipoproteins contributing to CVD risk; (4) impaired lipid storage in adipocytes associated with the accumulation of ectopic lipids in muscle cells and hepatocytes; and (5) increased vasoreactivity due to a reduction in endothelial nitric oxide synthase activity and nitric oxide production (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Obesity exacerbates insulin resistance and can impel cardiometabolic disease progression toward T2D, NAFLD, and CVD (9,10,22,23). Thus, beyond simple increases in adipose tissue mass, abnormalities in adipose tissue function and distribution are critically involved in the pathogenesis of cardiometabolic complications in obesity (8).…”

Section: Introduction: Obesity As a Disease-rationale And Mechanismsmentioning

confidence: 99%

Proposal for a Scientifically Correct and Medically Actionable Disease Classification System (ICD) for Obesity

Garvey

Mechanick

2020

Obesity

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Objective Obesity is responsible for a huge burden of suffering and social costs, and yet many patients lack access to evidence‐based therapies. The diagnostic term “obesity” and inadequate International Classification of Diseases(ICD) codes contribute to suboptimal efforts to prevent and treat obesity as a chronic disease. The goal of this review is to develop a medically actionable classification system based on the diagnostic term “adiposity‐based chronic disease” (ABCD) that reflects disease pathophysiology and specific complications causing morbidity and mortality. Methods A coding system based on the diagnosis of ABCD with four domains is proposed: A codes reflect pathophysiology, B codes indicate BMI classification, C codes specify specific biomechanical and cardiovascular complications remediable by weight loss, and D codes indicate the degree of the severity of complications. Supplemental codes identify aggravating factors that complicate care and that are relevant to a personalized therapeutic plan. Results The coding system addresses pathophysiology and therapeutic goals and differential risk, presence, and severity of specific complications that are integral to ABCD as a chronic disease. Conclusions The scientifically correct and medically actionable approach to diagnosis and disease coding will lead to greater acknowledgement of ABCD as a disease and accessibility to evidence‐based therapies on behalf of patients across the life cycle.

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“…Moreover, increased plasma FFA are associated with IR (22, 23) through intramyocellular and intrahepatic accumulation of TG and other metabolites (24). TG is not considered a signaling lipid, and thus it is thought to be more likely that diacylglycerol, the synthetic precursor of TG, ceramide, and other lipids are implicated in the pathogenesis of hepatic IR through several mechanisms including reduced insulin receptor tyrosine kinase activity, insulin receptor destabilization and reduced insulin-stimulated glycogen synthase activity (25–28). FFA may also mediate IR through pro-inflammatory effects (29, 30).…”

Section: Introductionmentioning

confidence: 99%

Pathogenesis of Lipid Disorders in Insulin Resistance: a Brief Review

2018

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Purpose of the review: Insulin resistance (IR) is recognized to play an important role in the pathogenesis of dyslipidemia. This review summarizes the complex interplay between IR and dyslipidemia in people with and without diabetes. Recent findings: IR impacts the metabolism of triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and very low-density lipoprotein cholesterol (VLDL-C) by several mechanisms. Trials with insulin sensitizing therapies, including biguanides and thiazolidinediones, have provided inconsistent results on lipid lowering in people with and without diabetes. In this review, we focus on the pathophysiological interplay between IR and dyslipidemia and recapitulate lipid and lipoprotein data from insulin sensitizing trials. Conclusion: Further research elucidating the reciprocal relationship between IR and dyslipidemia is needed to better target these important risk factors for cardiovascular disease.

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Roles of Diacylglycerols and Ceramides in Hepatic Insulin Resistance

Cited by 268 publications

References 125 publications

Ceramides and diabetes mellitus: an update on the potential molecular relationships

Ceramides and diabetes mellitus: an update on the potential molecular relationships

Proposal for a Scientifically Correct and Medically Actionable Disease Classification System (ICD) for Obesity

Pathogenesis of Lipid Disorders in Insulin Resistance: a Brief Review

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