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Gerald I Shulman - One of the best experts on this subject based on the ideXlab platform.

  • Diacylglycerol-mediated Insulin Resistance
    Nature Medicine, 2010
    Co-Authors: Derek M. Erion, Gerald I Shulman
    Abstract:

    Understanding the molecular mechanisms of Insulin Resistance remains a major medical challenge of the twenty-first century. Over the last half-century, many hypotheses have been proposed to explain Insulin Resistance, and, most recently, inflammation associated with alterations in adipocytokines has become the prevailing hypothesis. Here we discuss diacylglycerol-mediated Insulin Resistance as an alternative and unifying hypothesis to explain the most common forms of Insulin Resistance associated with obesity and type 2 diabetes mellitus, as well as lipodystrophy and aging.

  • etiology of Insulin Resistance
    The American Journal of Medicine, 2006
    Co-Authors: Kitt Falk Petersen, Gerald I Shulman
    Abstract:

    Type 2 diabetes mellitus is a major cause of morbidity and mortality worldwide, and the prevalence is set to increase dramatically over the coming decades. Understanding the metabolic pathways that lead to type 2 diabetes is therefore an important healthcare objective. Novel investigational techniques based on magnetic resonance spectroscopy (MRS) have allowed real-time insight into the molecular defects in patients with type 2 diabetes, revealing that Insulin Resistance is a product of decreased Insulin-stimulated skeletal muscle glycogen synthesis, which can mostly be attributed to decreased Insulin-stimulated glucose transport (Glut 4) activity. This defect appears to be a result of intracellular lipid-induced inhibition of Insulin-stimulated Insulin-receptor substrate (IRS)–1 tyrosine phosphorylation resulting in reduced IRS-1–associated phosphatidyl inositol 3 kinase activity. The hypothesis that Insulin Resistance is a result of accumulation of intracellular lipid metabolites (e.g., fatty acyl CoAs, diacylglycerol) in skeletal muscle and hepatocytes is supported by observations in patients and mouse models of lipodystrophy. Furthermore, the increase in hepatic Insulin sensitivity observed in patients with type 2 diabetes following weight loss is also accompanied by a significant reduction in intrahepatic fat without any changes in circulating adipocytokines (interleukin-6, resistin, leptin). Finally, recent MRS studies in healthy, lean, elderly subjects and lean Insulin-resistant offspring of parents with type 2 diabetes have demonstrated that reduced mitochondrial activity may also lead to increased intramyocellular lipid content and Insulin Resistance in skeletal muscle in these individuals. In summary, in vivo MRS has proved to be an important tool for elucidating the causal chain of events that causes Insulin Resistance. Understanding the cellular mechanism(s) of Insulin Resistance in turn offers the prospect of better targeted and more effective therapeutic interventions for treatment and prevention of type 2 diabetes.

  • Etiology of Insulin Resistance
    American Journal of Medicine, 2006
    Co-Authors: Kitt Falk Petersen, Gerald I Shulman
    Abstract:

    Type 2 diabetes mellitus is a major cause of morbidity and mortality worldwide, and the prevalence is set to increase dramatically over the coming decades. Understanding the metabolic pathways that lead to type 2 diabetes is therefore an important healthcare objective. Novel investigational techniques based on magnetic resonance spectroscopy (MRS) have allowed real-time insight into the molecular defects in patients with type 2 diabetes, revealing that Insulin Resistance is a product of decreased Insulin-stimulated skeletal muscle glycogen synthesis, which can mostly be attributed to decreased Insulin-stimulated glucose transport (Glut 4) activity. This defect appears to be a result of intracellular lipid-induced inhibition of Insulin-stimulated Insulin-receptor substrate (IRS)-1 tyrosine phosphorylation resulting in reduced IRS-1-associated phosphatidyl inositol 3 kinase activity. The hypothesis that Insulin Resistance is a result of accumulation of intracellular lipid metabolites (e.g., fatty acyl CoAs, diacylglycerol) in skeletal muscle and hepatocytes is supported by observations in patients and mouse models of lipodystrophy. Furthermore, the increase in hepatic Insulin sensitivity observed in patients with type 2 diabetes following weight loss is also accompanied by a significant reduction in intrahepatic fat without any changes in circulating adipocytokines (interleukin-6, resistin, leptin). Finally, recent MRS studies in healthy, lean, elderly subjects and lean Insulin-resistant offspring of parents with type 2 diabetes have demonstrated that reduced mitochondrial activity may also lead to increased intramyocellular lipid content and Insulin Resistance in skeletal muscle in these individuals. In summary, in vivo MRS has proved to be an important tool for elucidating the causal chain of events that causes Insulin Resistance. Understanding the cellular mechanism(s) of Insulin Resistance in turn offers the prospect of better targeted and more effective therapeutic interventions for treatment and prevention of type 2 diabetes. © 2006 Elsevier Inc. All rights reserved.

  • cellular mechanisms of Insulin Resistance
    Journal of Clinical Investigation, 2000
    Co-Authors: Gerald I Shulman
    Abstract:

    It is estimated that by the year 2020 there will be approximately 250 million people affected by type 2 diabetes mellitus worldwide (1). Although the primary factors causing this disease are unknown, it is clear that Insulin Resistance plays a major role in its development. Evidence for this comes from (a) the presence of Insulin Resistance 10–20 years before the onset of the disease (2, 3); (b) cross-sectional studies demonstrating that Insulin Resistance is a consistent finding in patients with type 2 diabetes (3–6); and (c) prospective studies demonstrating that Insulin Resistance is the best predictor of whether or not an individual will later become diabetic (2, 3). Here, I focus on some recent advances in our understanding of human Insulin Resistance that have been made using nuclear magnetic resonance spectroscopy (NMR). This technique takes advantage of the spin properties of the nuclei of certain isotopes, such as 1H, 13C, and 31P, which endow the isotopes with a magnetic component that can be used to measure the concentration of intracellular metabolites noninvasively and to assess biochemical differences between normal and diabetic subjects. Drawing on NMR studies from my laboratory and others, I first consider the control of glucose phosphorylation and transport in regulating muscle responses to Insulin. I then turn to the effects of fatty acids on Insulin responses, showing that commonly accepted models that attempt to explain the association of Insulin Resistance and obesity are incompatible with recent findings. Finally, I propose an alternative model that appears to fit these and other available data.

Henry N Ginsberg - One of the best experts on this subject based on the ideXlab platform.

  • Insulin Resistance and cardiovascular disease
    Journal of Clinical Investigation, 2000
    Co-Authors: Henry N Ginsberg
    Abstract:

    Clearly, Insulin Resistance is not simply a problem of deficient glucose uptake in response to Insulin, but a multifaceted syndrome that increases significantly the risk for cardiovascular disease. The links between Insulin Resistance and the associated dyslipidemia, hypertension, hypercoagulability, and atherosclerosis are numerous and complex. This complexity derives both from the almost certain multiple causes of the Insulin Resistance syndrome and from the interaction of genes predisposing to Insulin Resistance with other genes that have their own, independent impact on lipid metabolism, blood pressure regulation, coagulation, and artery wall biology. Nonetheless, I suggest that dysregulation of fatty acid metabolism plays a central role in the development of this phenotype. Thus, the association between Insulin Resistance and dyslipidemia is clearly initiated by increased FFA release from, or defective uptake of FFAs into, adipocytes. Recent studies linking fatty acids to endothelial dysfunction, together with the clear role of VLDL in the stimulation of PAI-1, further support the view that dysregulation of fatty acid metabolism sits close to the center of the pathophysiology of the Insulin Resistance syndrome, at least as it relates to risk for cardiovascular disease.

Christopher K. Glass - One of the best experts on this subject based on the ideXlab platform.

  • Macrophages, Inflammation, and Insulin Resistance
    Annual Review of Physiology, 2010
    Co-Authors: Jerrold M. Olefsky, Christopher K. Glass
    Abstract:

    Obesity induces an Insulin-resistant state in adipose tissue, liver, and muscle and is a strong risk factor for the development of type 2 diabetes mellitus. Insulin Resistance in the setting of obesity results from a combination of altered functions of Insulin target cells and the accumulation of macrophages that secrete proinflammatory mediators. At the molecular level, Insulin Resistance is promoted by a transition in macrophage polarization from an alternative M2 activation state maintained by STAT6 and PPARs to a classical M1 activation state driven by NF-κB, AP1, and other signal-dependent transcription factors that play crucial roles in innate immunity. Strategies focused on inhibiting the inflammation/Insulin Resistance axis that otherwise preserve essential innate immune functions may hold promise for therapeutic intervention.

Jerrold M. Olefsky - One of the best experts on this subject based on the ideXlab platform.

  • Macrophages, Inflammation, and Insulin Resistance
    Annual Review of Physiology, 2010
    Co-Authors: Jerrold M. Olefsky, Christopher K. Glass
    Abstract:

    Obesity induces an Insulin-resistant state in adipose tissue, liver, and muscle and is a strong risk factor for the development of type 2 diabetes mellitus. Insulin Resistance in the setting of obesity results from a combination of altered functions of Insulin target cells and the accumulation of macrophages that secrete proinflammatory mediators. At the molecular level, Insulin Resistance is promoted by a transition in macrophage polarization from an alternative M2 activation state maintained by STAT6 and PPARs to a classical M1 activation state driven by NF-κB, AP1, and other signal-dependent transcription factors that play crucial roles in innate immunity. Strategies focused on inhibiting the inflammation/Insulin Resistance axis that otherwise preserve essential innate immune functions may hold promise for therapeutic intervention.

  • Inflammation and Insulin Resistance
    FEBS Letters, 2008
    Co-Authors: Carl De Luca, Jerrold M. Olefsky
    Abstract:

    Obesity-induced chronic inflammation is a key component in the pathogenesis of Insulin Resistance and the Metabolic syndrome. In this review, we focus on the interconnection between obesity, inflammation and Insulin Resistance. Pro-inflammatory cytokines can cause Insulin Resistance in adipose tissue, skeletal muscle and liver by inhibiting Insulin signal transduction. The sources of cytokines in Insulin resistant states are the Insulin target tissue themselves, primarily fat and liver, but to a larger extent the activated tissue resident macrophages. While the initiating factors of this inflammatory response remain to be fully determined, chronic inflammation in these tissues could cause localized Insulin Resistance via autocrine/paracrine cytokine signaling and systemic Insulin Resistance via endocrine cytokine signaling all of which contribute to the abnormal metabolic state. © 2007 Federation of European Biochemical Societies.

A. P. Rocchini - One of the best experts on this subject based on the ideXlab platform.

  • Insulin Resistance, Obesity and Hypertension
    Journal of Nutrition, 1995
    Co-Authors: A. P. Rocchini
    Abstract:

    Although controversy exists as to the role that Insulin Resistance and hyperInsulinemia play in the pathogenesis of hypertension, data are presented that strongly suggest that selective Insulin Resistance and hypertension are directly related. This paper summarizes how Insulin Resistance may be linked to obesity hypertension and describes some of the other cardiovascular implications that Insulin Resistance may have in the hypertensive obese individual.

  • Insulin Resistance, obesity and hypertension : Insulin Resistance, obesity and hypertension
    Journal of Nutrition, 1995
    Co-Authors: A. P. Rocchini
    Abstract:

    Although controversy exists as to the role that Insulin Resistance and hyperInsulinemia play in the pathogenesis of hypertension, data are presented that strongly suggest that selective Insulin Resistance and hypertension are directly related. This paper summarizes how Insulin Resistance may be linked to obesity hypertension and describes some of the other cardiovascular implications that Insulin Resistance may have in the hypertensive obese individual.