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Metabolic Mechanisms of Muscle Insulin Resistance

Deborah M. Muoio, Timothy R. Koves, Jie An, and Christopher B. Newgard

Contents

Introduction

Inter-organ Communication and Development of Muscle Insulin Resistance Metabolic Adaptations Leading to Insulin Resistance in Muscle—A Problem of Impaired or Increased Fatty Acid Oxidation? Transcription-Based Mechanisms of Metabolic Reprogramming in Muscle in Response to Overnutrition Upregulation of Fatty Acid Oxidation as a Mechanism for Generating Lipid

Species that Impair Insulin Action—A Unifying Hypothesis? Acknowledgements References

Summary

Obesity has emerged as one of the leading global health threats of the 21st century. The current worldwide pandemic has been triggered by lifestyle habits that promote overconsumption of energy rich foods while also discouraging routine physical activity. These environmental factors impose a chronic energy imbalance that leads to a steady gain of body fat and a constellation of accompanying metabolic abnormalities. As adiposity increases, so does the risk of developing insulin resistance and type 2 diabetes, evidenced by the fact that over 80% of type 2 diabetic pateints are obese. Skeletal muscle is a primary target tissue of these disorders and a progressive loss of muscle insulin sensitivity contributes to deteriorating glucose control. Compelling evidence suggests that the development of skeletal muscle insulin resistance is intimately associated with systemic dyslipidemia and intramuscular lipid accumulation. Conversely, the antidiabetic effects of exercise coincide with marked improvements in lipid homeostasis, both systemically and locally. These findings have inspired a new area of metabolic research centered on the concept of "lipotoxicity" and the goal of understanding the molecular mechanisms that link chronic lipid oversupply to tissue dysfunction and the onset of disease. This chapter provides an overview of recent advances in this area, placing emphasis on lipid-induced functional impairments in skeletal muscle and new perspectives on the pathophysiology that drives insulin resistance.

Key Words: Diabetes; fat oxidation; insulin action; lipids; metabolic profiling; mitochondria; skeletal muscle; exercise; peroxisome proliferator activated receptors.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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