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Frontiers of Medicine

Front Med    2013, Vol. 7 Issue (1) : 14-24     DOI: 10.1007/s11684-013-0262-6
REVIEW |
Mechanisms of insulin resistance in obesity
Jianping Ye()
Antioxidant and Gene Regulation Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA70808, USA
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Abstract

Obesity increases the risk for type 2 diabetes through induction of insulin resistance. Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been several well-documented hypotheses for insulin resistance. In those hypotheses, inflammation, mitochondrial dysfunction, hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention. Oxidative stress, endoplasmic reticulum (ER) stress, genetic background, aging, fatty liver, hypoxia and lipodystrophy are active subjects in the study of these concepts. However, none of those concepts or views has led to an effective therapy for type 2 diabetes. The reason is that, there has been no consensus for a unifying mechanism of insulin resistance. In this review article, literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance, in which insulin resistance is a result of energy surplus in cells. The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance. In support, many of existing insulin sensitizing medicines inhibit ATP production in mitochondria. The effective therapies such as weight loss, exercise, and caloric restriction all reduce ATP in insulin sensitive cells. This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity, which may apply to insulin resistance in aging and lipodystrophy.

Keywords type 2 diabetes      energy expenditure      inflammation      lipotoxicity      mitochondria      hyperinsulinemia      adenosine monophosphate-activated protein kinase (AMPK)     
Corresponding Authors: Ye Jianping,Email:yej@pbrc.edu   
Issue Date: 05 March 2013
 Cite this article:   
Jianping Ye. Mechanisms of insulin resistance in obesity[J]. Front Med, 2013, 7(1): 14-24.
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http://journal.hep.com.cn/fmd/EN/10.1007/s11684-013-0262-6
http://journal.hep.com.cn/fmd/EN/Y2013/V7/I1/14
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Fig.1  Mitochondria over activation in the pathogenesis of insulin resistance. In obesity, lipids induce mitochondrial over activation by boosting fatty acid β-oxidation to enhance energy disposal especially in muscle, liver and brown fat. As a result, a large amount of ATP is generated from the fatty acid catabolism if the extra energy cannot be released in heat. When ATP level exceeds the threshold, the energy surplus will trigger a negative feedback reaction to attenuate the substrate-induced mitochondrial function. In the mechanism, ATP inactivates AMPK to reduce insulin-induced glucose uptake in order to decrease ATP production. In this model, insulin resistance represents a cellular protective mechanism that is aimed to control the ATP stress response in the muscle and liver. Insulin-sensitizing agents rescue the tissue from insulin resistance by inhibiting mitochondrial β-oxidation.
Fig.1  Mitochondria over activation in the pathogenesis of insulin resistance. In obesity, lipids induce mitochondrial over activation by boosting fatty acid β-oxidation to enhance energy disposal especially in muscle, liver and brown fat. As a result, a large amount of ATP is generated from the fatty acid catabolism if the extra energy cannot be released in heat. When ATP level exceeds the threshold, the energy surplus will trigger a negative feedback reaction to attenuate the substrate-induced mitochondrial function. In the mechanism, ATP inactivates AMPK to reduce insulin-induced glucose uptake in order to decrease ATP production. In this model, insulin resistance represents a cellular protective mechanism that is aimed to control the ATP stress response in the muscle and liver. Insulin-sensitizing agents rescue the tissue from insulin resistance by inhibiting mitochondrial β-oxidation.
Fig.2  Hyperinsulinemia in obesity.
Fig.2  Hyperinsulinemia in obesity.
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