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      Mitochondrial metabolism and diabetes

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          Abstract

          The oversupply of calories and sedentary lifestyle has resulted in a rapid increase of diabetes prevalence worldwide. During the past two decades, lines of evidence suggest that mitochondrial dysfunction plays a key role in the pathophysiology of diabetes. Mitochondria are vital to most of the eukaryotic cells as they provide energy in the form of adenosine triphosphate by oxidative phosphorylation. In addition, mitochondrial function is an integral part of glucose‐stimulated insulin secretion in pancreatic β‐cells. In the present article, we will briefly review the major functions of mitochondria in regard to energy metabolism, and discuss the genetic and environmental factors causing mitochondrial dysfunction in diabetes. In addition, the pathophysiological role of mitochondrial dysfunction in insulin resistance and β‐cell dysfunction are discussed. We argue that mitochondrial dysfunction could be the central defect causing the abnormal glucose metabolism in the diabetic state. A deeper understanding of the role of mitochondria in diabetes will provide us with novel insights in the pathophysiology of diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00047.x, 2010)

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          Most cited references73

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          Epidemic obesity and type 2 diabetes in Asia.

          The proportions of people with type 2 diabetes and obesity have increased throughout Asia, and the rate of increase shows no sign of slowing. People in Asia tend to develop diabetes with a lesser degree of obesity at younger ages, suffer longer with complications of diabetes, and die sooner than people in other regions. Childhood obesity has increased substantially and the prevalence of type 2 diabetes has now reached epidemic levels in Asia. The health consequences of this epidemic threaten to overwhelm health-care systems in the region. Urgent action is needed, and advocacy for lifestyle changes is the first step. Countries should review and implement interventions, and take a comprehensive and integrated public-health approach. At the level of primary prevention, such programmes can be linked to other non-communicable disease prevention programmes that target lifestyle-related issues. The cost of inaction is clear and unacceptable.
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            Mitochondrial diseases in man and mouse.

            Over the past 10 years, mitochondrial defects have been implicated in a wide variety of degenerative diseases, aging, and cancer. Studies on patients with these diseases have revealed much about the complexities of mitochondrial genetics, which involves an interplay between mutations in the mitochondrial and nuclear genomes. However, the pathophysiology of mitochondrial diseases has remained perplexing. The essential role of mitochondrial oxidative phosphorylation in cellular energy production, the generation of reactive oxygen species, and the initiation of apoptosis has suggested a number of novel mechanisms for mitochondrial pathology. The importance and interrelationship of these functions are now being studied in mouse models of mitochondrial disease.
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              Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.

              Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.
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                Author and article information

                Journal
                J Diabetes Investig
                J Diabetes Investig
                10.1111/(ISSN)2040-1124
                JDI
                ST
                Journal of Diabetes Investigation
                Blackwell Publishing Ltd (Oxford, UK )
                2040-1116
                2040-1124
                06 July 2010
                19 October 2010
                : 1
                : 5 ( doiID: 10.1111/jdi.2010.1.issue-5 )
                : 161-169
                Affiliations
                [ 1 ]Departments of Internal Medicine
                [ 2 ]Molecular Medicine and Biopharmaceutical Sciences, Seoul National University College of Medicine
                [ 3 ]Department of Internal Medicine, University of Ulsan College of Medicine
                [ 4 ]Department of Internal Medicine, Eulji University College of Medicine, Seoul, Korea
                Author notes
                [*] [* ] Corresponding author. Hong Kyu Lee Tel.: +82‐2‐970‐8458 Fax: +82‐2‐970‐4630
E‐mail address: hkleemd@ 123456eulji.ac.kr
                Article
                JDI47
                10.1111/j.2040-1124.2010.00047.x
                4020716
                24843427
                d944a85b-b0e6-473c-a36e-31ff2e77af89
                © 2010 Asian Association for the Study of Diabetes and Blackwell Publishing Asia Pty Ltd
                History
                Page count
                Figures: 2, Tables: 0, Pages: 9
                Categories
                Review Article
                Custom metadata
                2.0
                October 2010
                Converter:WILEY_ML3GV2_TO_NLM version:3.9.3 mode:remove_FC converted:04.02.2014

                insulin resistance,mitochondrial dysfunction,type 2 diabetes mellitus

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