Elsevier

Advanced Drug Delivery Reviews

Volume 61, Issue 14, 30 November 2009, Pages 1343-1352
Advanced Drug Delivery Reviews

Targeting mitochondrial biogenesis for preventing and treating insulin resistance in diabetes and obesity: Hope from natural mitochondrial nutrients

https://doi.org/10.1016/j.addr.2009.06.007Get rights and content

Abstract

Insulin resistance is an important feature of type 2 diabetes and obesity. The underlying mechanisms of insulin resistance are still unclear and may involve pathological changes in multiple tissues. Mitochondrial dysfunction, including mitochondrial loss and over-production of oxidants, has been suggested to be involved in the development of insulin resistance. Increasing evidence suggests that targeting mitochondria to protect mitochondrial function as a unique measure, i.e. mitochondrial medicine, could prevent and ameliorate various diseases associated with mitochondrial dysfunction. In this review, we have summarized recent progress in pharmaceutical and nutritional studies of drugs and nutrients to targeting mitochondria by stimulating mitochondrial metabolism (biogenesis and degradation) to improve mitochondrial function and decrease oxidative stress for preventing and ameliorating insulin resistance. We have focused on nutrients from natural sources to stimulating mitochondrial biogenesis in cellular systems and in animal models. The in vitro and in vivo studies, especially our own work on the effects and mechanisms of mitochondrial targeting nutrients or their combinations, may help us to understand the importance and mechanisms of mitochondrial biogenesis in insulin resistance, and provide hope for developing mitochondria-targeting agents for preventing and treating insulin resistance in type 2 diabetes and obesity.

Introduction

Insulin resistance is an important feature of type 2 diabetes and obesity. The underlying mechanisms of insulin resistance are still unclear. Adipose, skeletal muscle and liver are major organs involved in the glucose metabolism and therefore, play important roles in insulin resistance. Oxidative stress has been suggested to be involved in the pathology of insulin resistance. Studies have shown that insulin resistance is associated with mitochondrial (mt) dysfunction, such as reduced mitochondrial number and ATP production [1], [2]. In prediabetic and diabetic humans, the expression of genes involved in oxidative phosphorylation (OXPHOS) is significantly reduced in the skeletal muscle [3]. Mitochondria are the major sites of reactive oxygen species (ROS) production in the body. If the efficiency of OXPHOS is reduced (e.g. by deletions of energy metabolism genes from the mt genome), more O2. is generated at the expense of ATP. Therefore, reducing oxidative damage by improving mitochondrial function seems a rational way to prevent and treat insulin resistance. In this review, we summarized the available evidence with a focus on our recent studies of natural nutritional products on stimulating mitochondrial biogenesis as a strategy to improve mitochondrial function and reducing oxidative stress, leading to prevention and amelioration of insulin resistance.

Section snippets

Reactive oxygen species, oxidative damage and insulin resistance

Normal metabolism uses oxygen; however, excess oxygen is also toxic to all life forms. The theoretical reduction of oxygen to water by the electron transport chain involves a coordinated four-electron transfer. During this process, reactive oxygen species (ROS), such as superoxide, hydrogen peroxide, hydroxyl radical, and nitric oxide, are generated and may cause oxidative damage to biomolecules, such as lipids, proteins, and nucleic acids [4]. This dark side of oxygen has been extensively

Mitochondrial metabolism: biogenesis, degradation, and dynamics

Mitochondrial biogenesis in mammalian tissues is modulated through control of peroxisome proliferator-activated receptor- (PPAR)-γ coactivator-1α (PGC-1α) expression. Though many pathways are not well understood, it is known that the critical factors involved in mitochondrial biogenesis include: 1) those that stimulate PGC-1α gene transcription, such as calcium/calmodulin-dependent protein kinase IV (CaMKIV), AMP-activated protein kinase (AMPK), and nitric oxide; 2) those that are stimulated by

Agents for preventing/treating insulin resistance stimulate mitochondrial metabolism

Because mitochondria are the main site of ROS generation and calcium overload, which consequently lead to mitochondrial dysfunction, DNA damage, cell death, mitochondrial disease and resulting in mitochondria-related diseases, including diabetes and obesity, the main aims of mitochondrial medicine are to develop agents and drugs that target mitochondria to protect mitochondrial function and inhibit mitochondrial damage and cell death associated with various diseases [45], [46], [47], [48]. The

Perspectives and future directions

Mitochondrial dysfunction appears to be a key contributor to insulin resistance. Preventing mitochondrial dysfunction by enhancing mitochondrial biogenesis seems a plausible strategy for preventing or treating insulin resistance. We have identified natural compounds and nutrients which can target mitochondrial biogenesis and function. We hypothesized that these mitochondrial nutrients or their combinations may be effective in regulating PGC-1α activity so as to enhance mitochondrial biogenesis,

Acknowledgements

The authors thank Dr. Edward Sharman at University of California, Irvine for critical reading of this manuscript. This study was supported by Pujiang Talent Award (05PG14104) and a grant (074319105) from the Shanghai Science and Technology Committee, Shanghai, China, National Natural Science Foundation of China Grants (30871002), a support of DSM Nutritional Product, Switzerland, and a UC Davis Center for Human and Nutrition Pilot Award (CHNR08-318).

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