Enhanced autophagy plays a cardinal role in mitochondrial dysfunction in type 2 diabetic Goto-Kakizaki (GK) rats: ameliorating effects of (-)-epigallocatechin-3-gallate.

Abstract

Oxidative stress and mitochondrial dysfunction are known to play important roles in type 2 diabetes mellitus (T2DM) and insulin resistance. However, the pathology of T2DM remains complicated; in particular, the mechanisms of mitochondrial dysfunction in skeletal muscle and other insulin-sensitive tissues are as yet unclear. In the present study, we investigated the underlying mechanisms of oxidative stress and mitochondrial dysfunction by focusing on mitochondrial dynamics, including mitochondrial biogenesis and autophagy, in skeletal muscle of a nonobese diabetic animal model--the Goto-Kakizaki (GK) rat. The results showed that GK rats exhibited impaired glucose metabolism, increased oxidative stress and decreased mitochondrial function. These dysfunctions were found to be associated with induction of LC3B, Beclin1 and DRP1 (key molecules mediating the autophagy pathway), while they appeared not to affect the mitochondrial biogenesis pathway. In addition, (-)-epigallocatechin-3-gallate (EGCG) was tested as a potential autophagy-targeting nutrient, and we found that EGCG treatment improved glucose tolerance and glucose homeostasis in GK rats, and reduced oxidative stress and mitochondrial dysfunction in skeletal muscle. Amelioration of excessive muscle autophagy in GK rats through the down-regulation of the ROS-ERK/JNK-p53 pathway leads to improvement of glucose metabolism, reduction of oxidative stress and inhibition of mitochondrial loss and dysfunction. These results suggest (a) that hyperglycemia-associated oxidative stress may induce autophagy through up-regulation of the ROS-ERK/JNK-p53 pathway, which may contribute to mitochondrial loss in soleus muscle of diabetic GK rats, and (b) that EGCG may be a potential autophagy regulator useful in treatment of insulin resistance.

• Authors: Jiong Yan, Zhihui Feng, Jia Liu, Weili Shen, Ying Wang, Karin Wertz, Peter Weber, Jiangang Long, Jiankang Liu
• Journal: The Journal of nutritional biochemistry (J Nutr Biochem) Vol. 23 Issue 7 Pg. 716-24 (Jul 2012) ISSN: 1873-4847 [Electronic] United States
• PMID: 21820301 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Blood Glucose
• Hypoglycemic Agents
• Tumor Suppressor Protein p53
• Catechin
• epigallocatechin gallate
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Autophagy (drug effects)
• Blood Glucose
• Catechin (analogs & derivatives, pharmacology)
• Diabetes Mellitus, Type 2 (drug therapy, metabolism, physiopathology)
• Down-Regulation
• Fasting
• Hypoglycemic Agents (pharmacology)
• Insulin Resistance
• Male
• Mitochondria (drug effects, metabolism)
• Mitogen-Activated Protein Kinases (genetics, metabolism)
• Muscle, Skeletal (drug effects, metabolism, physiopathology)
• Oxidative Stress (drug effects)
• Rats
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Up-Regulation