Wei Yu, Wenliang Zha, Hu Peng, Qiurong Wang, Shuning Zhang and Jun Ren* Pages 2077 - 2085 ( 9 )
Background: Insulin resistance refers to a pathological state of compromised sensitivity of insulin to promote glucose uptake and utilization, resulting in compensatory excessive insulin secretion and hyperinsulinemia in an effort to maintain glucose homeostasis. Akt2 represents an important member of the Akt family and plays an essential role in the maintenance of insulin signaling.
Methods: This study was designed to examine the effects of trehalose on kidney and skeletal muscle (rectus femoris muscle) injury in an Akt2 knockout-induced model of insulin resistance. Akt2 knockout (Akt2-/-) and adult WT mice were treated with trehalose (1 mg/g/d) intraperitoneally for 2 days, followed by providing 2% trehalose in drinking water for 2 months. Intraperitoneal glucose tolerance test (IPGTT), protein carbonyl content and mitochondrial function (aconitase activity) were examined. Apoptosis and autophagy protein markers were monitored using western blot analysis.
Results: Akt2 ablation impaired glucose tolerance, promoted protein carbonyl formation and decreased aconitase activity in kidney and skeletal muscles, associated with pronounced apoptosis and overt autophagy, the effects of which, with the exception of IPGTT, were greatly ameliorated or negated by trehalose treatment. Moreover, phosphorylation of mTOR was downregulated in both kidney and skeletal muscles from Akt2-/- mice, the effect of which was attenuated by trehalose. Levels of Akt (pan and Akt2) were much lower in Akt2-/- mice, the effect of which was unaffected by trehalose treatment although trehalose itself upregulated Akt levels.
Conclusion: These data suggest that the autophagy inducer trehalose rescued against insulin resistance-induced kidney and skeletal muscle injury, apoptosis and excessive autophagy, possibly in association with restored mTOR phosphorylation without affecting Akt.
Akt2, trehalose, kidney, skeletal muscle, autophagy, apoptosis.
Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, Department of Emergency, Shanghai Tenth People's Hospital, School of Medicine Tongji University, Shanghai, 200072, Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071