AMPD1: a novel therapeutic target for reversing insulin resistance

BMC Endocrine Disorders

Takayuki Morisaki²  Edward W Holmes⁴  Tetsuaki Hirase¹  Andreas Tandelilin¹  Takuya Shintani²  Naomi Sugimoto²  Keiko Toyama²  Hiroko Morisaki¹  Jidong Cheng³ 

[1] Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan;Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan;Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515031, P. R. China;Sanford Consortium for Regenerative Medicine, San Diego, CA, USA

关键词: Glucose metabolism;    AMP kinase;    Insulin resistance;    Diabetes;    Adenine nucleotide;    AMP deaminase;   

Others  :  1084690
DOI  :  10.1186/1472-6823-14-96

 received in 2014-10-07, accepted in 2014-12-09,  发布年份 2014

【 摘 要 】

Background

Insulin resistance is one of the hallmark manifestations of obesity and Type II diabetes and reversal of this pathogenic abnormality is an attractive target for new therapies for Type II diabetes. A recent report that metformin, a drug known to reverse insulin resistance, demonstrated in vitro the metformin can inhibit AMP deaminase (AMPD) activity. Skeletal muscle is one of the primary organs contributing to insulin resistance and that the AMPD1 gene is selectively expressed at high levels in skeletal muscle.

Methods

Recognizing the background above, we asked if genetic disruption of the AMPD1 gene might ameliorate the manifestations of insulin resistance. AMPD1 deficient homozygous mice and control mice fed normal chow diet or a high-fat diet, and blood analysis, glucose tolerance test and insulin tolerance test were performed. Also, skeletal muscle metabolism and gene expression including nucleotide levels and activation of AMP activated protein kinase (AMP kinase) were evaluated in both conditions.

Results

Disruption of the AMPD1 gene leads to a less severe state of insulin resistance, improved glucose tolerance and enhanced insulin clearance in mice fed a high fat diet. Given the central role of AMP kinase in insulin action, and its response to changes in AMP concentrations in the cell, we examined the skeletal muscle of the AMPD1 deficient mice and found that they have greater AMP kinase activity as evidenced by higher levels of phosphorylated AMP kinase.

Conclusions

Taken together these data suggest that AMPD may be a new drug target for the reversal of insulin resistance and the treatment of Type II diabetes.

【 授权许可】

   
2014 Cheng et al.; licensee BioMed Central Ltd.

【 图 表 】

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