AMPD1: a novel therapeutic target for reversing insulin resistance.

Takayuki Morisaki,Edward W Holmes,Tetsuaki Hirase,Hiroko Morisaki,Andreas Tandelilin,Takuya Shintani,Jidong Cheng,Keiko Toyama,Naomi Sugimoto

doi:10.1186/1472-6823-14-96

Abstract

BackgroundInsulin 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.MethodsRecognizing 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.ResultsDisruption 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.ConclusionsTaken 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.Electronic supplementary materialThe online version of this article (doi:10.1186/1472-6823-14-96) contains supplementary material, which is available to authorized users.

Highlights

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
The results described in this report demonstrate that mice rendered deficient in AMPD1 enzyme activity have a milder state of insulin resistance, improved glucose tolerance, and enhanced insulin clearance when fed a high fat diet when compared to controls with normal skeletal muscle AMP deaminase (AMPD) enzyme activity
Glucose and insulin dynamics To test the basic premise of this study, i.e. does a loss of AMPD activity alter insulin resistance, we examined blood glucose and insulin levels in wild-type and A1 (−/−) mice fed a standard chow diet (CD) and a high fat diet (HFD)

Summary

Introduction

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. Given that skeletal muscle is one of the major organs that contributes to insulin resistance it stands to reason that therapies directed to targets expressed in this tissue may offer novel approaches to treating these disorders. A recent report demonstrated that AMP deaminase (AMPD) isolated from skeletal muscle is inhibited by metformin, one of the best known drugs for reversing the pathologic state of insulin resistance [4]. While the results of this study are intriguing it is difficult to assess if inhibition of AMPD is the target responsible for the in vivo effects of this drug on insulin action since many studies have reported that metformin affects the activity of numerous enzymatic activities [5]

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Results

Discussion

Conclusion