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AMPD1: a novel therapeutic target for reversing insulin resistance.

Cheng J, Morisaki H, Toyama K, Sugimoto N, Shintani T, Tandelilin A, Hirase T, Holmes EW, Morisaki T - BMC Endocr Disord (2014)

Bottom Line: 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.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.Also, skeletal muscle metabolism and gene expression including nucleotide levels and activation of AMP activated protein kinase (AMP kinase) were evaluated in both conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. morisaki@ri.ncvc.go.jp.

ABSTRACT

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.

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Related in: MedlinePlus

Western blot study for phosphorylation of AMPK and ACC. Phosphorylation of AMPK and ACC in skeletal muscles. Antibody for phosphorylated AMPK, AMPK, ACC, or phosphorylated ACC was used. P-AMPKα (Thr172): phosphorylated AMPK at Thr172, AMPK: total AMPK. P-ACC (Ser79): phosphorylated ACC at Ser79. ACC: total ACC. Wt: wild type mice, A(−/−): AMPD1 deficient homozygote mice. CD: fed with normal chow diet, HFD: after high fat diet challenge.
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Fig5: Western blot study for phosphorylation of AMPK and ACC. Phosphorylation of AMPK and ACC in skeletal muscles. Antibody for phosphorylated AMPK, AMPK, ACC, or phosphorylated ACC was used. P-AMPKα (Thr172): phosphorylated AMPK at Thr172, AMPK: total AMPK. P-ACC (Ser79): phosphorylated ACC at Ser79. ACC: total ACC. Wt: wild type mice, A(−/−): AMPD1 deficient homozygote mice. CD: fed with normal chow diet, HFD: after high fat diet challenge.

Mentions: A potential consequence of loss of AMPD activity in skeletal muscle, and a potential explanation for the observed changes in insulin sensitivity, might be differential activation of AMP activated protein kinase (AMPK) in the A1(−/−) mice. As shown in Figure 5, phosphorylation of AMPK was greater in gastrocnemius muscle of A1(−/−) than in Wt animals fed the standard CD. Upon HFD challenge, we observed an even greater increase in phosphorylation of AMPK in gastrocnemius muscle of A1(−/−) compared with Wt animals. Also, acetyl-CoA carboxylase (ACC) was similarly phosphorylated in A1(−/−) mice and this change was prominent after HFD challenge.Table 2


AMPD1: a novel therapeutic target for reversing insulin resistance.

Cheng J, Morisaki H, Toyama K, Sugimoto N, Shintani T, Tandelilin A, Hirase T, Holmes EW, Morisaki T - BMC Endocr Disord (2014)

Western blot study for phosphorylation of AMPK and ACC. Phosphorylation of AMPK and ACC in skeletal muscles. Antibody for phosphorylated AMPK, AMPK, ACC, or phosphorylated ACC was used. P-AMPKα (Thr172): phosphorylated AMPK at Thr172, AMPK: total AMPK. P-ACC (Ser79): phosphorylated ACC at Ser79. ACC: total ACC. Wt: wild type mice, A(−/−): AMPD1 deficient homozygote mice. CD: fed with normal chow diet, HFD: after high fat diet challenge.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4274759&req=5

Fig5: Western blot study for phosphorylation of AMPK and ACC. Phosphorylation of AMPK and ACC in skeletal muscles. Antibody for phosphorylated AMPK, AMPK, ACC, or phosphorylated ACC was used. P-AMPKα (Thr172): phosphorylated AMPK at Thr172, AMPK: total AMPK. P-ACC (Ser79): phosphorylated ACC at Ser79. ACC: total ACC. Wt: wild type mice, A(−/−): AMPD1 deficient homozygote mice. CD: fed with normal chow diet, HFD: after high fat diet challenge.
Mentions: A potential consequence of loss of AMPD activity in skeletal muscle, and a potential explanation for the observed changes in insulin sensitivity, might be differential activation of AMP activated protein kinase (AMPK) in the A1(−/−) mice. As shown in Figure 5, phosphorylation of AMPK was greater in gastrocnemius muscle of A1(−/−) than in Wt animals fed the standard CD. Upon HFD challenge, we observed an even greater increase in phosphorylation of AMPK in gastrocnemius muscle of A1(−/−) compared with Wt animals. Also, acetyl-CoA carboxylase (ACC) was similarly phosphorylated in A1(−/−) mice and this change was prominent after HFD challenge.Table 2

Bottom Line: 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.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.Also, skeletal muscle metabolism and gene expression including nucleotide levels and activation of AMP activated protein kinase (AMP kinase) were evaluated in both conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. morisaki@ri.ncvc.go.jp.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus