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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

Body weight and fat accumulation change after high fat diet (HFD) challenge. A. Body weight change. Wt-CD: wild type mice fed with normal chow diet, A1(−/−)-CD: AMPD1 deficient homozygote mice fed with normal chow diet, Wt-HFD: wild type mice after HFD challenge, A(−/−)-HFD: AMPD1 deficient homozygote mice after HFD challenge. B. Food intake during HFD challenge. C. CT scan. D. Fat ratio calculated by the CT scan exam. Wt: wild type mice, A(−/−): AMPD1 deficient homozygote mice.
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Fig4: Body weight and fat accumulation change after high fat diet (HFD) challenge. A. Body weight change. Wt-CD: wild type mice fed with normal chow diet, A1(−/−)-CD: AMPD1 deficient homozygote mice fed with normal chow diet, Wt-HFD: wild type mice after HFD challenge, A(−/−)-HFD: AMPD1 deficient homozygote mice after HFD challenge. B. Food intake during HFD challenge. C. CT scan. D. Fat ratio calculated by the CT scan exam. Wt: wild type mice, A(−/−): AMPD1 deficient homozygote mice.

Mentions: Both wild-type and A1(−/−) mice gained weight on the HFD relative to the cohorts fed CD but there was no difference in the incremental weight gain between the Wt and A1(−/−) mice on a HFD (Figure 4A). Food consumption was comparable in the two groups of mice on a HFD (Figure 4B). Total body fat was assessed by CT scans, and while both groups of mice accumulated more fat on the HFD relative to those on the standard CD, consistent with the greater rate of weight gain on the HFD, there was no detectable difference in total body fat relative to total body weight in the A1(−/−) mice compared to Wt mice (Figure 4C and D). Because of the central role skeletal muscle plays in insulin resistance [3] and because AMPD1 is predominately expressed in this tissue, fat content of the skeletal muscle was assessed. As with total body fat, skeletal muscle fat increased in both groups of mice while on the HFD (data not shown) but there was no obvious difference between the A1(−/−) and wild-type mice on HFD (Additional file 1: Figure S1).Figure 4


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)

Body weight and fat accumulation change after high fat diet (HFD) challenge. A. Body weight change. Wt-CD: wild type mice fed with normal chow diet, A1(−/−)-CD: AMPD1 deficient homozygote mice fed with normal chow diet, Wt-HFD: wild type mice after HFD challenge, A(−/−)-HFD: AMPD1 deficient homozygote mice after HFD challenge. B. Food intake during HFD challenge. C. CT scan. D. Fat ratio calculated by the CT scan exam. Wt: wild type mice, A(−/−): AMPD1 deficient homozygote mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig4: Body weight and fat accumulation change after high fat diet (HFD) challenge. A. Body weight change. Wt-CD: wild type mice fed with normal chow diet, A1(−/−)-CD: AMPD1 deficient homozygote mice fed with normal chow diet, Wt-HFD: wild type mice after HFD challenge, A(−/−)-HFD: AMPD1 deficient homozygote mice after HFD challenge. B. Food intake during HFD challenge. C. CT scan. D. Fat ratio calculated by the CT scan exam. Wt: wild type mice, A(−/−): AMPD1 deficient homozygote mice.
Mentions: Both wild-type and A1(−/−) mice gained weight on the HFD relative to the cohorts fed CD but there was no difference in the incremental weight gain between the Wt and A1(−/−) mice on a HFD (Figure 4A). Food consumption was comparable in the two groups of mice on a HFD (Figure 4B). Total body fat was assessed by CT scans, and while both groups of mice accumulated more fat on the HFD relative to those on the standard CD, consistent with the greater rate of weight gain on the HFD, there was no detectable difference in total body fat relative to total body weight in the A1(−/−) mice compared to Wt mice (Figure 4C and D). Because of the central role skeletal muscle plays in insulin resistance [3] and because AMPD1 is predominately expressed in this tissue, fat content of the skeletal muscle was assessed. As with total body fat, skeletal muscle fat increased in both groups of mice while on the HFD (data not shown) but there was no obvious difference between the A1(−/−) and wild-type mice on HFD (Additional file 1: Figure S1).Figure 4

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