Limits...
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.

Show MeSH

Related in: MedlinePlus

Glucose tolerance test and insulin tolerance test. A. Glucose tolerance test in mice fed with normal chow diet (CD). B. Glucose tolerance test in mice after high fat diet (HFD) challenge. C. Insulin tolerance test in mice fed with normal chow diet (CD). D. Insulin tolerance test in mice fed with normal chow diet (CD). Wt: wild type mice, A1(−/−): AMPD1 deficient homozygote mice. *: significant difference between Wt and A1(−/−) mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Glucose tolerance test and insulin tolerance test. A. Glucose tolerance test in mice fed with normal chow diet (CD). B. Glucose tolerance test in mice after high fat diet (HFD) challenge. C. Insulin tolerance test in mice fed with normal chow diet (CD). D. Insulin tolerance test in mice fed with normal chow diet (CD). Wt: wild type mice, A1(−/−): AMPD1 deficient homozygote mice. *: significant difference between Wt and A1(−/−) mice.

Mentions: Glucose and insulin dynamics were further assessed with glucose and insulin tolerance tests in these mice (Figure 2). Figure 2A demonstrates that blood glucose levels were not appreciably different in the wild-type and A1(−/−) mice on a standard chow diet after a glucose challenge. In contrast, Figure 2B shows the A1(−/−) mice maintained on a HFD had a more rapid return of blood glucose levels to normal levels than did the wild type animals following a glucose challenge. Figure 2C and D illustrate the results of the insulin tolerance test in these two groups of mice. The A1(−/−) mice maintained on a HFD had significantly lower blood glucose levels 30 and 60 min after insulin administration.Figure 1


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)

Glucose tolerance test and insulin tolerance test. A. Glucose tolerance test in mice fed with normal chow diet (CD). B. Glucose tolerance test in mice after high fat diet (HFD) challenge. C. Insulin tolerance test in mice fed with normal chow diet (CD). D. Insulin tolerance test in mice fed with normal chow diet (CD). Wt: wild type mice, A1(−/−): AMPD1 deficient homozygote mice. *: significant difference between Wt and A1(−/−) mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Glucose tolerance test and insulin tolerance test. A. Glucose tolerance test in mice fed with normal chow diet (CD). B. Glucose tolerance test in mice after high fat diet (HFD) challenge. C. Insulin tolerance test in mice fed with normal chow diet (CD). D. Insulin tolerance test in mice fed with normal chow diet (CD). Wt: wild type mice, A1(−/−): AMPD1 deficient homozygote mice. *: significant difference between Wt and A1(−/−) mice.
Mentions: Glucose and insulin dynamics were further assessed with glucose and insulin tolerance tests in these mice (Figure 2). Figure 2A demonstrates that blood glucose levels were not appreciably different in the wild-type and A1(−/−) mice on a standard chow diet after a glucose challenge. In contrast, Figure 2B shows the A1(−/−) mice maintained on a HFD had a more rapid return of blood glucose levels to normal levels than did the wild type animals following a glucose challenge. Figure 2C and D illustrate the results of the insulin tolerance test in these two groups of mice. The A1(−/−) mice maintained on a HFD had significantly lower blood glucose levels 30 and 60 min after insulin administration.Figure 1

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