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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

mRNA expression of various molecules after high fat diet challenge. Insulin-R: insulin receptor, Lept-R : reptin receptor, Pgk1:phosphoglyceratekinase 1, Gck: glucokinase, Ascl: acyl-CoA synthetase, A1R: adenosine type 1 receptor. Wt: wild type mice, A(−/−): AMPD1 deficient homozygote mice. CD: fed with normal chow diet, HFD: after high fat diet challenge. *: significant difference between Wt and A1(−/−) mice.
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Fig6: mRNA expression of various molecules after high fat diet challenge. Insulin-R: insulin receptor, Lept-R : reptin receptor, Pgk1:phosphoglyceratekinase 1, Gck: glucokinase, Ascl: acyl-CoA synthetase, A1R: adenosine type 1 receptor. Wt: wild type mice, A(−/−): AMPD1 deficient homozygote mice. CD: fed with normal chow diet, HFD: after high fat diet challenge. *: significant difference between Wt and A1(−/−) mice.

Mentions: Expression of a number of genes has been associated with changes in insulin sensitivity [10]. A limited survey of these genes, as judged by mRNA levels, revealed no significant differences in expression of any of these genes with one exception (Figure 6). Leptin receptor mRNA was about 50% more abundant in skeletal muscle of the A1(−/−) mice.Figure 6


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)

mRNA expression of various molecules after high fat diet challenge. Insulin-R: insulin receptor, Lept-R : reptin receptor, Pgk1:phosphoglyceratekinase 1, Gck: glucokinase, Ascl: acyl-CoA synthetase, A1R: adenosine type 1 receptor. Wt: wild type mice, A(−/−): AMPD1 deficient homozygote mice. CD: fed with normal chow diet, HFD: after high fat diet challenge. *: 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

Fig6: mRNA expression of various molecules after high fat diet challenge. Insulin-R: insulin receptor, Lept-R : reptin receptor, Pgk1:phosphoglyceratekinase 1, Gck: glucokinase, Ascl: acyl-CoA synthetase, A1R: adenosine type 1 receptor. Wt: wild type mice, A(−/−): AMPD1 deficient homozygote mice. CD: fed with normal chow diet, HFD: after high fat diet challenge. *: significant difference between Wt and A1(−/−) mice.
Mentions: Expression of a number of genes has been associated with changes in insulin sensitivity [10]. A limited survey of these genes, as judged by mRNA levels, revealed no significant differences in expression of any of these genes with one exception (Figure 6). Leptin receptor mRNA was about 50% more abundant in skeletal muscle of the A1(−/−) mice.Figure 6

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