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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

Insulin production. A. C-peptide levels in mice fed with normal chow diet (CD) and after high fat diet (HFD) challenge. B. C-peptide/Insulin ratios in mice fed with normal chow diet (CD) and after high fat diet (HFD) challenge. Wt: wild type mice, A1(−/−): AMPD1 deficient homozygote mice. *: significant difference between Wt and A1(−/−) mice.
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Fig3: Insulin production. A. C-peptide levels in mice fed with normal chow diet (CD) and after high fat diet (HFD) challenge. B. C-peptide/Insulin ratios in mice fed with normal chow diet (CD) and after high fat diet (HFD) challenge. Wt: wild type mice, A1(−/−): AMPD1 deficient homozygote mice. *: significant difference between Wt and A1(−/−) mice.

Mentions: Prior studies have demonstrated insulin clearance is reduced in obese, hyperinsulinemic human subjects [8], and a recent study has indicated insulin clearance is associated with AMPD1 haplotype in man [9]. To assess insulin clearance in the A1(−/−) animals we determined insulin levels relative to insulin production as measured by C-peptide levels. As shown in Figure 3, the ratio of C-peptide/insulin was significantly reduced in both groups of animals on a HFD, though the reduction in the ratio was significantly lower in the A1(−/−) mice than in Wt mice.Figure 3


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)

Insulin production. A. C-peptide levels in mice fed with normal chow diet (CD) and after high fat diet (HFD) challenge. B. C-peptide/Insulin ratios in mice fed with normal chow diet (CD) and after high fat diet (HFD) challenge. 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

Fig3: Insulin production. A. C-peptide levels in mice fed with normal chow diet (CD) and after high fat diet (HFD) challenge. B. C-peptide/Insulin ratios in mice fed with normal chow diet (CD) and after high fat diet (HFD) challenge. Wt: wild type mice, A1(−/−): AMPD1 deficient homozygote mice. *: significant difference between Wt and A1(−/−) mice.
Mentions: Prior studies have demonstrated insulin clearance is reduced in obese, hyperinsulinemic human subjects [8], and a recent study has indicated insulin clearance is associated with AMPD1 haplotype in man [9]. To assess insulin clearance in the A1(−/−) animals we determined insulin levels relative to insulin production as measured by C-peptide levels. As shown in Figure 3, the ratio of C-peptide/insulin was significantly reduced in both groups of animals on a HFD, though the reduction in the ratio was significantly lower in the A1(−/−) mice than in Wt mice.Figure 3

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