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Transcriptome alteration in the diabetic heart by rosiglitazone: implications for cardiovascular mortality.

Wilson KD, Li Z, Wagner R, Yue P, Tsao P, Nestorova G, Huang M, Hirschberg DL, Yock PG, Quertermous T, Wu JC - PLoS ONE (2008)

Bottom Line: Specifically, the cumulative upregulation of (1) a matrix metalloproteinase gene that has previously been implicated in plaque rupture, (2) potassium channel genes involved in membrane potential maintenance and action potential generation, and (3) sphingolipid and ceramide metabolism-related genes, together give cause for concern over rosiglitazone's safety.Lastly, in vivo imaging studies revealed minimal differences between rosiglitazone-treated and untreated db/db mouse hearts, indicating that rosiglitazone's effects on gene expression in the heart do not immediately turn into detectable gross functional changes.A smaller number of unique and interesting changes in gene expression were noted with rosiglitazone treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Stanford University School of Medicine, Stanford, California, United States of America.

ABSTRACT

Background: Recently, the type 2 diabetes medication, rosiglitazone, has come under scrutiny for possibly increasing the risk of cardiac disease and death. To investigate the effects of rosiglitazone on the diabetic heart, we performed cardiac transcriptional profiling and imaging studies of a murine model of type 2 diabetes, the C57BL/KLS-lepr(db)/lepr(db) (db/db) mouse.

Methods and findings: We compared cardiac gene expression profiles from three groups: untreated db/db mice, db/db mice after rosiglitazone treatment, and non-diabetic db/+ mice. Prior to sacrifice, we also performed cardiac magnetic resonance (CMR) and echocardiography. As expected, overall the db/db gene expression signature was markedly different from control, but to our surprise was not significantly reversed with rosiglitazone. In particular, we have uncovered a number of rosiglitazone modulated genes and pathways that may play a role in the pathophysiology of the increase in cardiac mortality as seen in several recent meta-analyses. Specifically, the cumulative upregulation of (1) a matrix metalloproteinase gene that has previously been implicated in plaque rupture, (2) potassium channel genes involved in membrane potential maintenance and action potential generation, and (3) sphingolipid and ceramide metabolism-related genes, together give cause for concern over rosiglitazone's safety. Lastly, in vivo imaging studies revealed minimal differences between rosiglitazone-treated and untreated db/db mouse hearts, indicating that rosiglitazone's effects on gene expression in the heart do not immediately turn into detectable gross functional changes.

Conclusions: This study maps the genomic expression patterns in the hearts of the db/db murine model of diabetes and illustrates the impact of rosiglitazone on these patterns. The db/db gene expression signature was markedly different from control, and was not reversed with rosiglitazone. A smaller number of unique and interesting changes in gene expression were noted with rosiglitazone treatment. Further study of these genes and molecular pathways will provide important insights into the cardiac decompensation associated with both diabetes and rosiglitazone treatment.

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Related in: MedlinePlus

Insulin resistance and mean body/heart weights of rosiglitazone-treated, untreated, and control mice.(A) Plasma NEFA levels at 0, 1, and 3 months in untreated db/db mice (n = 10), rosiglitazone-treated db/db mice (n = 10), and db/+ mice (n = 10). NEFA levels were higher in both the treated and untreated db/db groups at baseline when compared to db/+ control mice. Compared to untreated db/db mice, NEFA levels in the rosiglitazone-treated db/db group decreased significantly during the first month (960.9 vs. 1501.0 mmol/L, P<0.05), and decreased further by the third month to near db/+ control levels. (B) Fasting insulin levels in the three groups at 0, 1, and 3 months. At baseline, both treated and untreated db/db groups had increased levels of insulin compared to db/+ control. Insulin levels dramatically increased in untreated db/db mice at 1 month, but progressively decreased in rosiglitazone-treated mice. (C) Insulin tolerance testing at 3 months. Serum glucose levels after insulin injection were significantly higher in untreated db/db mice when compared to db/+ mice; the rosiglitazone-treated db/db group had moderately elevated glucose levels after insulin administration. These results corroborate the NEFA and insulin studies that demonstrate improved insulin sensitivity with rosiglitazone treatment. (D) Mean body weights of the three groups of mice at 0, 1, and 3 months. Weights of both treated and untreated db/db mice were markedly higher than db/+ controls at baseline. Furthermore, rosiglitazone-treated mice had generally higher mean body weights when compared to untreated mice. (E) Mean heart/body weight ratios at sacrifice (4 months after treatment initiation). No significant difference between treated and untreated groups (3.27 vs. 2.58, P = 0.13), though there does appear to be a downward trend in the data. Heart/body weight ratio was significantly higher in the db/+ group compared to both db/db groups. Values are mean±SEM. *P<0.05 vs. age-matched db/+; #P<0.05 vs. age-matched untreated db/db.
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pone-0002609-g001: Insulin resistance and mean body/heart weights of rosiglitazone-treated, untreated, and control mice.(A) Plasma NEFA levels at 0, 1, and 3 months in untreated db/db mice (n = 10), rosiglitazone-treated db/db mice (n = 10), and db/+ mice (n = 10). NEFA levels were higher in both the treated and untreated db/db groups at baseline when compared to db/+ control mice. Compared to untreated db/db mice, NEFA levels in the rosiglitazone-treated db/db group decreased significantly during the first month (960.9 vs. 1501.0 mmol/L, P<0.05), and decreased further by the third month to near db/+ control levels. (B) Fasting insulin levels in the three groups at 0, 1, and 3 months. At baseline, both treated and untreated db/db groups had increased levels of insulin compared to db/+ control. Insulin levels dramatically increased in untreated db/db mice at 1 month, but progressively decreased in rosiglitazone-treated mice. (C) Insulin tolerance testing at 3 months. Serum glucose levels after insulin injection were significantly higher in untreated db/db mice when compared to db/+ mice; the rosiglitazone-treated db/db group had moderately elevated glucose levels after insulin administration. These results corroborate the NEFA and insulin studies that demonstrate improved insulin sensitivity with rosiglitazone treatment. (D) Mean body weights of the three groups of mice at 0, 1, and 3 months. Weights of both treated and untreated db/db mice were markedly higher than db/+ controls at baseline. Furthermore, rosiglitazone-treated mice had generally higher mean body weights when compared to untreated mice. (E) Mean heart/body weight ratios at sacrifice (4 months after treatment initiation). No significant difference between treated and untreated groups (3.27 vs. 2.58, P = 0.13), though there does appear to be a downward trend in the data. Heart/body weight ratio was significantly higher in the db/+ group compared to both db/db groups. Values are mean±SEM. *P<0.05 vs. age-matched db/+; #P<0.05 vs. age-matched untreated db/db.

Mentions: We analyzed a number of metabolic parameters to confirm insulin resistance in our db/db murine model of diabetes before proceeding with microarrays. Insulin resistance is strongly associated with obesity, and one mechanism may be the generation of metabolic messengers such as free fatty acids by adipose tissue that inhibit insulin action on muscle [18], [19]. We measured plasma non-esterified fatty acid (NEFA) and insulin levels to follow insulin resistance in our three groups of mice. Figure 1a shows plasma NEFA levels in the three groups of mice. Compared to untreated db/db mice, NEFA levels in the rosiglitazone-treated db/db mice decreased dramatically. Fasting insulin levels (Figure 1b) and insulin tolerance testing (Figure 1c) further confirmed the improved insulin sensitivity with rosiglitazone treatment.


Transcriptome alteration in the diabetic heart by rosiglitazone: implications for cardiovascular mortality.

Wilson KD, Li Z, Wagner R, Yue P, Tsao P, Nestorova G, Huang M, Hirschberg DL, Yock PG, Quertermous T, Wu JC - PLoS ONE (2008)

Insulin resistance and mean body/heart weights of rosiglitazone-treated, untreated, and control mice.(A) Plasma NEFA levels at 0, 1, and 3 months in untreated db/db mice (n = 10), rosiglitazone-treated db/db mice (n = 10), and db/+ mice (n = 10). NEFA levels were higher in both the treated and untreated db/db groups at baseline when compared to db/+ control mice. Compared to untreated db/db mice, NEFA levels in the rosiglitazone-treated db/db group decreased significantly during the first month (960.9 vs. 1501.0 mmol/L, P<0.05), and decreased further by the third month to near db/+ control levels. (B) Fasting insulin levels in the three groups at 0, 1, and 3 months. At baseline, both treated and untreated db/db groups had increased levels of insulin compared to db/+ control. Insulin levels dramatically increased in untreated db/db mice at 1 month, but progressively decreased in rosiglitazone-treated mice. (C) Insulin tolerance testing at 3 months. Serum glucose levels after insulin injection were significantly higher in untreated db/db mice when compared to db/+ mice; the rosiglitazone-treated db/db group had moderately elevated glucose levels after insulin administration. These results corroborate the NEFA and insulin studies that demonstrate improved insulin sensitivity with rosiglitazone treatment. (D) Mean body weights of the three groups of mice at 0, 1, and 3 months. Weights of both treated and untreated db/db mice were markedly higher than db/+ controls at baseline. Furthermore, rosiglitazone-treated mice had generally higher mean body weights when compared to untreated mice. (E) Mean heart/body weight ratios at sacrifice (4 months after treatment initiation). No significant difference between treated and untreated groups (3.27 vs. 2.58, P = 0.13), though there does appear to be a downward trend in the data. Heart/body weight ratio was significantly higher in the db/+ group compared to both db/db groups. Values are mean±SEM. *P<0.05 vs. age-matched db/+; #P<0.05 vs. age-matched untreated db/db.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2481284&req=5

pone-0002609-g001: Insulin resistance and mean body/heart weights of rosiglitazone-treated, untreated, and control mice.(A) Plasma NEFA levels at 0, 1, and 3 months in untreated db/db mice (n = 10), rosiglitazone-treated db/db mice (n = 10), and db/+ mice (n = 10). NEFA levels were higher in both the treated and untreated db/db groups at baseline when compared to db/+ control mice. Compared to untreated db/db mice, NEFA levels in the rosiglitazone-treated db/db group decreased significantly during the first month (960.9 vs. 1501.0 mmol/L, P<0.05), and decreased further by the third month to near db/+ control levels. (B) Fasting insulin levels in the three groups at 0, 1, and 3 months. At baseline, both treated and untreated db/db groups had increased levels of insulin compared to db/+ control. Insulin levels dramatically increased in untreated db/db mice at 1 month, but progressively decreased in rosiglitazone-treated mice. (C) Insulin tolerance testing at 3 months. Serum glucose levels after insulin injection were significantly higher in untreated db/db mice when compared to db/+ mice; the rosiglitazone-treated db/db group had moderately elevated glucose levels after insulin administration. These results corroborate the NEFA and insulin studies that demonstrate improved insulin sensitivity with rosiglitazone treatment. (D) Mean body weights of the three groups of mice at 0, 1, and 3 months. Weights of both treated and untreated db/db mice were markedly higher than db/+ controls at baseline. Furthermore, rosiglitazone-treated mice had generally higher mean body weights when compared to untreated mice. (E) Mean heart/body weight ratios at sacrifice (4 months after treatment initiation). No significant difference between treated and untreated groups (3.27 vs. 2.58, P = 0.13), though there does appear to be a downward trend in the data. Heart/body weight ratio was significantly higher in the db/+ group compared to both db/db groups. Values are mean±SEM. *P<0.05 vs. age-matched db/+; #P<0.05 vs. age-matched untreated db/db.
Mentions: We analyzed a number of metabolic parameters to confirm insulin resistance in our db/db murine model of diabetes before proceeding with microarrays. Insulin resistance is strongly associated with obesity, and one mechanism may be the generation of metabolic messengers such as free fatty acids by adipose tissue that inhibit insulin action on muscle [18], [19]. We measured plasma non-esterified fatty acid (NEFA) and insulin levels to follow insulin resistance in our three groups of mice. Figure 1a shows plasma NEFA levels in the three groups of mice. Compared to untreated db/db mice, NEFA levels in the rosiglitazone-treated db/db mice decreased dramatically. Fasting insulin levels (Figure 1b) and insulin tolerance testing (Figure 1c) further confirmed the improved insulin sensitivity with rosiglitazone treatment.

Bottom Line: Specifically, the cumulative upregulation of (1) a matrix metalloproteinase gene that has previously been implicated in plaque rupture, (2) potassium channel genes involved in membrane potential maintenance and action potential generation, and (3) sphingolipid and ceramide metabolism-related genes, together give cause for concern over rosiglitazone's safety.Lastly, in vivo imaging studies revealed minimal differences between rosiglitazone-treated and untreated db/db mouse hearts, indicating that rosiglitazone's effects on gene expression in the heart do not immediately turn into detectable gross functional changes.A smaller number of unique and interesting changes in gene expression were noted with rosiglitazone treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Stanford University School of Medicine, Stanford, California, United States of America.

ABSTRACT

Background: Recently, the type 2 diabetes medication, rosiglitazone, has come under scrutiny for possibly increasing the risk of cardiac disease and death. To investigate the effects of rosiglitazone on the diabetic heart, we performed cardiac transcriptional profiling and imaging studies of a murine model of type 2 diabetes, the C57BL/KLS-lepr(db)/lepr(db) (db/db) mouse.

Methods and findings: We compared cardiac gene expression profiles from three groups: untreated db/db mice, db/db mice after rosiglitazone treatment, and non-diabetic db/+ mice. Prior to sacrifice, we also performed cardiac magnetic resonance (CMR) and echocardiography. As expected, overall the db/db gene expression signature was markedly different from control, but to our surprise was not significantly reversed with rosiglitazone. In particular, we have uncovered a number of rosiglitazone modulated genes and pathways that may play a role in the pathophysiology of the increase in cardiac mortality as seen in several recent meta-analyses. Specifically, the cumulative upregulation of (1) a matrix metalloproteinase gene that has previously been implicated in plaque rupture, (2) potassium channel genes involved in membrane potential maintenance and action potential generation, and (3) sphingolipid and ceramide metabolism-related genes, together give cause for concern over rosiglitazone's safety. Lastly, in vivo imaging studies revealed minimal differences between rosiglitazone-treated and untreated db/db mouse hearts, indicating that rosiglitazone's effects on gene expression in the heart do not immediately turn into detectable gross functional changes.

Conclusions: This study maps the genomic expression patterns in the hearts of the db/db murine model of diabetes and illustrates the impact of rosiglitazone on these patterns. The db/db gene expression signature was markedly different from control, and was not reversed with rosiglitazone. A smaller number of unique and interesting changes in gene expression were noted with rosiglitazone treatment. Further study of these genes and molecular pathways will provide important insights into the cardiac decompensation associated with both diabetes and rosiglitazone treatment.

Show MeSH
Related in: MedlinePlus