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Cardiac β-Adrenoceptor Expression Is Reduced in Zucker Diabetic Fatty Rats as Type-2 Diabetes Progresses.

Haley JM, Thackeray JT, Thorn SL, DaSilva JN - PLoS ONE (2015)

Bottom Line: At 10 weeks, myocardial [3H]CGP12177 was normal in hyperglycemic ZDF (17±4.1mM) compared to ZL, but reduced 16-25% at 16 weeks of age as diabetes and hyperglycemia (22±2.4mM) progressed.In the heart, Western blotting at 10 weeks indicated normal β1-AR (98±9%), reduced β2-AR (76±10%), and elevated β3-AR (108±6).At 16 weeks, β1-AR expression became reduced (69±16%), β2-AR expression decreased further (68±14%), and β3-AR remained elevated, similar to 10 weeks (112±9%).

View Article: PubMed Central - PubMed

Affiliation: Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, Canada K1Y4W7; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Roger Guindon Hall, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5.

ABSTRACT

Objectives: Reduced cardiac β-adrenoceptor (β-AR) expression and cardiovascular dysfunction occur in models of hyperglycemia and hypoinsulinemia. Cardiac β-AR expression in type-2 diabetes models of hyperglycemia and hyperinsulinemia, remain less clear. This study investigates cardiac β-AR expression in type-2 diabetic Zucker diabetic fatty (ZDF) rats.

Methods: Ex vivo biodistribution experiments with [3H]CGP12177 were performed in Zucker lean (ZL) and ZDF rats at 10 and 16 weeks of age as diabetes develops. Blood glucose, body mass, and diet consumption were measured. Western blotting of β-AR subtypes was completed in parallel. Echocardiography was performed at 10 and 16 weeks to assess systolic and diastolic function. Fasted plasma insulin, free fatty acids (FFA), leptin and fed-state insulin were also measured.

Results: At 10 weeks, myocardial [3H]CGP12177 was normal in hyperglycemic ZDF (17±4.1mM) compared to ZL, but reduced 16-25% at 16 weeks of age as diabetes and hyperglycemia (22±2.4mM) progressed. Reduced β-AR expression not apparent at 10 weeks also developed by 16 weeks of age in ZDF brown adipose tissue. In the heart, Western blotting at 10 weeks indicated normal β1-AR (98±9%), reduced β2-AR (76±10%), and elevated β3-AR (108±6). At 16 weeks, β1-AR expression became reduced (69±16%), β2-AR expression decreased further (68±14%), and β3-AR remained elevated, similar to 10 weeks (112±9%). While HR was reduced at 10 and 16 weeks in ZDF rats, no significant changes were observed in diastolic or systolic function.

Conclusions: Cardiac β-AR are reduced over 6 weeks of sustained hyperglycemia in type-2 diabetic ZDF rats. This indicates cardiac [3H]CGP12177 retention and β1- and β2-AR expression are inversely correlated with the progression of type-2 diabetes.

No MeSH data available.


Related in: MedlinePlus

Animal model characteristics of ZDF and ZL animals.Blood glucose (A), body mass (B), and diet consumed (C). Data are mean ± SD. n = 7–10 per group. *p<0.05 vs ZL, Students t-test.
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pone.0127581.g001: Animal model characteristics of ZDF and ZL animals.Blood glucose (A), body mass (B), and diet consumed (C). Data are mean ± SD. n = 7–10 per group. *p<0.05 vs ZL, Students t-test.

Mentions: Starting from 8 weeks of age, ZDF rats exhibited moderate hyperglycemia (8.9±1.7mM) compared to ZL (5.9±0.27mM). During the course of the experiment blood glucose in ZDF gradually increased to 17±4.1 mM at 10 weeks, and began to plateau at 19±2.3 mM by 12 weeks, reaching 22±2.4 mM by 16 weeks (Fig 1A). ZDF had a significantly greater body mass than ZL controls (259±17g versus 212±18g) starting at 8 weeks of age (Fig 1B). The increase in ZDF body mass began to plateau and was not significantly greater than ZL by 12 weeks. At 16 weeks ZL rats were 409±31g and ZDF rats were 378±30g despite the qualitative appearance of greater body fat in ZDF rats. Diet consumption in kcal per day was calculated at 10 and 16 weeks in line with terminal biodistribution experiments. At 10 weeks ZDF animals consumed significantly more than ZL controls (99±8.7 versus 67±3.2 kcal/day respectively), a trend that was exaggerated by 16 weeks (190±27 kcal/day versus 120±1.4 kcal/day) (Fig 1C). HOMA-IR was significantly elevated in ZDF rats by 68% and 75% at 10 and 16 weeks of age respectively (Table 1).


Cardiac β-Adrenoceptor Expression Is Reduced in Zucker Diabetic Fatty Rats as Type-2 Diabetes Progresses.

Haley JM, Thackeray JT, Thorn SL, DaSilva JN - PLoS ONE (2015)

Animal model characteristics of ZDF and ZL animals.Blood glucose (A), body mass (B), and diet consumed (C). Data are mean ± SD. n = 7–10 per group. *p<0.05 vs ZL, Students t-test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4440709&req=5

pone.0127581.g001: Animal model characteristics of ZDF and ZL animals.Blood glucose (A), body mass (B), and diet consumed (C). Data are mean ± SD. n = 7–10 per group. *p<0.05 vs ZL, Students t-test.
Mentions: Starting from 8 weeks of age, ZDF rats exhibited moderate hyperglycemia (8.9±1.7mM) compared to ZL (5.9±0.27mM). During the course of the experiment blood glucose in ZDF gradually increased to 17±4.1 mM at 10 weeks, and began to plateau at 19±2.3 mM by 12 weeks, reaching 22±2.4 mM by 16 weeks (Fig 1A). ZDF had a significantly greater body mass than ZL controls (259±17g versus 212±18g) starting at 8 weeks of age (Fig 1B). The increase in ZDF body mass began to plateau and was not significantly greater than ZL by 12 weeks. At 16 weeks ZL rats were 409±31g and ZDF rats were 378±30g despite the qualitative appearance of greater body fat in ZDF rats. Diet consumption in kcal per day was calculated at 10 and 16 weeks in line with terminal biodistribution experiments. At 10 weeks ZDF animals consumed significantly more than ZL controls (99±8.7 versus 67±3.2 kcal/day respectively), a trend that was exaggerated by 16 weeks (190±27 kcal/day versus 120±1.4 kcal/day) (Fig 1C). HOMA-IR was significantly elevated in ZDF rats by 68% and 75% at 10 and 16 weeks of age respectively (Table 1).

Bottom Line: At 10 weeks, myocardial [3H]CGP12177 was normal in hyperglycemic ZDF (17±4.1mM) compared to ZL, but reduced 16-25% at 16 weeks of age as diabetes and hyperglycemia (22±2.4mM) progressed.In the heart, Western blotting at 10 weeks indicated normal β1-AR (98±9%), reduced β2-AR (76±10%), and elevated β3-AR (108±6).At 16 weeks, β1-AR expression became reduced (69±16%), β2-AR expression decreased further (68±14%), and β3-AR remained elevated, similar to 10 weeks (112±9%).

View Article: PubMed Central - PubMed

Affiliation: Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, Canada K1Y4W7; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Roger Guindon Hall, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5.

ABSTRACT

Objectives: Reduced cardiac β-adrenoceptor (β-AR) expression and cardiovascular dysfunction occur in models of hyperglycemia and hypoinsulinemia. Cardiac β-AR expression in type-2 diabetes models of hyperglycemia and hyperinsulinemia, remain less clear. This study investigates cardiac β-AR expression in type-2 diabetic Zucker diabetic fatty (ZDF) rats.

Methods: Ex vivo biodistribution experiments with [3H]CGP12177 were performed in Zucker lean (ZL) and ZDF rats at 10 and 16 weeks of age as diabetes develops. Blood glucose, body mass, and diet consumption were measured. Western blotting of β-AR subtypes was completed in parallel. Echocardiography was performed at 10 and 16 weeks to assess systolic and diastolic function. Fasted plasma insulin, free fatty acids (FFA), leptin and fed-state insulin were also measured.

Results: At 10 weeks, myocardial [3H]CGP12177 was normal in hyperglycemic ZDF (17±4.1mM) compared to ZL, but reduced 16-25% at 16 weeks of age as diabetes and hyperglycemia (22±2.4mM) progressed. Reduced β-AR expression not apparent at 10 weeks also developed by 16 weeks of age in ZDF brown adipose tissue. In the heart, Western blotting at 10 weeks indicated normal β1-AR (98±9%), reduced β2-AR (76±10%), and elevated β3-AR (108±6). At 16 weeks, β1-AR expression became reduced (69±16%), β2-AR expression decreased further (68±14%), and β3-AR remained elevated, similar to 10 weeks (112±9%). While HR was reduced at 10 and 16 weeks in ZDF rats, no significant changes were observed in diastolic or systolic function.

Conclusions: Cardiac β-AR are reduced over 6 weeks of sustained hyperglycemia in type-2 diabetic ZDF rats. This indicates cardiac [3H]CGP12177 retention and β1- and β2-AR expression are inversely correlated with the progression of type-2 diabetes.

No MeSH data available.


Related in: MedlinePlus