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Published on: November 16, 2011
Direct renin inhibition modulates insulin resistance in caveolin-1-deficient mice
Somlak Chuengsamarn1, Amanda E Garza, Alexander W Krug
1Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Objective:
To test the hypothesis that aliskiren improves the metabolic phenotype in a genetic mouse model of the metabolic syndrome (the caveolin-1 (cav-1) knock out (KO) mouse).
Materials/Methods:
Eleven-week-old cav-1 KO and genetically matched wild-type (WT) mice were randomized to three treatment groups: placebo (n=8/group), amlodipine (6 mg/kg/day, n=18/ group), and aliskiren (50 mg/kg/day, n=18/ group). After three weeks of treatment, all treatment groups were assessed for several measures of insulin resistance (fasting insulin and glucose, HOMA-IR, and the response to an intraperitoneal glucose tolerance test (ipGTT)) as well as for triglyceride levels and the blood pressure response to treatment.
Results:
Treatment with aliskiren did not affect the ipGTT response but significantly lowered the HOMA-IR and insulin levels in cav-1 KO mice. However, treatment with amlodipine significantly degraded the ipGTT response, as well as the HOMA-IR and insulin levels in the cav-1 KO mice. Aliskiren also significantly lowered triglyceride levels in the cav-1 KO but not in the WT mice. Moreover, aliskiren treatment had a significantly greater effect on blood pressure readings in the cav-1 KO vs. WT mice, and was marginally more effective than amlodipine.
Conclusions:
Our results support the hypothesis that aliskiren reduces insulin resistance as indicated by improved HOMA-IR in cav-1 KO mice whereas amlodipine treatment resulted in changes consistent with increased insulin resistance. In addition, aliskiren was substantially more effective in lowering blood pressure in the cav-1 KO mouse model than in WT mice and marginally more effective than amlodipine.
Insights
Aliskiren improved insulin resistance and lowered triglycerides in a genetic metabolic syndrome mouse model. Amlodipine worsened insulin resistance, while aliskiren effectively reduced blood pressure in these mice.
Area of Science:
- Metabolic Syndrome Research
- Pharmacology
- Genetics
Background:
- Metabolic syndrome is a cluster of conditions increasing heart disease, stroke, and diabetes risk.
- Genetic mouse models are crucial for understanding metabolic syndrome pathophysiology.
- Caveolin-1 (cav-1) knockout mice serve as a model for metabolic syndrome.
Purpose of the Study:
- To evaluate aliskiren's efficacy in improving the metabolic phenotype of cav-1 knockout mice.
- To compare aliskiren's effects with amlodipine in this genetic model.
Main Methods:
- Eleven-week-old cav-1 knockout and wild-type mice were used.
- Mice were randomized into placebo, amlodipine, and aliskiren treatment groups.
- Insulin resistance, triglyceride levels, and blood pressure were assessed after three weeks.
Main Results:
- Aliskiren significantly reduced HOMA-IR and insulin levels in cav-1 KO mice.
- Amlodipine treatment worsened the glucose tolerance test (ipGTT) response and insulin resistance markers.
- Aliskiren lowered triglyceride levels and demonstrated greater blood pressure reduction in cav-1 KO mice.
Conclusions:
- Aliskiren supports the hypothesis of reducing insulin resistance in cav-1 KO mice.
- Amlodipine treatment showed effects consistent with increased insulin resistance.
- Aliskiren was more effective in lowering blood pressure in the cav-1 KO model compared to WT mice.
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