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Central insulin regulates heart rate and arterial blood flow: an endothelial nitric oxide synthase-dependent mechanism altered during diabetes

¹Inserm U858, Institute of Molecular Medicine I²MR, Research team « Functional Genomic of Metabolic Diseases », IFR31, CHU Rangueil, BP 84225, 31432 Toulouse Cedex 4, France
²CHUV Lausanne, Switzerland
³Inserm U558, Toulouse, France

Central neural insulin regulates glucose homeostasis, but less is known about its cardiovascular effects. Endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) represents a molecular link between metabolic and cardiovascular disease. Its role in the central nervous system remains to be determined.

Objective: We studied the effects of central insulin infusion on femoral arterial blood flow (BF) and heart rate (HR) in normal chow, high-fat diet diabetic (HFD), and eNOS null mice. Design: We recorded HR and femoral BF (ultrasonic flow probe) during 3-hour central insulin infusion in conscious freely moving mice. To study the role of NO in this setting, we assessed total and phosphorylated eNOS in the hypothalamus, and examined the effects of brain infusion of NO-donors/NOS-inhibitors on cardiovascular responsiveness to central insulin in these experimental mouse models.

Results: In normal mice, central insulin rapidly increased the HR by 30%, and more progressively increased BF by 40%. In HFD-mice, insulin's cardiovascular effects were blunted and associated with a 50% reduction of the total and phosphorylated eNOS expression in the hypothalamus, suggesting a causal link. In line with this hypothesis, in eNOS null mice and central-L-NMMA-infused normal mice, insulin's cardiovascular effects were abolished, whereas central NO-donor infusion restored these effects in eNOS null mice. In HFD-mice, central NO-donor infusion mimicked the cardiovascular responses evoked by central insulin in normal mice.

Conclusion: Central insulin has cardiovascular effects in conscious freely moving mice that are mediated, at least in part, by central neural eNOS. These effects are impaired in insulin resistant HFD-mice.

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