1: Diabetes. 2007 Dec;56(12):2872-7. Epub 2007 Sep 5.

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

Cabou C, Cani PD, Campistron G, Knauf C, Mathieu C, Sartori C, Amar J, Scherrer
U, Burcelin R.

Inserm U858, Institute of Molecular Medicine, IFR31, CHU Rangueil, BP 84225,
31432 Toulouse Cedex 4, France.

OBJECTIVE: 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. We studied the effects of central insulin infusion on femoral
arterial blood flow and heart rate in normal chow-fed, high-fat diet-fed
diabetic, and eNOS-null mice. RESEARCH DESIGN AND METHODS: We recorded heart rate
and femoral blood flow (ultrasonic flow probe) during 3-h 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 heart rate by 
30% and more progressively increased blood flow by 40%. In high-fat diet-fed
mice, the cardiovascular effects of insulin 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 N(G)-monomethyl-L-arginine-infused normal mice, the
cardiovascular effects of insulin were abolished, whereas central NO donor
infusion restored these effects in eNOS-null mice. In high-fat diet-fed mice,
central NO donor infusion mimicked the cardiovascular responses evoked by central
insulin in normal mice. CONCLUSIONS: 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 high-fat diet-fed
mice.

PMID: 17804761 [PubMed - in process]

Related Links

    Partial gene deletion of endothelial nitric oxide synthase predisposes to
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[Diabetes. 2004] PMID:15277387

    Clustering of cardiovascular risk factors mimicking the human metabolic syndrome 
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