Clustering of cardiovascular risk factors mimicking the human metabolic syndrome X in eNOS null mice.

AIMS/HYPOTHESIS: The metabolic syndrome comprises a clustering of cardiovascular risk factors but the underlying mechanism is not known. Mice with targeted disruption of endothelial nitric oxide synthase (eNOS) are hypertensive and insulin resistant. We wondered, whether eNOS deficiency in mice is associated with a phenotype mimicking the human metabolic syndrome. METHODS AND RESULTS: In addition to arterial pressure and insulin sensitivity (euglycaemic hyperinsulinaemic clamp), we measured the plasma concentration of leptin, insulin, cholesterol, triglycerides, free fatty acids, fibrinogen and uric acid in 10 to 12 week old eNOS-/- and wild type mice. We also assessed glucose tolerance under basal conditions and following a metabolic stress with a high fat diet. As expected eNOS-/- mice were hypertensive and insulin resistant, as evidenced by fasting hyperinsulinaemia and a roughly 30 percent lower steady state glucose infusion rate during the clamp. eNOS-/- mice had a 1.5 to 2-fold elevation of the cholesterol, triglyceride and free fatty acid plasma concentration. Even though body weight was comparable, the leptin plasma level was 30% higher in eNOS-/- than in wild type mice. Finally, uric acid and fibrinogen were elevated in the eNOS-/- mice. Whereas under basal conditions, glucose tolerance was comparable in knock out and control mice, on a high fat diet, knock out mice became significantly more glucose intolerant than control mice. CONCLUSIONS: A single gene defect, eNOS deficiency, causes a clustering of cardiovascular risk factors in young mice. We speculate that defective nitric oxide synthesis could trigger many of the abnormalities making up the metabolic syndrome in humans.

Neuropeptide Y secretion from a human insulinoma.

Neuropeptide Y (NPY) is a 36 aminoacid peptide known to inhibit glucose-stimulated insulin secretion. NPY has been shown to be synthesized and secreted by rat islets of Langerhans. More recently, we described the presence on NPY within human islets of Langerhans and in several pancreatic endocrine tumors. In this report, we describe the case of a patient presenting with an insulinoma who underwent the surgical resection of the tumor and was studied in vivo and in vitro for NPY production. Using a highly specific and sensitive two-site amplified enzyme-linked immunosorbent assay, we detected high plasma NPY levels in the patient prior to the surgical resection of the tumor which returned to normal after surgery. NPY was secreted from the tumor when kept in primary cell culture. Furthermore, immunohistochemistry of the insulinoma revealed the presence of NPY and its C-flanking peptide together with insulin, chromogranin and neuron specific enolase. It is concluded that elevated circulating NPY levels observed in this patient with an insulinoma reflected in vivo secretion by the tumor and it is hypothesized that NPY could potentially be used as an endocrine marker in patients with suspected insulinoma.