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The Leu7Pro Polymorphism of PreproNPY Is Associated with Decreased Insulin Secretion, Delayed Ghrelin Suppression, and Increased Cardiovascular Responsiveness to Norepinephrine during Oral Glucose Tolerance Test

Departments of Pharmacology and Clinical Pharmacology (U.J., U.P., M.K., J.K.), Physics (T.K.), and Biostatistics (T.V.), University of Turku, FI-20520 Turku, Finland; and Department of Ophthalmology (U.J.), Turku City Hospital, FI-20700 Turku, Finland; and Department of Pediatrics (T.J.), Turku University Hospital, FI-20520 Turku, Finland

Address all correspondence and requests for reprints to: Jaana Kallio, M.D., Ph.D., Department of Pharmacology and Clinical Pharmacology, University of Turku, Itäinen Pitkäkatu 4, FI-20520 Turku, Finland. E-mail: jaana.kallio{at}utu.fi.

Context: Neuropeptide Y (NPY) plays a role in angiogenesis, cardiovascular regulation, and hormone secretion. The leucine7 to proline7 (Leu7Pro) polymorphism of preproNPY is associated with vascular diseases and has an impact on hormone levels in healthy subjects.

Objective: The current study investigated the role of the Leu7Pro polymorphism in metabolic and cardiovascular autonomic regulation.

Design and Subjects: A 5-h oral glucose tolerance test was performed on 27 healthy volunteers representing two preproNPY genotypes (Leu7/Pro7 and Leu7/Leu7) matched for age, sex, body mass index and physical activity.

Main Outcome Measures: Simultaneously we performed cardiovascular autonomic function tests and plasma measurements of sympathetic transmitters, glucose, insulin, and ghrelin.

Results: The subjects with Leu7/Pro7 genotype had decreased plasma NPY, norepinephrine (NE), and insulin concentrations and insulin to glucose ratios. The suppression of ghrelin concentrations after glucose ingestion was delayed in these subjects. They also had increased heart rate variability indices and baroreflex sensitivity. However, they displayed significant negative association of NE concentration with variability of low-frequency R-R-intervals and with baroreflex sensitivity.

Conclusions: The Leu7Pro polymorphism of preproNPY is related to decreased level of basal sympathetic activity, decreased insulin secretion, and delayed ghrelin suppression during oral glucose tolerance test. The increased responsiveness of autonomic functions to NE associated with the polymorphism may be connected to increased cardiovascular vulnerability.

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