Abstract 16174: Nardilysin is a Critical Regulator of Insulin Secretion and Glucose Metabolism
Background: We have previously shown that nardilysin (N-arginine dibasic convertase; NRDc) enhances ectodomain shedding of several membrane-anchored proteins. Analysis of NRDc-deficient (NRDc-/-) mice revealed that NRDc regulates growth, axonal maturation and myelination. Meanwhile, NRDc-/- mice also show lean phenotype, indicating that NRDc may play some roles in energy metabolism.
Methods and results: NRDc-/- and wild-type (NRDc+/+) mice (n=7,10 each) underwent intraperitoneal glucose tolerance test (2 mg/g body weight). Blood samples were collected before (0min) and 30, 60, and 120 min after glucose administration. Glucose-induced insulin secretion was markedly decreased in NRDc-/- mice at 30 and 60 min (0 min: NRDc-/- 0.43±0.09 ng/ml vs NRDc+/+ 0.38±0.07 ng/ml, p=0.33; 30 min: 0.46±0.06 vs 0.75±0.10, p=0.02; 60 min: 0.43±0.09 vs 0.83±0.15, p=0.03; 120 min: 0.58±0.10 vs 0.62±0.09, p=0.37), while NRDc-/- mice showed only mild glucose intolerance (0 min: NRDc-/- 123±14 mg/dl vs NRDc+/+ 126±13 mg/dl, p=0.46; 30 min: 444±35 vs 409±28, p=0.22; 60 min: 434±38 vs 319±28, p=0.01; 120 min: 283±43 vs 192±27, p=0.04). Observation by electron microscopy and immunohistochemistry with anti-insulin antibody showed normal islet morphology and insulin production in NRDc-/- mice. To examine the capacity of insulin secretion, we isolated islets from NRDc-/- and NRDc+/+ mice and measured glucose- or KCl-stimulated insulin secretion. Consistent with the in vivo results, NRDc-/- islets showed severely reduced glucose-stimulated insulin secretion (0.86±0.15-fold relative to unstimulated controls), while NRDc +/+ islets showed normal glucose-stimulated insulin secretion (4.6±1.7-fold relative to untreated controls). On the other hand, NRDc-/- islets showed normal KCl-stimulated insulin secretion (3.4±0.9-fold relative to unstimulated controls), indicating that the response to glucose is specifically impaired in NRDc-/- islets.
Conclusions: NRDc-deficient mice showed abnormal glucose metabolism due to impaired glucose-stimulated insulin secretion of pancreatic islets. Our findings indicate that NRDc is a novel and critical regulator of insulin secretion, which may play an important role in glucose metabolism.
- © 2013 by American Heart Association, Inc.