Journal article
Neprilysin deficiency protects against fat-induced insulin secretory dysfunction by maintaining calcium influx
S Zraika, DS Koh, BM Barrow, B Lu, SE Kahn, S Andrikopoulos
Diabetes | Published : 2013
DOI: 10.2337/db11-1593
Abstract
Neprilysin contributes to free fatty acid (FFA)-induced cellular dysfunction in nonislet tissues in type 2 diabetes. Here, we show for the first time that with prolonged FFA exposure, islet neprilysin is upregulated and this is associated with reduced insulin premRNA and ATP levels, oxidative/nitrative stress, impaired potassium and calcium channel activities, and decreased glucose-stimulated insulin secretion (GSIS). Genetic ablation of neprilysin specifically protects against FFA-induced impairment of calcium influx and GSIS in vitro and in vivo but does not ameliorate other FFA-induced defects. Importantly, adenoviral overexpression of neprilysin in islets cultured without FFA reproduces ..
View full abstractGrants
Awarded by National Institute of Diabetes and Digestive and Kidney Diseases
Funding Acknowledgements
This study was supported by National Institutes of Health (NIH) Grant DK-080945 (to S.Z.), the Department of Veterans Affairs, VA Puget Sound Health Care System, the Diabetes Australia Research Trust, and the National Health and Medical Research Council (NHMRC) of Australia. Calcium influx and rubidium efflux studies as well as histological studies were performed at the University of Washington's Diabetes Research Center Cell Function Analysis Core and Cellular and Molecular Imaging Core, respectively, both of which are supported by NIH Grant DK-017047. S.A. was the recipient of a Career Development Award from the NHMRC of Australia.