SAT032 Circulating Neprilysin Activity Is Increased In Type 2 Diabetes And Fatty Liver Disease, And Reduces Following Bariatric Surgery And Liraglutide Therapy

Disclosure: S.A. Kjeldsen: None. L. Gluud: None. M. Werge: None. J. Pedersen: None. F. Bendtsen: None. K. Alexiadou: None. T. Tan: None. S.S. Torekov: None. E.W. Iepsen: None. N.J. Jensen: None. M. Richter: None. B. Hartmann: None. J.J. Holst: None. B. Holst: None. J. Holt: None. S. Madsbad: None. M.S. Svane: None. K.N. Bojsen-Møller: None. N.J. Wewer Albrechtsen: None. The neutral endopeptidase neprilysin (NEP) cleaves peptides important for metabolism, including GLP-1. Plasma levels of GLP-1 are reduced in patients with T2D, but the reason is unknown. Long-term treatment with the NEP inhibitor sacubitril (in combination with valsartan) improves glycemic control in individuals with T2D and heart failure. Here, we investigate plasma activity and protein levels of NEP in patients with obesity, T2D, and/or NAFLD diagnosed using biopsy or ultrasound, following bariatric surgery (RYGB and sleeve gastrectomy), and after treatment with GLP-1. We hypothesized that NEP activity (NEPa) is increased in patients with T2D, and that GLP-1 agonism reduces NEPa in a weight loss-independent manner. Here we show that plasma levels of NEPa are increased by 51% in patients with T2D (n=33) compared to individuals with normal glucose tolerance (NGT, n=160) (mean ± SD; 2734 ± 3646 vs. 1809 ± 2039 pmol/ml/min, P=0.02). Plasma NEPa was not increased in obesity (n=188) compared to lean controls (n=15) (1944 ± 2392 vs. 1373 ± 1918, P=0.4), but was increased by 76% in NAFLD (n=51) compared to non-NAFLD controls (n=43) (2629 ± 3219 vs. 1497 ± 1404, P=0.02). There were no differences in plasma NEP protein between any of the comparator groups, suggesting that changes in NEPa in metabolic disease are post-translational modifications of the enzyme or other mechanisms influencing NEPa. Bariatric surgery (RYGB, n=66 and SG, n=20) reduced plasma NEPa by 60% (P