570-P: Osteoprotegerin Induces Endothelial Dysfunction and Is Associated with Vascular Complications In Type 2 Diabetes
Authors: MADDALONI ERNESTO , PARK KYOUNGMIN , GUIDA MICHELA DI , CORAGGIO LUCIA , LUORDI CECILIA , D’ONOFRIO LUCA , BARONI MARCO G. , CAVALLO MARIA G. , D’ANGELO PAOLA , COSMO SALVATORE DE , LEONETTI FRIDA , MORANO SUSANNA , MORVIDUCCI LELIO , POZZILLI PAOLO , PRUDENTE SABRINA , PUGLIESE GIUSEPPE , TRISCHITTA VINCENZO , HOLMAN RURY R. , KING GEORGE L. , BUZZETTI RAFFAELLA ,   OMNIPOD HORIZON STUDY GROUP
Published: June 2020

Novel markers of vascular disease in diabetes could help identify new disease pathways and enhance risk stratification. Osteoprotegerin (OPG) and osteopontin (OPN) are key molecules involved in bone and vascular calcification processes, both compromised in diabetes. To evaluate whether OPG and/or OPN are associated with diabetic vascular complications, we measured their serum concentrations in 995 type 2 diabetes subjects enrolled in the Sapienza University Mortality and Morbidity Event Rate (SUMMER) Study. Any association with history of cardiovascular disease (CVD), diabetic retinopathy (DR) and reduced eGFR were examined with ANOVA, correcting for age, gender, HbA1c and lipid profile. Among the population, 15.7% had CVD, 18.4% had DR, 12.0% had an eGFR between 45-59 ml/min/1.73m2 and 7.5% had an eGFR &lt;45 ml/min/1.73m2. Serum OPG, but OPN, concentrations stratified according to the presence of CVD, DR or reduced eGFR (p&lt;0.001). Specifically, OPG levels were higher in patients with than in those without CVD (median [IQR]: 11.5 [11.7] vs.10.0 [9.5], p=0.004) or DR (13.3 [14.7] vs.9.7 [8.9], p&lt;0.001), and in patients with an eGFR &lt;45 ml/min/1.73m2 (17.0 [23.5]) compared with an eGFR 45-59 ml/min/1.73m2 (13.2 [13.5]) and ≥60 ml/min/1.73m2 (9.4 [8.7] (p &lt;0.001).To explore potential mechanisms for the association of vascular complications with OPG and/or OPN, we assessed insulin-mediated eNOS activity in bovine aortic endothelial cells cultures (BAECs) with OPG or OPN in the presence of insulin. OPG, but not OPN, inhibited insulin-induced eNOS activation in a dose-dependent manner. Additionally, OPG inhibited insulin-induced activation of both pERK and pAKT in BAECs. In summary, our results show that OPG associates with vascular disease in diabetes and suggest that this effect is mediated by endothelial insulin-resistance and reduced insulin-induced NO production.

Disclosure
E. Maddaloni: Consultant; Self; Merck KGaA. Speaker’s Bureau; Self; Abbott, AstraZeneca, Pikdare. K. Park: None. M. Di Guida: None. L. Coraggio: None. C. Luordi: None. L. D’Onofrio: None. M.G. Baroni: None. M.G. Cavallo: None. P. D’Angelo: None. S. De Cosmo: None. F. Leonetti: None. S. Morano: None. L. Morviducci: None. P. Pozzilli: Advisory Panel; Self; Abbott, AstraZeneca, Eli Lilly and Company. Research Support; Self; Medtronic, Sanofi. S. Prudente: None. G. Pugliese: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mundipharma International, Sanofi-Aventis, Sigma-tau, Takeda Pharmaceutical Company Limited. Other Relationship; Self; Laboratori Guidotti. V. Trischitta: None. R.R. Holman: Advisory Panel; Self; Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Bayer AG, Merck Sharp & Dohme Corp. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc. R. Buzzetti: Advisory Panel; Self; Sanofi. Speaker’s Bureau; Self; AstraZeneca, Lilly Diabetes, Merck Sharp & Dohme Corp.

Funding
European Foundation for the Study of Diabetes; AstraZeneca (MS 2017_2); Società Italiana di Diabetologia