Effect of dipeptidyl peptidase-4 inhibitors on complement activation

TY - JOUR

T1 - Effect of dipeptidyl peptidase-4 inhibitors on complement activation

AU - Hoffmann-Petersen, Ingeborg T

AU - Holt, Charlotte B

AU - Jensen, Lisbeth

AU - Hage, Camilla

AU - Mellbin, Linda G

AU - Thiel, Steffen

AU - Hansen, Troels K

AU - Østergaard, Jakob A

N1 - This article is protected by copyright. All rights reserved.

PY - 2021/3

Y1 - 2021/3

N2 - AIMS: Adverse activation of the complement cascade in the innate immune system appears to be involved in development of vascular complications in diabetes. Dipeptidyl peptidase-4 (DPP-4) is a cell surface serine protease expressed in a variety of tissues. DPP-4 inhibitors are widely used in treatment of type 2 diabetes and appear to yield beneficial pleiotropic effects beyond their glucose-lowering action, e.g. renoprotective and anti-inflammatory properties, but the exact mechanisms remain unknown. We hypothesized that DPP-4 inhibitors block adverse complement activation by inhibiting complement-activating serine proteases.MATERIALS AND METHODS: We analyzed the effects of 7 different DPP-4 inhibitors on the lectin and classical pathway of the complement system in vitro by quantifying complement factor C4b deposition onto mannan or IgG coated surfaces, respectively. Furthermore, plasma concentrations of mannan-binding lectin (MBL), soluble membrane attack complex (sMAC), and C4b deposition were quantified in 71 patients with a recent acute coronary syndrome and glucose disturbances, randomly assigned to sitagliptin 100 mg (n=34) or placebo (n=37) for 12 weeks.RESULTS: All the 7 DPP-4 inhibitors tested in the study directly inhibited functional activity of the lectin pathway in a dose-dependent manner with varying potency in vitro. In vivo, MBL, sMAC, and C4b declined significantly during follow-up in both groups without significant effect of sitagliptin.CONCLUSIONS: We demonstrated an inhibitory effect of DPP-4 inhibitors on the lectin pathway in vitro. The clinical relevance of this effect of DPP-4 inhibitors remains to be fully elucidated. This article is protected by copyright. All rights reserved.

AB - AIMS: Adverse activation of the complement cascade in the innate immune system appears to be involved in development of vascular complications in diabetes. Dipeptidyl peptidase-4 (DPP-4) is a cell surface serine protease expressed in a variety of tissues. DPP-4 inhibitors are widely used in treatment of type 2 diabetes and appear to yield beneficial pleiotropic effects beyond their glucose-lowering action, e.g. renoprotective and anti-inflammatory properties, but the exact mechanisms remain unknown. We hypothesized that DPP-4 inhibitors block adverse complement activation by inhibiting complement-activating serine proteases.MATERIALS AND METHODS: We analyzed the effects of 7 different DPP-4 inhibitors on the lectin and classical pathway of the complement system in vitro by quantifying complement factor C4b deposition onto mannan or IgG coated surfaces, respectively. Furthermore, plasma concentrations of mannan-binding lectin (MBL), soluble membrane attack complex (sMAC), and C4b deposition were quantified in 71 patients with a recent acute coronary syndrome and glucose disturbances, randomly assigned to sitagliptin 100 mg (n=34) or placebo (n=37) for 12 weeks.RESULTS: All the 7 DPP-4 inhibitors tested in the study directly inhibited functional activity of the lectin pathway in a dose-dependent manner with varying potency in vitro. In vivo, MBL, sMAC, and C4b declined significantly during follow-up in both groups without significant effect of sitagliptin.CONCLUSIONS: We demonstrated an inhibitory effect of DPP-4 inhibitors on the lectin pathway in vitro. The clinical relevance of this effect of DPP-4 inhibitors remains to be fully elucidated. This article is protected by copyright. All rights reserved.

KW - complement system

KW - diabetes

KW - dipeptidyl peptidase-4 inhibitors

KW - lectin pathway

UR - http://www.scopus.com/inward/record.url?scp=85089477263&partnerID=8YFLogxK

U2 - 10.1002/dmrr.3385

DO - 10.1002/dmrr.3385

M3 - Journal article

C2 - 32662092

SN - 1520-7560

VL - 37

JO - Diabetes/Metabolism Research and Reviews

JF - Diabetes/Metabolism Research and Reviews

IS - 3

M1 - e3385

ER -