- S.L.C. Geijselaers (1)
- M.M.J. Greevenbroek van (3)
- H.F. Hendriks (1)
- E. Hertle (1)
- E.H. Jansen (1)
- E.J.H.M. Jansen (1)
- C.J.H. Kallen van der (3)
- F.J. Kok (1)
- G. Schaafsma (1)
- C.G. Schalkwijk (3)
- C.D.A. Stehouwer (3)
- N. Wlazlo (2)
- E.C. Zoete de (1)
Complement Factor 3 is associated with insulin resistance and with incident type 2 diabetes mellitus over a 7-year follow-up period: the CODAM study
Wlazlo, N. ; Greevenbroek, M.M.J. van; Ferreira, I. ; Feskens, E.J.M. ; Kallen, C.J.H. van der; Schalkwijk, C.G. ; Bravenboer, B. ; Stehouwer, C.D.A. - \ 2014
Diabetes Care 37 (2014)7. - ISSN 0149-5992 - p. 1900 - 1909.
acylation-stimulating protein - nlrp3 inflammasome activation - population-based cohort - low-grade inflammation - c-reactive protein - transcriptional regulation - 3t3-l1 adipocytes - glucose-tolerance - c5a receptor - risk-factors
OBJECTIVE - Immune dysregulation can affect insulin resistance (IR) and b-cell function and hence contribute to development of type 2 diabetes mellitus (T2DM). The complement system, as a regulator of immune and inflammatory homeostasis, may be a relevant contributor therein. However, longitudinal studies focusing on complement as a determinant of T2DMand IR are scarce. Therefore, we prospectively investigated the association of plasma complement factor 3 (C3) with (estimates of) IR in muscle, liver, and adipocytes, as well as with glucose tolerance, including incident T2DM. RESEARCH DESIGN AND METHODS - Fasting C3, nonesterified fatty acids, glucose, and insulin (the latter two during oral glucose tolerance tests) weremeasured at baseline (n = 545) and after 7 years of follow-up (n = 394) in a prospective cohort study. RESULTS - Over the 7-year period, C3 levels (per 0.1 g/L) were longitudinally associated with higher homeostasis model assessment of IR (HOMA2-IR; b = 15.2% [95% CI 12.9–17.6]), hepatic IR (b = 6.1%[95% CI 4.7–7.4]), adipocyte IR (b = 16.0% [95%CI 13.0–19.1]), fasting glucose (b = 1.8% [95% CI 1.2–2.4]), 2-h glucose (b = 5.2% [95% CI 3.7–6.7]), and area under the curve for glucose (b = 3.6% [95% CI 2.7–4.6]). In addition, greater changes in C3 (per 0.1 g/L) were associated with greater changes in HOMA2-IR (b = 0.08 [95% CI 0.02–0.15]) and greater changes in hepatic IR (b = 0.87 [95% CI 0.12–1.61]) over 7 years, but not glucose tolerance. Moreover, baseline C3 was associated with the 7-year incidence of T2DM (odds ratio 1.5 [95% CI 1.1–2.0]). CONCLUSIONS - Changes in C3 were associated with changes in several measures of IR and may reflect progression of metabolic dysregulation, which eventually leads to abnormalities in glucose tolerance and T2DM.
Distinct associations of complement C3a and its precursor C3 with atherosclerosis and cardiovascular disease
Hertle, E. ; Greevenbroek, M.M.J. van; Arts, I.C.W. ; Kallen, C.J.H. van der; Geijselaers, S.L.C. ; Feskens, E.J.M. ; Jansen, E.H. ; Schalkwijk, C.G. ; Stehouwer, C.D.A. - \ 2014
Thrombosis and Haemostasis 111 (2014)6. - ISSN 0340-6245 - p. 1102 - 1111.
coronary-artery-disease - acylation-stimulating protein - intima-media thickness - low-grade inflammation - metabolic syndrome - anaphylatoxins c3a - insulin-resistance - diabetes-mellitus - endothelial-cells - cigarette-smoke
Complement C3 is a novel risk factor for cardiovascular disease (CVD), but the underlying mechanism is currently unknown. We determined the associations of the anaphylatoxin C3a, the activation product of C3, and of C3 itself with estimates of atherosclerosis and CVD. We studied associations of C3a and C3 with carotid intima-media thickness (cIMT), ankle-arm blood pressure index (AAIx) and CVD in cross-sectional analyses among 545 participants of the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study (61% men, 59.4 ± 6.9 years) and examined effect modification by smoking. We conducted linear and logistic regression analyses with adjustments for age, sex, glucose metabolism status, lipids, adiposity, renal function, blood pressure, pack-years smoked, physical activity, use of medication and investigated mediation by inflammation. C3a was independently associated with cIMT (ß=0.032 mm, [95% confidence interval: 0.004; 0.060]) and AAIx (ß=-0.022, [-0.043; –0.001]), but C3 was not. Effect modification by smoking was only observed for CVD (Psmoking*C3a=0.008, Psmoking*C3=0.018), therefore these associations were stratified for smoking behaviour. Both C3a (odds ratio [OR] =2.96, [1.15; 7.62]) and C3 (OR =1.98, [1.21; 3.22]) were independently associated with CVD in heavy smokers. The association of C3 with CVD was independent of C3a. Low-grade inflammation did partially explain the association of C3a with AAIx, but not the other observed associations. This suggests that C3a and C3 have distinct roles in pathways leading to CVD. C3a may promote atherosclerosis and additionally advance CVD in heavy smokers. Conversely, C3 may be associated with CVD in heavy smokers via pathways other than atherosclerosis.
Low-grade inflammation and insulin resistance independently explain substantial parts of the association between body fat and serum C3: The CODAM study
Wlazlo, N. ; Greevenbroek, M.M.J. van; Ferreira, I. ; Jansen, E.J.H.M. ; Feskens, E.J.M. ; Kallen, C.J.H. van der; Schalkwijk, C.G. ; Bravenboer, B. ; Stehouwer, C.D.A. - \ 2012
Metabolism : Clinical and Experimental 61 (2012)12. - ISSN 0026-0495 - p. 1787 - 1796.
acylation-stimulating protein - complement c3 - adipose-tissue - metabolic syndrome - reactive protein - population - expression - obesity - risk - component-3
OBJECTIVE: To investigate the role of low-grade inflammation and insulin resistance (HOMA2-IR) in adiposity-related increases in serum complement factor 3 (C3). Although C3 has been linked to type 2 diabetes and cardiovascular diseases, and C3 levels are closely related to body fat, the underlying mechanisms explaining this association are still unknown. METHODS: Adiposity measures (including BMI, waist circumference (WC), sagittal diameter and several skinfolds), HOMA2-IR and markers of inflammation (hs-CRP, IL-6, SAA, haptoglobin, ceruloplasmin, sICAM-1) were determined in 532 individuals (62% men, mean age 59±6.9yrs) from the Cohort on Diabetes and Atherosclerosis Maastricht study. Markers of inflammation were standardized and compiled into an averaged inflammation score. Cross-sectional associations between adiposity measures and C3 and the mediating role of low-grade inflammation and/or HOMA2-IR herein were analysed with multiple linear regression models. RESULTS: Adiposity measurements were significantly associated with C3 levels, with the strongest (adjusted) associations found for WC (ß=0.383; 95%CI 0.302-0.464) and sagittal diameter (ß=0.412; 95%CI 0.333-0.490). Further adjustment for inflammation and HOMA2-IR attenuated these associations to ß=0.115 (95%CI 0.030-0.200) and ß=0.163 (95%CI 0.082-0.244) respectively. Multiple mediation analyses showed that inflammation [ß=0.090 (95%CI 0.060-0.126)] and HOMA2-IR [ß=0.179 (95%CI 0.128-0.236)] each explained, independently of one another, a significant portion of the association between WC and C3 (23% and 47%, respectively). Similar mediation by inflammation (19-27%) and HOMA2-IR (37-56%) was found for other adiposity measures. CONCLUSION: Systemic low-grade inflammation and insulin resistance may represent two independent pathways by which body fat leads to elevated C3 levels.
Effect of moderate alcohol consumption on adipokines and insulin sensitivity in lean and overweight men: a diet intervention study
Beulens, J.W.J. ; Zoete, E.C. de; Kok, F.J. ; Schaafsma, G. ; Hendriks, H.F. - \ 2008
European Journal of Clinical Nutrition 62 (2008). - ISSN 0954-3007 - p. 1098 - 1105.
acylation-stimulating protein - randomized controlled-trial - glucose-tolerance - diabetic subjects - wine consumption - resistance - ghrelin - adiponectin - metabolism - humans
Objective: Moderate alcohol consumption is associated with a decreased risk of type II diabetes. This study investigates the effect of moderate alcohol consumption on adipokines and insulin sensitivity. Subjects: Twenty healthy, lean (body mass index (BMI) 18.5¿25 kg/m2; n=11) or overweight (BMI>27 kg/m2; n=9) men (18¿25 years). Methods: Three cans of beer (40 g alcohol) or alcohol-free beer daily during 3 weeks. Results: Adiponectin and ghrelin concentrations increased (P