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

N. Wlazlo, M.M.J. van Greevenbroek, I. Ferreira, E.J.M. Feskens, C.J.H. van der Kallen, C.G. Schalkwijk, B. Bravenboer, C.D.A. Stehouwer

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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.
Original languageEnglish
Pages (from-to)1900-1909
JournalDiabetes Care
Issue number7
Publication statusPublished - 2014


  • 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


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