Complement factor 3 is associated with insulin resistance and with incident type 2 diabetes over a 7-year follow-up period: the CODAM Study.
OBJECTIVE
Immune dysregulation can affect insulin resistance (IR) and β-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 T2DM and 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.


METHODS
Fasting C3, nonesterified fatty acids, glucose, and insulin (the latter two during oral glucose tolerance tests) were measured 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; β = 15.2% [95% CI 12.9-17.6]), hepatic IR (β = 6.1% [95% CI 4.7-7.4]), adipocyte IR (β = 16.0% [95% CI 13.0-19.1]), fasting glucose (β = 1.8% [95% CI 1.2-2.4]), 2-h glucose (β = 5.2% [95% CI 3.7-6.7]), and area under the curve for glucose (β = 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 (β = 0.08 [95% CI 0.02-0.15]) and greater changes in hepatic IR (β = 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.
Department of Internal Medicine, Catharina Hospital, Eindhoven, the NetherlandsCARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the NetherlandsDepartment of Internal Medicine/Laboratory for Metabolism and Vascular Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands nickwlazlo@gmail.com.
Nick
N
Wlazlo
CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the NetherlandsDepartment of Internal Medicine/Laboratory for Metabolism and Vascular Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.
Marleen M J
MM
van Greevenbroek
CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the NetherlandsDepartment of Internal Medicine/Laboratory for Metabolism and Vascular Medicine, Maastricht University Medical Centre, Maastricht, the NetherlandsDepartment of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Centre, Maastricht, the NetherlandsCAPHRI School for Public Health and Primary Care, Maastricht University Medical Centre, Maastricht, the Netherlands.
Isabel
I
Ferreira
Division of Human Nutrition, Section of Nutrition and Epidemiology, Wageningen University, Wageningen, the Netherlands.
Edith J M
EJ
Feskens
CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the NetherlandsDepartment of Internal Medicine/Laboratory for Metabolism and Vascular Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.
Carla J H
CJ
van der Kallen
CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the NetherlandsDepartment of Internal Medicine/Laboratory for Metabolism and Vascular Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.
Casper G
CG
Schalkwijk
Department of Internal Medicine, Catharina Hospital, Eindhoven, the Netherlands.
Bert
B
Bravenboer
CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the NetherlandsDepartment of Internal Medicine/Laboratory for Metabolism and Vascular Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.
Coen D A
CD
Stehouwer
D017667:Adipocytes / Q000378:metabolism; D000368:Aged; D001786:Blood Glucose; D015331:Cohort Studies; D003176:Complement C3 / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D005215:Fasting; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D005951:Glucose Tolerance Test; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies
D001786:Blood Glucose; D003176:Complement C3; D005230:Fatty Acids, Nonesterified; D007328:Insulin