Complement C3 Is a Risk Factor for the Development of Diabetes

Abstract

Cross-sectional studies have reported strong correlations between plasma levels of complement C3, insulin, and glucose. This prospective study explored whether elevated levels of C3, C4, and other inflammationsensitive plasma proteins (ISPs; fibrinogen, orosomucoid, ␣1-antitrypsin, haptoglobin, and ceruloplasmin) are associated with the development of diabetes. Plasma proteins were measured in 2,815 nondiabetic healthy men, age 38 -50 years, who were reexamined after a mean follow-up of 6.1 years. Diabetes development (n ‫؍‬ 123) was studied in relation to baseline levels of plasma proteins. After adjusting for age, screening year, and glucose at baseline, the odds ratio (95% CI) for developing diabetes was 1.00, 2.4 (1.1-5.3), 2.9 (1.4 -6.0), and 5.6 (2.8 -10.9), respectively, for men with C3 in the 1st, 2nd, 3rd, and 4th quartiles (trend: P < 0.00001). Fibrinogen, haptoglobin, C4, and the number of elevated ISPs were also related to future diabetes in this model. Only C3 was significantly associated with diabetes development after further adjustments for potential confounders, including BMI, insulin, and other inflammatory markers. We concluded that the risk of developing diabetes is related to levels of complement C3. Diabetes 54:570 -575, 2005 C omplement C3 and C4 are the major plasma proteins of the immune system complement pathways. The synthesis of these proteins is increased in response to inflammation and infection but at a slower rate than for traditional acute phase proteins (1,2). Both C3 and C4 have shown substantial correlations with obesity (3-6), and high gene expression of these complement components has been reported in omental adipose tissue in obese men (3). High C3 levels have been reported in subjects with diabetes and insulin resistance (6 -9).It has been shown that the cleavage product of C3, acylation-stimulating protein (ASP), is a paracrine metabolic factor that stimulates the uptake of glucose and fat storage in human adipose tissue (10 -12). ASP deficiency in mice has been associated with resistance to weight gain on a high-fat diet, despite increased food intake (13). However, whether C3 is associated with an increased risk of developing diabetes is unknown.Several inflammatory markers have been associated with the incidence of diabetes, including C-reactive protein (CRP) (14 -17), orosomucoid (18), sialic acid (18), white blood cells (18,19), and interleukin (IL)-6 (20). It has been proposed that diabetes is a disease of the innate immune system (21). However, several studies have reported a nonsignificant relation between inflammation and incidence of diabetes. Negative or inconclusive results have been reported for CRP (17,22), haptoglobin (18), fibrinogen (16,18), white blood cells (16), and ␣1-antitrypsin (18). It is unclear whether the discrepancies among studies are related to differences with respect to inflammatory markers, study populations, or other factors.Previous substudies from the Malmö Preventive Study have shown that the risk of developing cardiovascular diseases,...

New insights into complement C3 and inflammation in hypertension

“…Even at baseline, the levels of C3 and C4 correlated well with blood pressure. This is consistent with their previous report that baseline C3 levels predict the future development of diabetes mellitus, 28 as well as other studies that have demonstrated high baseline CRP levels predicting the subsequent development of hypertension. 29 The study by Engstrom et al 27 further emphasises the role of inflammation in the development of hypertension.…”

Weight gain in relation to plasma levels of complement factor 3: results from a population-based cohort study

“…The distributions of the other plasma proteins (fibrinogen, haptoglobin, ceruloplasmin, orosomucoid, α1-antitrypsin) have been presented elsewhere [22]. The correlation between C3 and C4 was r=0.47 and the correlations between C3 and the other proteins were all below 0.3 in this cohort [16].…”

“…A study from this cohort showed that high levels of fibrinogen, ceruloplasmin, α1-antitrypsin, orosomucoid and haptoglobin were associated with weight gain [15]. However, C3 shows only modest correlations with these inflammatory markers (all r<0.3) [16]. The relationship between C3 and weight gain was essentially unchanged after adjustment for inflammatory proteins and, conversely, the number of elevated ISPs was associated with weight gain even after adjustments for C3.…”

“…However, the correlations between levels of C3 and levels of these inflammatory markers are small and we recently reported that C3 is associated with incidence of diabetes independently of these proteins [16]. Based on the findings from animal models, we explored the hypothesis that C3 could be associated with future weight increase independently of other inflammatory markers.…”

Associations of low-grade inflammation with physical activity, fitness and fatness in prepubertal children; the European Youth Heart Study

“…Both C-reactive protein and fibrinogen have been recognized as cardiovascular risk factors, and nowadays there is an increasing evidence about the link between C3 and C4, and vascular disease. [51][52][53] A 4-year follow-up study in adults showed that C3 and C4 increased threefold the C-reactive protein-related incidence of atrial fibrillation. 53 Moreover, it was also reported that in the absence of elevated complement components, high C-reactive protein was not associated with atrial fibrillation.…”