Activation of the alternative complement pathway occurs in obese T2DM patients and is enhanced in the post-prandial hyperchylomicronic condition, which induces overproduction of ASP and C3a-mediated tissue inflammation. Therefore, complement-mediated inflammation may contribute to the acceleration of diabetic microangiopathy in addition to the development of macroangiopathy.

Diabetic complication is comprised of a wide variety of pathophysiological factors involving proinflammatory cytokines, adipokines, and oxidative stress, among others. Each of these complications differs in their incidence and the stage of their occurrence. We examined cytokines and stress markers in 48 patients with type 2 diabetes mellitus and compared the difference of their contribution to pathogenesis between nephropathy and other diabetic complications. Hemoglobin A1c correlated with the level of low-density lipoprotein-cholesterol, and significantly elevated in the severe macroangiopathy group. Cystatin C increased in the severe microangiopathy groups but did not increase in the macroangiopathy group. The levels of interleukin 18 (IL-18), high-sensitive CRP (H-CRP), liver-type fatty acid binding protein, and 8-hydroxy-2-deoxyguanosine increased in the severe microangiopathy group. These data suggest the participation of proinflammatory signaling and oxidative stress in the progression of microangiopathy. In particular, IL-18 and H-CRP were significantly elevated only in the severe nephropathy group but did not significantly elevate in other complications. These data suggest another effect of IL-18 on glomerulus in addition to its proinflammatory effect. In conclusion, we propose that IL18 has a specific role that contributes more closely to the progression of diabetic nephropathy than other diabetic complications.

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Background/Aims: Mannose-binding lectin (MBL) is characteristic of an acute-phase-reacting protein like C-reactive protein (CRP). However, the prognostic value of the serum MBL level has not been examined. The aim of this study was to evaluate whether the serum MBL level can predict all-cause mortality in hemodialysis (HD) patients. Methods: A total of 131 patients without active infection, who had been on maintenance HD for at least 2 years, were included in this study. The serum MBL, high-sensitivity CRP (hs-CRP) level, nutrition markers, and biochemical parameters were measured in June 1999. The cohort was then followed prospectively for 36 months, and clinical data were recorded. Results: The MBL level of the 131 HD patients was 9.054 ± 5.115 µg/ml (mean ± SD). During the follow-up period, 18 patients (9 males and 9 females) died and 113 (64 males and 49 females) survived. The two leading causes of death were cardiovascular events (n = 6, 33.3%) and infection (n = 4, 22.2%). The serum MBL level was significantly lower among the nonsurvivors (6.596 ± 4.990 µg/ml) than among the survivors (9.445 ± 5.046 µg/ml; p < 0.05). There was a significant, although very weak, correlation between the MBL level and albumin level (p < 0.05), but there was no correlationbetween the MBL level and the hs-CRP level. The patients were divided into two groups according to the serum MBL level (<5 and >5 µg/ml). Multivariate analysis of factors predicting all-cause mortality in multivariate logistic regression analysis identified a serum MBL level <5 µg/ml as a variable that independently predicted all-cause mortality (adjusted odds ratio: 7.632; 95% CI: 2.244–25.961; p = 0.0011). Other significant and independent predictors for mortality included the hs-CRP level (every 100 µg/dl increase), hypertension and diabetes mellitus. Conclusions: Our findings suggest that the serum MBL level is a significant predictor of outcome in HD patients. HD patients with a low level of serum MBL should be carefully monitored.

Acylation stimulating protein (ASP) is a fragment of the third component of complement (C3) that is generated in the presence of chylomicron, and plays a role in the synthesis of triacylglycerol by transporting free fatty acids into adipocytes. However, the precise mechanism of ASP generation, especially the role of chylomicron in ASP generation, is unknown. We examined the mechanism through which chylomicron induces ASP generation. Ultracentrifugationally separated chylomicron was incubated with normal human serum (NHS) under various conditions, and the amounts of complement activation products and ASP in the incubation mixture were determined by enzyme-linked immunosorbent assay (ELISA). Upon incubation of NHS with various amounts of chylomicron for 120 min, ASP was generated in a dose-dependent manner. The time course of the production of ASP was similar to the time course of the C3 tick-over phenomenon that occurred by depletion of factor H from the serum. The complement activation induced by chylomicron was different from the usual complement activation that occurs under the regulation of factor H and factor I with respect to the time course and the amount of ASP produced. Our results indicate that chylomicron accelerates C3 tick-over by regulating the role of factor H, leading to the overproduction of ASP.