Elevated Properdin and Enhanced Complement Activation in First-Degree Relatives of South Asian Subjects With Type 2 Diabetes

Abstract

OBJECTIVEEmerging data implicate activation of the complement cascade in the pathogenesis of type 2 diabetes. The objective of the current study was to evaluate the relationships between components of the complement system, metabolic risk factors, and family history of type 2 diabetes in healthy South Asians.RESEARCH DESIGN AND METHODSWe recruited 119 healthy, first-degree relatives of South Asian subjects with type 2 diabetes (SARs) and 119 age- and sex-matched, healthy South Asian control subjects (SACs). Fasting blood samples were taken for measurement of complement factors and standard metabolic risk factors.RESULTSSARs were characterized by significantly higher properdin (mean concentration 12.6 [95% CI 12.2–13.1] mg/L vs. SACs 10.1 [9.7–10.5] mg/L, P < 0.0001), factor B (187.4 [180.1–195.0] mg/L vs. SACs 165.0 [158.0–172.2] mg/L, P < 0.0001), and SC5b-9 (92.0 [86.1–98.3] ng/mL vs. SACs 75.3 [71.9–78.9] ng/mL, P < 0.0001) and increased homeostasis model assessment of insulin resistance (2.86 [2.61–3.13] vs. SACs 2.31 [2.05–2.61], P = 0.007). C-reactive protein did not differ between SARs and SACs (P = 0.17). In subgroup analysis of 25 SARs and 25 SACs with normal oral glucose tolerance tests, properdin, factor B, and SC5b-9 remained significantly elevated in SARs.CONCLUSIONSIncreased properdin and complement activation are associated with a family history of type 2 diabetes in South Asians independent of insulin resistance, and predate the development of impaired fasting glucose and impaired glucose tolerance. Properdin and SC5b-9 may be novel biomarkers for future risk of type 2 diabetes in this high-risk population and warrant further investigation.

Complement Alternative Pathway Activation in Human Nonalcoholic Steatohepatitis

“…Recently, elevated plasma levels of properdin and factor B were found in subjects at risk of developing type 2 diabetes [20] . This is consistent with a role for the alternative pathway in NASH, since insulin resistance is an independent risk factor for NASH [21] .…”

High glucose‐induced complement component 3 up‐regulation via RAGE‐p38MAPK‐NF‐κB signalling in astrocytes: In vivo and in vitro studies

“…Complement is the critical part of the innate immunity system that identifies pathogens and damaged cells, which initiates the phagocytosis and proinflammatory responses. Elevated complement proteins in circulation of patients with diabetes have been considered as strong predictors of the development of diabetes and related complications . Although brain was traditionally considered as an immune‐privileged organ, it has been recently recognized that neuronal cells in the CNS could synthesize many complement system components, which maintain immunosurveillance and biological activities in the brain .…”

“…Elevated complement proteins in circulation of patients with diabetes have been considered as strong predictors of the development of diabetes and related complications. 11 Although brain was traditionally considered as an immune-privileged organ, it has been recently recognized that neuronal cells in the CNS could synthesize many complement system components, which maintain immunosurveillance and biological activities in the brain. 12,13 Specifically, complement component 3 (C3), the critical central component of three complement cascades, 14 not only mediates the synaptic pruning and synaptic refinement during brain development, 15 but also exerts detrimental effects on the CNS in the adulthood.…”

Polymorphisms in genes related to the complement system and antibody-mediated cardiac allograft rejection

“…34,35 It has been shown that properdin deficiency results in an increased risk of infection; infection mortality rates of 33%-75% have been reported. 36 It has been hypothesized that higher levels of properdin, such as the levels shown in our AMR cohort, result in a higher capacity to activate the alternative pathway and may therefore represent activation of the alternative pathway in relevant situations, such as cardiovascular events, 37 type 2 diabetes mellitus, 38 and AMR. Human studies on the alternative pathway factor properdin in relation to transplantation are scarce.…”