The complement system in Type 1 (insulin-dependent) diabetes

Abstract

The complement proteins C1q, r, s, C2, C4, C3, factor B, C5, C6, and the inhibitors, C1 inhibitors, factors I and H were measured in 35 patients with recently diagnosed Type 1 (insulin-dependent) diabetes, 76 patients with longer-duration disease (30 with complications) and 43 first-degree healthy relatives. We found that C1q, C4 and C3 were reduced significantly in all groups of patients (p less than 0.001 for each protein in recent onset and uncomplicated patients; p less than 0.01, p less than 0.01 and p less than 0.05 respectively, for patients with complications) compared to 60 control subjects and that C4 was also reduced in healthy relatives (p less than 0.001). C4 allotypes were examined in 63 subjects (selected from the patient groups) in order to clarify the role of null alleles in the production of the C4 abnormality. These showed serum C4 to be reduced significantly in 50 patients without null alleles (patient mean 0.24 g/l; control subject mean 0.34 g/l) (p less than 0.0001), although levels were lowest in the 13 patients with one or more null alleles (mean 0.19 g/l). Finally, to examine the metabolic basis for the low concentrations of C4 and C3, the turnover of highly-purified, radiolabelled C4 and C3 was measured in seven recently diagnosed patients; four of these had low levels of C4. The data showed that three out of four of these patients had reduced synthesis of C3 and C4 and normal values for fractional catabolic rate. Two patients showed features of C4 hypercatabolism. We conclude that several early complement proteins are reduced in Type 1 diabetes, irrespective of duration or complications.(ABSTRACT TRUNCATED AT 250 WORDS)

A novel mechanism for hypofibrinolysis in diabetes: the role of complement C3

“…This is consistent with previous work showing that improved glycaemic control in diabetes is associated with reduction in inflammatory markers [27]. Studies on C3 levels in autoimmune diabetes showed contradictory results ranging from elevated C3 [28,29], to normal or reduced levels [30]. In the current study, samples were collected from individuals who had the condition for longer than 5 years, minimising the risk of an active autoimmune process interfering with C3 levels.…”

The behaviour of human vitronectin in vivo: effects of complement activation, conformation and phosphorylation

“…Presumably this rapid plasma disappearance reflects the multifunctional nature of vitronectin with its capacity to be activated by a number of agents to form multimolecular complexes. In comparison with results obtained previously for other human complement proteins in rabbits such as C3 (T 1=2 , 35-40 h [26] ), and C9 (T 1=2 , 20 . 6-29 .…”

“…A native but spontaneously multimerized 125 I-labelled preparation was also rapidly cleared from the circulation, with a concomitant increase in the release of free 125 I, so that the rapid clearance of urea activated vitronectin was not simply a function of its treatment. These and other data [13,26] demonstrate the sensitivity of in vivo metabolic parameters of proteins to their structure. We did not specifically investigate the fate of vitronectin sequestered by organs, but it remains likely that the spleen, lung and liver, or the reticuloendothelial elements therein, are sites of its metabolism.…”

Two distinct HLA-DR3 haplotypes are associated with age related heterogeneity in Type 1 (insulin-dependent) diabetes

“…Charlesworth et al [26] have recently demonstrated in young diabetic patients reduced serum levels of several complement proteins which partially, although not exclusively, depended on the presence of null alleles. This observation and our data which associate C4BQO by itself with young age of onset are in accordance with the hypothesis of a relationship between diminished protection against viruses due to a defective complement mechanism and early-onset diabetes, raised already several years ago [27].…”