Evidence for complement-dependent and -independent inhibition of insulin secretion from clonal beta-cells incubated in the presence of sera of newly diagnosed IDDM patients

Abstract

There are conflicting reports on the effect of serum from patients with insulin-dependent diabetes mellitus (IDDM) or normal human serum on -cell function and insulin secretion. Here, we report that the sera of newly diagnosed IDDM patients potently suppresses insulin secretion from a clonal rat pancreatic -cell line (BRIN-BD11), but do not alter cell viability. Indeed, the viability of the -cells was not significantly different between cells cultured in 10% (v/v) IDDM sera, normal human sera, or fetal calf serum after 24, 48 and 72 h. Alanine-stimulated insulin secretion from cells cultured for 24 h in (10% v/v) IDDM patient sera was reduced to 48% of that secreted from cells cultured in (10% v/v) normal human sera. After depletion of the complement components C1q and C3, the inhibition of insulin secretion induced by IDDM patient sera was significantly reversed (no significant difference was observed between cells cultured in complementdepleted IDDM patient sera and cells cultured in normal human sera or complement-depleted normal human sera).The concentration of glutamic acid decarboxylase (GAD) autoantibodies was markedly increased in the sera of six out of nine newly diagnosed IDDM patients in this study, whereas insulin auto-antibodies (IAA) were detected in the sera of three of the nine patients and islet-cell antibodies (ICA) in the sera of five of them. In addition, the concentration of soluble terminal complement complexes (SC5b-9) was greater in some of the -cell culture media samples after 24 h incubation when the incubation medium was supplemented with IDDM patient sera than when supplementation was with normal human sera.We propose that the mechanism of sera-induced inhibition of insulin secretion from clonal -cells may involve complement-and cytokine-stimulated intracellular events that attenuate the metabolite-induced secretory process.

Expression of the adrenomedullin binding protein, complement factor H, in the pancreas and its physiological impact on insulin secretion

“…For instance, C1q and C3 seem to be responsible for the insulin secretion suppression induced by serum from newly diagnosed type 2 diabetic patients (Conroy et al 2000).…”

The role of the complement system in metabolic organs and metabolic diseases

“…In vitro , treatment of a rat pancreatic β-cell line with serum from newly diagnosed T1DM patients inhibited their capacity for insulin secretion [41, 42], a phenomenon that was dependent on C1q and C3, since depletion of these complement components reversed the inhibitory effect of the serum of T1DM patients [41]. Furthermore, complement activation, as assessed by the presence of MAC in the serum, was higher in newly diagnosed patients with T1DM than in control individuals, whereas conditioned medium of isolated rat islet cells treated with sera from T1DM patients displayed increased terminal complement activation when compared to medium from cells treated with control serum [41, 43]. These observations have led to a hypothesis that islet apoptosis in T1DM may be partially mediated by complement activation [41, 43, 44].…”

“…Furthermore, complement activation, as assessed by the presence of MAC in the serum, was higher in newly diagnosed patients with T1DM than in control individuals, whereas conditioned medium of isolated rat islet cells treated with sera from T1DM patients displayed increased terminal complement activation when compared to medium from cells treated with control serum [41, 43]. These observations have led to a hypothesis that islet apoptosis in T1DM may be partially mediated by complement activation [41, 43, 44]. …”

“…In contrast, increased complement action can contribute to metabolic pathology. In the pancreas, complement activation can contribute to β-cell apoptosis in T1DM [41, 43, 44, 53] and T2DM [33, 34]. In obesity, anaphylatoxins promote leukocyte recruitment to the AT, thereby facilitating inflammation and the associated insulin resistance [83, 84, 86].…”

Relationship Between Obesity and Immune System a Review Article

“…In the pancreas, complement activation can contribute to β-cell apoptosis in T1DM [44,45] and T2DM [46]. In obesity, anaphylatoxins promote leukocyte recruitment to the AT, thereby facilitating inflammation and the associated insulin resistance [39,47].…”