Abstract

Autoantibodies against CD38 (adenosine-5′-diphosphate[ADP]-ribosyl cyclase/cyclic ADP-ribose hydrolase) have been described in 10–12% of patients with type 2 diabetes. In human islets, anti-CD38 autoantibodies (CD38Abs) acutely stimulate insulin release (IR) and increase the cytosolic calcium concentration ([Ca²⁺]_i). Whether CD38Abs affect human islet cell function and survival upon prolonged in vitro exposure is not known. We cultured human islets for up to 7 days in the presence of sera from 10 patients with type 2 diabetes that had neither CD38Ab- nor [Ca²⁺]_i-mobilizing activity (−/−), sera from 6 patients with type 2 diabetes that was CD38Ab-positive and had [Ca²⁺]_i-mobilizing activity (+/+), or no sera (control). At baseline, +/+ sera caused a significant (P < 0.002) acute stimulation of IR (IR at 3.3 mmol/l glucose was 45 ± 19, 84 ± 24, and 34 ± 12 μU/ml in control, +/+, and −/− sera, respectively; the corresponding IR at 16.7 mmol/l glucose was 72 ± 25, 204 ± 56, and 80 ± 32 μU/ml). At 3 days, IR at 3.3 mmol/l glucose was 42 ± 18, 27 ± 11, and 43 ± 24 μU/ml (P = 0.0003) for control, +/+, and −/− sera, respectively, whereas at 16.7 mmol/l glucose, it was 95 ± 76, 45 ± 35, and 76 ± 42 μU/ml, respectively. After 7 days of exposure, the corresponding IR at 3.3 mmol/l glucose was 40 ± 11, 28 ± 12, and 35 ± 15 μU/ml, respectively, whereas at 16.7 mmol/l glucose it was 79 ± 39, 39 ± 17, and 62 ± 39 μU/ml. At both 3 and 7 days, IR still increased when switching from 3.3 to 16.7 mmol/l glucose (P < 0.0003), and incubation with +/+ sera induced a significant decrease in the insulin response (P < 0.002). At 7 days, the number of dead cells (as evaluated by an enzyme-linked immunosorbent assay technique) differed significantly between control (1.2 ± 0.3 OD units) cells, islets exposed to −/− sera (1.4 ± 0.1), and islets coincubated with +/+ sera (1.9 ± 0.4, P < 0.01). We conclude that prolonged exposure of human islets to sera positive for the presence of CD38Abs with [Ca²⁺]_i-mobilizing activity impairs β-cell function and viability in cultured human pancreatic islets.