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 ([Ca(2+)](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 [Ca(2+)](i)-mobilizing activity (-/-), sera from 6 patients with type 2 diabetes that was CD38Ab-positive and had [Ca(2+)](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 micro U/ml in control, +/+, and -/- sera, respectively; the corresponding IR at 16.7 mmol/l glucose was 72 +/- 25, 204 +/- 56, and 80 +/- 32 micro U/ml). At 3 days, IR at 3.3 mmol/l glucose was 42 +/- 18, 27 +/- 11, and 43 +/- 24 micro U/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 micro U/ml, respectively. After 7 days of exposure, the corresponding IR at 3.3 mmol/l glucose was 40 +/- 11, 28 +/- 12, and 35 +/- 15 micro U/ml, respectively, whereas at 16.7 mmol/l glucose it was 79 +/- 39, 39 +/- 17, and 62 +/- 39 micro U/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 [Ca(2+)](i)-mobilizing activity impairs beta-cell function and viability in cultured human pancreatic islets.