Further studies on IDDM serum induced pancreatic β cell death- evidence for a cytoprotective role for glutamine

Insulin-dependent diabetes mellitus (IDDM) is caused by macrophage, T-cell, B-cell and humoral factor mediated damage of the insulin-producing β-cells of the islets of Langerhans. Okamoto (1981, Mol Cell Biochem 37 43-61)proposed a unifying model for the mechanism of β-cell destruction. Central to this model are breaks in nuclear DNA of β-cells, inducing activation of the enzyme poly (ADP-ribose) synthetase (PARS), which poly ADP-ribosylates nuclear proteins using NAD⁺ as a substrate. As a result intracellular NAD⁺ & ATP levels fall dramatically, initially inhibiting insulin secretion and eventually resulting in β-cell death. We have evidence from studies with both primary islet cells (isolated from male Wistar rats) and the insulin secreting β-cell Unes, BRIN BD11 and CRI-G1, that there is an increase in DNA fragmentation followed by an increase in cell death when β-cells are incubated in the presence of newly diagnosed diabetic serum. These results support the findings of Berggren et al. (1993, Science 261 86-90). We propose that β-cell death can result from complement activation in diabetic serum due to the presence of complement binding auto antibodies. We report that protection of the β-cells from IDDM serum induced cell death can be achieved by provision of the metabolic fuel glutamine, which may boost intracellular ATP.