Insulin secretion by pancreas of athymic mice injected with peripheral mononuclear cells from insulin-dependent diabetic patients.

We studied the effect of peripheral blood mononuclear cells (PBMNC) from insulin-dependent diabetic (IDDM) children on the insulin secretion pattern of the pancreas from recipient athymic mice. PBMNC from healthy controls or IDDM patients in different stages of disease were injected into athymic mice. PBMNC from newly diagnosed IDDM children elicited basal nonfasting hyperglycemia and in vitro inhibition of the first and second phases of glucose-stimulated insulin secretion in recipient mice. Animals injected with cells from chronically IDDM children showed normoglycemia, abnormal tolerance to glucose, and inhibition of first-phase insulin secretion. Mitomycin C treatment of MNC from IDDM patients abolished insulin secretion inhibition in recipient mice. PBMNC from newly diagnosed and chronically IDDM patients showed positive anti-beta-cell cellular immune aggression. Mice injected with cells from patients during the remission period showed normoglycemia and no alteration of insulin secretion patterns. When relapsed to their former clinical stage, injection of the cells significantly inhibited first-phase glucose-induced insulin secretion in recipients. PBMNC from newly diagnosed IDDM patients were found to migrate to the pancreas of recipient mice preferably as compared with cells from controls. Cells from chronically IDDM patients cultured with concanavalin A (Con A) increased insulin secretion inhibition; despite this, cells from children during the remission period cultured with Con A failed to modify insulin secretion in recipients. These results show that injection of PBMNC from diabetic patients leads to insulin secretion impairment in recipient mice pancreas, and provide a basis for the study of mechanisms involved in the onset and modulation of anti-beta-cell cellular immune aggression induced by human PBMNC.

Beta-cell function in mice injected with mononuclear splenocytes from multiple-dose streptozotocin diabetic mice.

Multiple low doses of streptozotocin (mid sz 40 mg/kg/day, five consecutive days) induce autoimmune diabetes in mice. The aim of the present work was to study beta-cell function in mice injected with splenocytes from mid-sz diabetic mice. Mononuclear splenocytes (MS) from control or diabetic donors were injected into syngeneic C57BL/6J healthy mice (5 x 10(7) MS, ip). MS from diabetic donors did not produce basal hyperglycemia, but they induced abnormal ip glucose tolerance in recipient mice. These "diabetic" MS were also preferentially trapped by the recipient's pancreas. Perifused pancreas from mice injected with MS from mid sz-diabetic donors showed a diminished first and second phase of glucose-induced insulin secretion after 15 days of the cell injection. At this time, pancreatic insulin content among MS recipients did not differ from that found in controls or diabetic donors. Diabetic MS treated with Mitomycin C prior to transfer did not inhibit insulin secretion in recipient mice. Injection of MS from mice made diabetic by a single high sz dose (200 mg/kg) did not induce any alterations of the insulin secretion in recipients. There is enough evidence when using athymic and euthymic (BALB/c nu/nu and +/nu) mice to suggest that proliferation of the injected splenocytes enhanced the progression to the diabetic state, and that both donor and recipient T lymphocytes played an important part in this progression. The results suggest that injection of MS from mid sz-diabetic mice interfere with glucose-stimulated insulin secretion in recipient mice and provide a basis for the study of the mechanisms involved in the onset and modulation of autoimmune pancreatic aggression.