IMMUNOLOGICAL AND METABOLIC EFFECTS OF PROPHYLACTIC INSULIN THERAPY IN THE NOD-SCID SCID ADOPTIVE TRANSFER MODEL OF IDDM/

Prophylactic insulin therapy prevents IDDM in spontaneous animal model s of the disease and has shown promise in preventing the disease in hu mans. Although large clinical trials have been formed to use this ther apy, a comparative analysis of the efficiency of different pharmaceuti cal forms and doses of insulin in preventing IDDM has not been perform ed, and the mechanism underlying the observed prevention of disease is unknown. In the NOD-scid/scid adoptive transfer model of IDDM (10(7) new-onset NOD splenocytes injected intravenously into 6- to 8-week NOD /scid-scid recipients; insulitis develops at 6-9 days post-transfer an d 100% IDDM by 32 days post-transfer), life-table (log-rank) analyses revealed that IDDM can be delayed (compared with insulin-free diluent, once daily, n = 8) with equivalent efficiency by prophylactic adminis tration (-9-50 days post-transfer) of high (metabolism-altering) doses of short-acting (0.5 U, once daily, regular, n = 13) or long-acting ( 0.5 U, once daily, ultralente, n = 9) insulin as well as non-metabolis m-altering low-dose insulin (0.02 U, once daily, regular, n = 8). Furt hermore, IDDM was delayed with somatostatin (0.2 mu g, twice daily, n = 11), an agent that suppresses endogenous insulin production. No sign ificant difference was seen between the preventative effects of these agents. In an assessment of when therapies can be initiated and still maintain clinical efficiency, only prophylactic somatostatin therapy d elayed IDDM (n = 10, P = 0.02) when initiated at 14 days post-transfer , whereas the short-acting insulin regimen did not retard the onset of IDDM (n = 8, P = 0.25) compared with diluent-treated controls. The 24 -h urinary C-peptide levels were significantly reduced with short-acti ng (-56%, P = 0.01) and long-acting (-67%, P = 0.02) insulin products and somatostatin (-59%, P = 0.02) compared with diluent-treated contro ls. These results indicate that both immunological and metabolic (i.e. , beta-cell rest) factors may contribute to the beneficial effects of prophylactic insulin therapy.