Bowman M A, Campbell L, Darrow B L, Ellis T M, Suresh A, Atkinson M A
Department of Pathology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville 32610-0275, USA.
Diabetes. 1996 Feb;45(2):205-8. doi: 10.2337/diab.45.2.205.
Prophylactic insulin therapy prevents IDDM in spontaneous animal models of the disease and has shown promise in preventing the disease in humans. Although large clinical trials have been formed to use this therapy, a comparative analysis of the efficiency of different pharmaceutical forms and doses of insulin in preventing IDDM has not been performed, 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 and 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 administration (-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-metabolism-altering low-dose insulin (0.02 U, once daily, regular, n = 8). Furthermore, IDDM was delayed with somatostatin (0.2 microgram, twice daily, n = 11), an agent that suppresses endogenous insulin production. No significant 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 delayed 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-acting (-56%, P = 0.01) and long-acting (-67%, P = 0.02) insulin products and somatostatin (-59%, P = 0.02) compared with diluent-treated controls. These results indicate that both immunological and metabolic (i.e., beta-cell rest) factors may contribute to the beneficial effects of prophylactic insulin therapy.
预防性胰岛素治疗可预防该疾病自发动物模型中的胰岛素依赖型糖尿病（IDDM），并且在预防人类该疾病方面已显示出前景。尽管已经开展了大型临床试验来使用这种疗法，但尚未对不同剂型和剂量的胰岛素预防IDDM的效率进行比较分析，而且所观察到的疾病预防背后的机制尚不清楚。在IDDM的NOD-scid/scid过继转移模型中（将10⁷个新发NOD脾细胞静脉注射到6至8周龄的NOD/scid-scid受体中；转移后6至9天发生胰岛炎，转移后32天100%发生IDDM），生存表（对数秩）分析显示，通过预防性给药（转移后-9至50天）高剂量（改变代谢）的短效（0.5 U，每日一次，常规胰岛素，n = 13）或长效（0.5 U，每日一次，超长效胰岛素，n = 9）胰岛素以及不改变代谢的低剂量胰岛素（0.02 U，每日一次，常规胰岛素，n = 8），可以同等效率地延迟IDDM（与无胰岛素稀释剂相比，每日一次，n = 8）。此外，使用生长抑素（0.2微克，每日两次，n = 11）也可延迟IDDM，生长抑素是一种抑制内源性胰岛素产生的药物。这些药物的预防效果之间未观察到显著差异。在评估何时开始治疗并仍能保持临床疗效时，只有预防性生长抑素治疗在转移后14天开始时可延迟IDDM（n = 10，P = 0.02），而与用稀释剂处理的对照组相比，短效胰岛素方案并未延迟IDDM的发作（n = 8，P = 0.25）。与用稀释剂处理的对照组相比，短效（-56%，P = 0.01）和长效（-67%，P = 0.02）胰岛素产品以及生长抑素（-59%，P = 0.02）使24小时尿C肽水平显著降低。这些结果表明，免疫和代谢（即β细胞休息）因素可能都有助于预防性胰岛素治疗的有益效果。
