Huurman Volkert A L, Decochez Katelijn, Mathieu Chantal, Cohen Irun R, Roep Bart O
Department of Immunohematology and Blood transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Diabetes Metab Res Rev. 2007 May;23(4):269-75. doi: 10.1002/dmrr.691.
Type 1 diabetes results from a T-cell mediated autoimmune destruction of insulin-producing pancreatic beta-cells. The 60-kDa heat-shock protein (hsp60) is one of the known target self-antigens. An immunogenic peptide from hsp60, p277, arrested beta-cell destruction and maintained insulin production in newly diabetic non-obese diabetic (NOD) mice. A randomized, double-blind, phase Ib/II study of peptide treatment was undertaken in recent onset type 1 diabetes patients with remaining insulin production.
Forty-eight recent onset type 1 diabetes patients were assigned subcutaneous injections of 0.2, 1.0 or 2.5 mg peptide DiaPep277 (n = 12 per dosage) at entry, and 1, 6 and 12 months, or four placebo injections (n = 12). The primary clinical endpoints were safety and efficacy (glucagon-stimulated C-peptide production at 6 and 12 months); secondary endpoints were HbA1c levels and daily insulin dose adjusted for body weight at 2, 6, 12 and 18 months.
C-peptide levels decreased over time in all groups except the 2.5 mg-treated. The decrease in C-peptide production was less in treated patients versus placebo, mostly in the 2.5 mg group. HbA1c increased significantly in the 1.0 mg group and in the 2.5 mg group at 2 and 18 months, respectively. No differences were seen in daily insulin doses. One patient was withdrawn from the study possibly owing to a treatment-related adverse event.
Multiple DiaPep277 peptide administration seems safe and may have a beneficial effect on C-peptide levels over time, but this finding is not supported by lower HbA1c levels or daily insulin requirement. Further investigation on a larger scale is warranted.
1型糖尿病是由T细胞介导的对产生胰岛素的胰腺β细胞进行自身免疫破坏所致。60 kDa热休克蛋白（hsp60）是已知的靶自身抗原之一。hsp60的一种免疫原性肽p277可阻止β细胞破坏，并维持新患糖尿病的非肥胖糖尿病（NOD）小鼠的胰岛素分泌。对近期发病且仍有胰岛素分泌的1型糖尿病患者进行了一项肽治疗的随机、双盲、Ib/II期研究。
48例近期发病的1型糖尿病患者在入组时、第1、6和12个月皮下注射0.2、1.0或2.5 mg肽DiaPep277（每组12例），或注射4次安慰剂（12例）。主要临床终点是安全性和有效性（6个月和12个月时胰高血糖素刺激的C肽分泌）；次要终点是2、6、12和18个月时的糖化血红蛋白（HbA1c）水平以及根据体重调整的每日胰岛素剂量。
除2.5 mg治疗组外，所有组的C肽水平均随时间下降。与安慰剂组相比，治疗组患者C肽分泌的下降幅度较小，主要是在2.5 mg组。1.0 mg组和2.5 mg组分别在2个月和18个月时HbA1c显著升高。每日胰岛素剂量未见差异。1例患者因可能与治疗相关的不良事件退出研究。
多次给予DiaPep277肽似乎是安全的，且可能随时间推移对C肽水平产生有益影响，但较低的HbA1c水平或每日胰岛素需求量并未支持这一发现。有必要进行更大规模的进一步研究。
