Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Endocrinology & Metabolism, type 1 diabetes, hsp60, immunomodulation, intervention therapy, C-peptide, HbA(1c), insulin, randomized controlled trial, BETA-CELL FUNCTION, ANIMAL-MODELS, T-CELLS, CHILDREN, IMMUNOMODULATION, TRANSPLANTATION, PREDNISONE, REMISSION, MELLITUS, C-Peptide, Chaperonin 60, Diabetes Mellitus, Type 1, Double-Blind Method, Drug Therapy, Combination, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Immunologic Factors, Insulin, Peptide Fragments, Peptides, Time Factors, Treatment Outcome, 1103 Clinical Sciences, 3202 Clinical sciences

Abstract:

BACKGROUND: 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. METHODS: 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 HbA(1c) levels and daily insulin dose adjusted for body weight at 2, 6, 12 and 18 months. RESULTS: 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. HbA(1c) 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 One patient was withdrawn from the study possibly owing to a treatment-related adverse event. CONCLUSIONS: 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 HbA(1c) levels or daily insulin requirement. Further investigation on a larger scale is warranted. Copyright (c) 2006 John Wiley & Sons, Ltd.