氨基末端特异性抗谷氨酸脱羧酶（GAD65）自身抗体与GAD65抗体阳性且易发生酮症的糖尿病患者的β细胞功能储备及较轻临床表型的关联

Association of amino-terminal-specific antiglutamate decarboxylase (GAD65) autoantibodies with beta-cell functional reserve and a milder clinical phenotype in patients with GAD65 antibodies and ketosis-prone diabetes mellitus.

作者信息

Hampe Christiane S, Nalini Ramaswami, Maldonado Mario R, Hall Tyler R, Garza Gilberto, Iyer Dinakar, Balasubramanyam Ashok

机构信息

Robert H. Williams Laboratory, Department of Medicine, University of Washington, Seattle, Washington 98195, USA.

出版信息

J Clin Endocrinol Metab. 2007 Feb;92(2):462-7. doi: 10.1210/jc.2006-1719. Epub 2006 Nov 7.

DOI:10.1210/jc.2006-1719

PMID:17090641

Abstract

CONTEXT

We previously characterized patients presenting with diabetic ketoacidosis prospectively into four subgroups of ketosis-prone diabetes mellitus (KPDM), based on the presence or absence of beta-cell autoimmunity (A+ or A-) and beta-cell functional reserve (B+ or B-). The A+B- KPDM subgroup comprises patients with classic, autoimmune type 1 diabetes, whereas the A+B+ KPDM subgroup has only partial beta-cell loss and a distinct clinical phenotype.

OBJECTIVE

We hypothesized that epitope specificity of autoantibodies directed against the 65-kDa isoform of glutamate decarboxylase (GAD65) reflects differences in beta-cell destruction.

DESIGN

Sera of sequential GAD65Ab-positive KPDM patients admitted for diabetic ketoacidosis (n = 36) were analyzed for their epitope recognition using five GAD65-specific recombinant Fab and their ability to inhibit GAD65 enzymatic activity. All patients were followed longitudinally to assess beta-cell functional reserve and insulin dependence.

RESULTS

Binding to an amino-terminal epitope defined by monoclonal antibody DPD correlated positively with fasting serum C-peptide levels at baseline (P = 0.0008) and after 1 yr (P = 0.007). Binding to the DPD-defined epitope also correlated positively with area under the curve for C-peptide after glucagon stimulation (P = 0.007) and with homeostasis model assessment percent B at 1 yr (P = 0.03). Binding to the DPD-defined epitope was significantly stronger in A+B+ than in A+B- patients (P = 0.001). Sera of 16 patients (44%) significantly inhibited GAD65 enzymatic activity, but this did not correlate with beta-cell function.

CONCLUSION

DPD-defined epitope specificity is correlated directly with preserved beta-cell functional reserve in GAD65Ab-positive patients and is associated with the milder clinical phenotype of A+B+ KPDM.

摘要

背景

我们之前基于β细胞自身免疫（A+或A-）和β细胞功能储备（B+或B-）的有无，将糖尿病酮症酸中毒患者前瞻性地分为四个酮症倾向糖尿病（KPDM）亚组。A+B- KPDM亚组包括经典的自身免疫性1型糖尿病患者，而A+B+ KPDM亚组仅有部分β细胞丢失且具有独特的临床表型。

目的

我们假设针对谷氨酸脱羧酶65 kDa异构体（GAD65）的自身抗体的表位特异性反映了β细胞破坏的差异。

设计

对因糖尿病酮症酸中毒入院的连续GAD65Ab阳性KPDM患者（n = 36）的血清，使用五种GAD65特异性重组Fab分析其表位识别情况以及抑制GAD65酶活性的能力。对所有患者进行纵向随访，以评估β细胞功能储备和胰岛素依赖情况。

结果

与单克隆抗体DPD所定义的氨基末端表位结合，与基线时（P = 0.0008）和1年后（P = 0.007）的空腹血清C肽水平呈正相关。与DPD所定义表位的结合，也与胰高血糖素刺激后C肽曲线下面积呈正相关（P = 0.007），并与1年后的稳态模型评估B百分比呈正相关（P = 0.03）。在A+B+患者中，与DPD所定义表位的结合明显强于A+B-患者（P = 0.001）。16名患者（44%）的血清显著抑制GAD65酶活性，但这与β细胞功能无关。