Oak Shilpa, Gaur Lakshmi K, Radtke Jared, Patel Roshni, Iyer Dinakar, Ram Nalini, Gaba Ruchi, Balasubramanyam Ashok, Hampe Christiane S
University of Washington (S.O., L.K.G., J.R., C.S.H.), Seattle, Washington 98109; and Diabetes Research Center (R.P., D.I., N.R., R.G., A.B.), Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, and Endocrine Service (N.R., R.G., A.B.), Ben Taub General Hospital, Houston, Texas 77030.
J Clin Endocrinol Metab. 2014 Jun;99(6):E1040-4. doi: 10.1210/jc.2013-4189. Epub 2014 Mar 6.
Ketosis-prone diabetes (KPD), defined by presentation with diabetic ketoacidosis (DKA), comprises 4 subgroups based on the presence or absence of islet cell autoantibodies (A(-) or A(+)) and β-cell functional reserve (β(-) or β(+)). Among A(+) KPD, autoantibody epitope reactivity to 65-kDa glutamate decarboxylase (GAD65), defined by monoclonal GAD65Ab(DPD), was associated with greater β-cell functional reserve. In a majority of healthy individuals, GAD65Ab are present in the sera but are masked by anti-idiotypic antibodies; in contrast, overtly GAD65Ab-positive patients with autoimmune type 1 diabetes patients lack these anti-idiotypic antibodies.
Our objective was to determine the presence of masked and overt GAD65Ab(DPD) in relation to β-cell function and genetic risk factors in KPD patients.
We investigated the associations of masked and overt GAD65Ab(DPD) with β-cell functional reserve, and their relationship with human leukocyte antigen (HLA) class II haplotypes linked to autoimmune diabetes susceptibility or resistance, in a large KPD cohort.
Adult KPD patients (n = 384) were followed longitudinally in a research clinic.
β-Cell function, autoantibody status, GAD65Ab epitopes, and HLA class II haplotypes were evaluated.
Overall, KPD patients with β-cell functional reserve (β(+) subgroups) showed significantly higher frequency of masked GAD65Ab(DPD) than patients without β-cell functional reserve (β(-) subgroups): 112 of 144 (79%) compared with 59 of 100 (59%), respectively (P = .002). Masked or overt GAD65Ab(DPD) were also more frequent among autoantibody-positive patients with preserved β-cell functional reserve (A(+)β(+) KPD) than those lacking β-cell function (A(+)β(-) KPD): 77% compared with 55% (P = .01). The susceptibility HLA haplotypes DQA10301/DQB10302 and DQA10301/DQB10201 were associated with absence of overt or masked GAD65Ab(DPD) (odds Ratios 2.3 and 2.2, respectively).
Masked GAD65Ab(DPD) are strongly associated with preserved β-cell functional reserve among patients with KPD. Absence of GAD65Ab(DPD) reactivity is associated with 2 HLA class II susceptibility haplotypes for autoimmune type 1 diabetes.
酮症倾向糖尿病（KPD）以糖尿病酮症酸中毒（DKA）为特征，根据胰岛细胞自身抗体（A（-）或A（+））的有无以及β细胞功能储备（β（-）或β（+））分为4个亚组。在A（+）KPD中，由单克隆GAD65Ab（DPD）定义的针对65 kDa谷氨酸脱羧酶（GAD65）的自身抗体表位反应性与更高的β细胞功能储备相关。在大多数健康个体中，血清中存在GAD65Ab，但被抗独特型抗体掩盖；相反，自身免疫性1型糖尿病患者中明显GAD65Ab阳性的患者缺乏这些抗独特型抗体。
我们的目的是确定KPD患者中与β细胞功能和遗传危险因素相关的隐蔽性和显性GAD65Ab（DPD）的存在情况。
我们在一个大型KPD队列中研究了隐蔽性和显性GAD65Ab（DPD）与β细胞功能储备的关联，以及它们与与自身免疫性糖尿病易感性或抗性相关的人类白细胞抗原（HLA）II类单倍型的关系。
384例成年KPD患者在一家研究诊所接受纵向随访。
评估β细胞功能、自身抗体状态、GAD65Ab表位和HLA II类单倍型。
总体而言，具有β细胞功能储备的KPD患者（β（+）亚组）中隐蔽性GAD65Ab（DPD）的频率显著高于无β细胞功能储备的患者（β（-）亚组）：分别为144例中的112例（79%）和100例中的59例（59%）（P = 0.002）。在β细胞功能储备保留的自身抗体阳性患者（A（+）β（+）KPD）中，隐蔽性或显性GAD65Ab（DPD）也比缺乏β细胞功能的患者（A（+）β（-）KPD）更常见：分别为77%和55%（P = 0.01）。易感性HLA单倍型DQA10301/DQB10302和DQA10301/DQB10201与无显性或隐蔽性GAD65Ab（DPD）相关（优势比分别为2.3和2.2）。
在KPD患者中，隐蔽性GAD65Ab（DPD）与保留的β细胞功能储备密切相关。GAD65Ab（DPD）反应性的缺失与自身免疫性1型糖尿病的2种HLA II类易感性单倍型相关。
