Ketosis-Prone Diabetes: Dissection of a Heterogeneous Syndrome Using an Immunogenetic and β-Cell Functional Classification, Prospective Analysis, and Clinical Outcomes

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Abstract
Ketosis-prone diabetes is heterogeneous. Its causes could include novel β-cell functional defects. To characterize such defects, 103 patients with diabetic ketoacidosis were evaluated for β-cell autoimmunity and human leukocyte antigen (HLA) class II alleles, with longitudinal measurements of β-cell function and biochemical and clinical parameters. They were classified into four Aβ groups, based on the presence of glutamic acid decarboxylase (GAD)65, GAD67, or IA-2 autoantibodies (A+ or A−) and β-cell functional reserve (β+ or β−). The group distribution was: 18 A+β−, 23 A−β−, 11 A+β+, and 51 A−β+. Collectively, the two β− groups differed from the two β+ groups in earlier onset and longer duration of diabetes, lower body mass index, less glycemic improvement, and persistent insulin requirement. HLA class II genotyping showed that the A−β− group differed from the A+β− group in having lower frequencies of two alleles strongly associated with autoimmune type 1 diabetes susceptibility: DQA*03 and DQB1*02. Similarly, the A−β+ group differed from the A+β+ group in having a lower frequency of DQB1*02. Ketosis-prone diabetes comprises at least four etiologically distinct syndromes separable by autoantibody status, HLA genotype, and β-cell functional reserve. Novel, nonautoimmune causes of β-cell dysfunction are likely to underlie the A−β+ and A−β− syndromes.