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

Division of Endocrinology, Department of Medicine, Baylor College of Medicine (M.M., S.D., D.I., A.R., A.B.); and Endocrine Service, Ben Taub General Hospital (M.M., L.R., A.B.), Houston, Texas 77030; Robert J. Williams Laboratory, Department of Medicine, University of Washington School of Medicine (C.S.H., L.K.G., L.P.H., Å.L.); and Puget Sound Blood Center (L.K.G., D.B.), Seattle, Washington 98195

Address all correspondence and requests for reprints to: Ashok Balasubramanyam, M.D., Division of Endocrinology, BCM 719E, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: ashokb{at}bcm.tmc.edu.

Ketosis-prone diabetes is heterogeneous. Its causes could include novel ß-cell functional defects. To characterize such defects, 103 patients with diabetic ketoacidosis were evaluated for ß-cell autoimmunity and human leukocyte antigen (HLA) class II alleles, with longitudinal measurements of ß-cell function and biochemical and clinical parameters. They were classified into four Aß groups, based on the presence of glutamic acid decarboxylase (GAD)65, GAD67, or IA-2 autoantibodies (A+ or A-) and ß-cell functional reserve (ß+ or ß-). The group distribution was: 18 A+ß-, 23 A-ß-, 11 A+ß+, and 51 A-ß+. Collectively, the two ß- groups differed from the two ß+ 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-ß- group differed from the A+ß- group in having lower frequencies of two alleles strongly associated with autoimmune type 1 diabetes susceptibility: DQA*03 and DQB1*02. Similarly, the A-ß+ group differed from the A+ß+ 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 ß-cell functional reserve. Novel, nonautoimmune causes of ß-cell dysfunction are likely to underlie the A-ß+ and A-ß- syndromes.

This work was supported by a Juvenile Diabetes Foundation International Career Development Award, the Chao Scholars Fund, a Siegel Foundation Grant (to A.B.), an American Diabetes Association Career Development Award (to C.S.H.), and National Institutes of Health Grants DK26190 and DK53004 (to Å.L.).

Abbreviations: AUC, Area under the curve; BMI, body mass index; DKA, diabetic ketoacidosis; GAD, glutamic acid decarboxylase; GST, glucagon stimulation test; HbA_1c, glycosylated hemoglobin; HLA, human leukocyte antigen; MODY, maturity onset diabetes of youth.

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