The “A-β-” subtype of Ketosis-Prone Diabetes (KPD) is not predominantly a monogenic diabetic syndrome

Abstract

Objective — Ketosis-Prone Diabetes (KPD) is an emerging syndrome that encompasses several distinct phenotypic subgroups that share a predisposition to diabetic ketoacidosis. We investigated whether the “A-β-” subgroup of KPD, characterized by complete insulin dependence, absent β-cell functional reserve, lack of islet cell autoantibodies, and strong family history of type 2 diabetes, represents a monogenic form of diabetes.

Research design and methods — Over eight years, 37 patients with an A-β- phenotype were identified in our longitudinally followed cohort of KPD patients. Seven genes including HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, and PAX4 were directly sequenced in all patients. Selected gene regions were also sequenced in healthy, unrelated, ethnically-matched controls, consisting of 84 African-American, 96 Caucasian, and 95 Hispanic subjects.

Results — The majority (70%) of the A-β- KPD patients had no significant causal polymorphisms in either the proximal promoter or coding regions of the seven genes. The combination of six potentially significant low frequency, heterozygous sequence variants in HNF-1α (A174V or G574S), PDX1 (putative 5′-UTR CCAAT box, P33T, or P239Q) or PAX4 (R133W) were found in 27% (10/37) of patients with one additional patient revealing two variants, PDX1 P33T and PAX4 R133W. The A174V variant has not been previously reported.

Conclusions — Despite its well circumscribed, robust, and distinctive phenotype of severe, non-autoimmune mediated β-cell dysfunction, A-β- KPD is most likely not a predominantly monogenic diabetic syndrome. Several A-β- KPD patients have low-frequency variants in HNF1A, PDX1, or PAX4 genes, which may be of functional significance in their pathophysiology.