A-beta-subtype of ketosis-prone diabetes is not predominantly a monogenic diabetic syndrome

Diabetes Care. 2009 May;32(5):873-7. doi: 10.2337/dc08-1529. Epub 2009 Feb 19.


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-beta- subgroup of KPD, characterized by complete insulin dependence, absent beta-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 8 years, 37 patients with an A-beta- phenotype were identified in our longitudinally followed cohort of KPD patients. Seven genes, including hepatocyte nuclear factor 4A (HNF4A), glucokinase (GCK), HNF1A, pancreas duodenal homeobox 1 (PDX1), HNF1B, neurogenic differentiation 1 (NEUROD1), and PAX4, were directly sequenced in all patients. Selected gene regions were also sequenced in healthy, unrelated ethnically matched control subjects, consisting of 84 African American, 96 Caucasian, and 95 Hispanic subjects.

Results: The majority (70%) of the A-beta- 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-1 alpha (A174V or G574S), PDX1 (putative 5'-untranslated region 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, nonautoimmune-mediated beta-cell dysfunction, A-beta- KPD is most likely not a predominantly monogenic diabetic syndrome. Several A-beta- KPD patients have low-frequency variants in HNF1A, PDX1, or PAX4 genes, which may be of functional significance in their pathophysiology.

MeSH terms

  • Adult
  • Autoantibodies / blood
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Diabetes Mellitus, Type 1 / classification
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 2 / genetics
  • Female
  • Genetic Variation
  • Glucokinase / genetics
  • Glycated Hemoglobin / metabolism
  • Hepatocyte Nuclear Factor 1-beta / genetics
  • Hepatocyte Nuclear Factor 4 / genetics
  • Homeodomain Proteins / genetics
  • Humans
  • Insulin / therapeutic use
  • Insulin-Secreting Cells / physiology
  • Islets of Langerhans / immunology
  • Male
  • Middle Aged
  • Paired Box Transcription Factors / genetics
  • Trans-Activators / genetics


  • Autoantibodies
  • Basic Helix-Loop-Helix Transcription Factors
  • Glycated Hemoglobin A
  • HNF1B protein, human
  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 4
  • Homeodomain Proteins
  • Insulin
  • NEUROD1 protein, human
  • PAX4 protein, human
  • Paired Box Transcription Factors
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • Hepatocyte Nuclear Factor 1-beta
  • Glucokinase