Presence or absence of a known diabetic ketoacidosis precipitant defines distinct syndromes of "A-β+" ketosis-prone diabetes based on long-term β-cell function, human leukocyte antigen class II alleles, and sex predilection

Metabolism. 2010 Oct;59(10):1448-55. doi: 10.1016/j.metabol.2010.01.009. Epub 2010 Feb 19.


Ketosis-prone diabetes (KPD) is heterogeneous. Longitudinal follow-up revealed that patients with "A-β+" KPD (absent autoantibodies and preserved β-cell function) segregated into 2 subgroups with distinct evolution of β-cell function and glycemic control. Generalized linear analysis demonstrated that the variable that most significantly differentiated them was presence of a clinically evident precipitating event for the index diabetic ketoacidosis (DKA). Hence, we performed a comprehensive analysis of A-β+ KPD patients presenting with "provoked" compared with "unprovoked" DKA. Clinical, biochemical, and β-cell functional characteristics were compared between provoked and unprovoked A-β+ KPD patients followed prospectively for 1 to 8 years. Human leukocyte antigen class II allele frequencies were compared between these 2 groups and population controls. Unprovoked A-β+ KPD patients (n = 83) had greater body mass index, male preponderance, higher frequency of women with oligo-/anovulation, more frequent African American ethnicity, and less frequent family history of diabetes than provoked A-β+ KPD patients (n = 64). The provoked group had higher frequencies of the human leukocyte antigen class II type 1 diabetes mellitus susceptibility alleles DQB1*0302 (than the unprovoked group or population controls) and DRB1*04 (than the unprovoked group), whereas the unprovoked group had a higher frequency of the protective allele DQB1*0602. β-Cell secretory reserve and glycemic control improved progressively in the unprovoked group but declined in the provoked group. The differences persisted in comparisons restricted to patients with new-onset diabetes. "Unprovoked" A-β+ KPD is a distinct syndrome characterized by reversible β-cell dysfunction with male predominance and increased frequency of DQB1*0602, whereas "provoked" A-β+ KPD is characterized by progressive loss of β-cell reserve and increased frequency of DQB1*0302 and DRB1*04. Unprovoked DKA predicts long-term β-cell functional reserve, insulin independence, and glycemic control in KPD.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Alleles
  • Autoantibodies / blood*
  • Autoantibodies / physiology
  • Case-Control Studies
  • Diabetes Mellitus, Type 1 / classification*
  • Diabetes Mellitus, Type 1 / complications*
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / physiopathology
  • Diabetic Ketoacidosis / blood
  • Diabetic Ketoacidosis / etiology*
  • Diabetic Ketoacidosis / immunology
  • Diabetic Ketoacidosis / physiopathology
  • Disease Susceptibility / immunology
  • Disease Susceptibility / physiopathology
  • Ethnicity
  • Female
  • Gene Frequency
  • Histocompatibility Antigens Class II / genetics*
  • Histocompatibility Antigens Class II / immunology
  • Humans
  • Insulin-Secreting Cells / physiology*
  • Male
  • Middle Aged
  • Risk Factors
  • Sex Factors
  • Syndrome
  • Young Adult


  • Autoantibodies
  • Histocompatibility Antigens Class II