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.
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.
Nalini
Ramaswami
R
Translational Metabolism Unit, Baylor College of Medicine, Houston, TX 77030, USA.
Ozer
Kerem
K
Maldonado
Mario
M
Patel
Sanjeet G
SG
Hampe
Christiane S
CS
Guthikonda
Anu
A
Villanueva
Jesus
J
O'Brian Smith
E
E
Gaur
Lakshmi K
LK
Balasubramanyam
Ashok
A
D000328:Adult; D000483:Alleles; D001323:Autoantibodies / Q000097:blood* / Q000502:physiology; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000145:classification* / Q000150:complications* / Q000276:immunology / Q000503:physiopathology; D016883:Diabetic Ketoacidosis / Q000097:blood / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D004198:Disease Susceptibility / Q000276:immunology / Q000503:physiopathology; D005006:Ethnicity; D005260:Female; D005787:Gene Frequency; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000276:immunology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D012737:Sex Factors; D013577:Syndrome; D055815:Young Adult
D001323:Autoantibodies; D000949:Histocompatibility Antigens Class II