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

Abstract

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.

Figure 1. Reproductive / menstrual status of women with “unprovoked” compared to “provoked A-β+ KPD, at the time of index DKA

The different designs in each bar represent percentage of women with the indicated reproductive / menstrual status.

Figure 2. Longitudinal measures of beta cell function (HOMA2%B) and glycemic control (HbA1c) for the unprovoked A-β+ KPD (all new-onset), total provoked A-β+ KPD, and subgroup of new-onset provoked A-β+ KPD patients

Data points are mean ± SD. Diamonds / solid line = unprovoked A-β+ KPD; squares / dashed line = total provoked A-β+ KPD; triangle / dotted line = new-onset provoked A-β+ KPD. By repeated measures ANOVA, P=0.035 for differences in HOMA2%B, and P = 0.005 for group differences in HbA1c.

Figure 2. Longitudinal measures of beta cell function (HOMA2%B) and glycemic control (HbA1c) for the unprovoked A-β+ KPD (all new-onset), total provoked A-β+ KPD, and subgroup of new-onset provoked A-β+ KPD patients

Data points are mean ± SD. Diamonds / solid line = unprovoked A-β+ KPD; squares / dashed line = total provoked A-β+ KPD; triangle / dotted line = new-onset provoked A-β+ KPD. By repeated measures ANOVA, P=0.035 for differences in HOMA2%B, and P = 0.005 for group differences in HbA1c.