Recurrent diabetic ketoacidosis and a brief history of brittle diabetes research: contemporary and past evidence in diabetic ketoacidosis research including mortality, mental health and prevention

Abstract

Pharmacological, technological and educational approaches have advanced the treatment of Type 1 diabetes in the last four decades and yet diabetic ketoacidosis (DKA) continues to be a leading cause of admission in Type 1 diabetes. This article begins by reviewing the contemporary epidemiological evidence in DKA. It highlights a rise in DKA episodes in the last two decades, with DKA continuing to be the leading cause of death in young people with Type 1 diabetes, and that DKA episodes are a marker for subsequent all‐cause mortality. It also summarizes the limited evidence base for DKA prevention and associations with psychopathology. To emphasize the importance of this group with high‐risk Type 1 diabetes and the degree to which they have been overlooked in the past two decades, the article summarizes the research literature of recurrent DKA during 1976–1991 when it was extensively investigated as part of the phenomenon of ‘brittle diabetes’. This period saw numerous basic science studies investigating the pathophysiology of recurrent DKA. Subsequently, research centres published their experiences of brittle diabetes research participants manipulating their treatment under research conditions. Unfortunately, the driver for this behaviour and whether it was indicative of other people with ketoacidosis was not pursued. In summary, we suggest there has been a stasis in the approach to recurrent DKA prevention, which is likely linked to historical cases of mass sabotage of brittle diabetes research. Further investigation is required to clarify possible psychological characteristics that increase the risk of DKA and thereby targets for DKA prevention.

Diabetic ketoacidosis

“…Whether this is ketosis-prone T2DM is unknown, as genetic analyses on these individuals are unavailable. Psychological factors also influence the likelihood of developing DKA 55,56 . A report of ~350 adolescent girls and women (aged 13-60 years) suggested that disordered eating was a contributing factor in ~20% of recurrent episodes of DKA 57 .…”

Previous diabetic ketoacidosis as a risk factor for recurrence in a large prospective contemporary pediatric cohort: Results from the DPV initiative

“…Whereas the outcome of DKA has improved tremendously over the last decades, 4,30 the incidence remained stable, and recurring events or readmission to a hospital are frequent concerns 15,18,22‐24,31 . Previous studies of repetitive DKA events were designed as case–control‐studies, 30 analyzed only a group of patients with DKA‐related hospital admissions, covered a shorter period of time 18,19,24 or a smaller group of patients.…”

“…In a sensitivity analysis performed by us, the GISD_2012 was used to adjust models for regional deprivation, with similar results: a previous episode of DKA remained a significant risk factor for recurrence, underlining that patients with previous episodes should be followed closely. Targeted patient education may also help to reduce recurrence risk: structured patient education or multidisciplinary support programs can improve glycemic control 34 and reduce hospital admissions for DKA 22,35 . A language barrier is associated with higher HbA1c levels 36 and may partly explain the higher risk for DKA in patients with a migratory background.…”

“…In a different pediatric cohort, more than half of all reported DKA events could be attributed to only 5% of all patients 15 . Since DKA mortality is higher in patients with several episodes, 22 patients with relapsing DKA require special awareness. Growing up in a deprived area especially predisposes pediatric T1D patients to repetitive DKA 23 ; moreover, females, adolescents, and patients with psychiatric comorbidity are more likely to be readmitted for DKA within 30 days after discharge 24 .…”

Genetically engineered pigs manifesting pancreatic agenesis with severe diabetes

“…The pigs showed symptoms consistent with the brittle type of diabetes. 43 CSII may offer an alternative therapeutic strategy in this case. 28 However, the CSII pump was too heavy for use in neonatal pigs, and the use of the CSII pump attached to the piglets' cage (with the insertion of an insulin injection needle using a long tube) was also ineffective because the tubes became clogged, and the needles were detached.…”