Objective Unprovoked “A-β+” Ketosis-Prone Diabetes (KPD), a unique diabetic syndrome of adult-onset, obesity and proneness to ketoacidosis, is associated with rapid recovery of β cell function and insulin-independence. Whereas most patients experience prolonged remission, a subset relapses early to insulin dependence. We sought to define factors associated with early relapse. Methods We utilized a prospective, longitudinal database to analyze 50 unprovoked A-β+ KPD patients with ≥2 measurements of β cell function and glycemia following baseline assessment. Results 19 patients (38%) relapsed to insulin dependence <1y after the index DKA episode, while 31 (62%) remained insulin-independent for >1y (median 4.2y). Younger age at baseline (OR=0.947, P=0.033), and lower HOMA2-%β (OR=0.982, P=0.001), lower HOMA2-IR (OR=0.582, P=0.046) and higher HbA1c at 1y (OR=1.71, P=0.002) were associated with early relapse. A multivariate model with these variables and the interaction of HOMA2-%β and HbA1c at 1y provided a good fit (P<0.05). Conclusions Relapse to insulin dependence in unprovoked A-β+ KPD patients is associated with younger age and, after 1y, lack of robust increase in β cell functional reserve, and suboptimal glycemic control. Measurements of these parameters 1y after the index DKA episode can be used to assess the need for insulin therapy.

A previously healthy 36-year-old woman presented with visual hallucinations and acute psychosis manifested predominantly as hypersexuality. Laboratory testing demonstrated elevated free thyroxine levels, suppressed thyroid-stimulating hormone levels and presence of thyroid-stimulating immunoglobulin andthyroid peroxidase (TPO) antibodiesconsistent with Graves’ disease. Despite achieving biochemical euthyroidism, she remained profoundly hypersexual. She did not respond to additional treatment with antipsychotics and corticosteroids, prompting further evaluation. Cerebrospinal fluid analysis detected pleocytosis, elevated IgG, and presence of antibodies against anti-N-methyl-D-aspartate receptor (NMDAR), glutamic acid decarboxylase 65 and TPO. These results suggested a diagnosis of anti-NMDAR encephalitis. Prior to initiation of immunomodulator therapy, she was discovered to be pregnant with date of conception around the time of her original presentation. She received plasmapheresis with resolution of psychosis and decrease in free thyroxine levels. Graves’ disease remitted during the remainder of the pregnancy but relapsed 5 months post partum. She has not had further neuropsychiatric symptoms.

Compared with control participants, KPD patients have increased arginine availability in the euglycemic state, indicating a higher requirement. This is compromised during hyperglycemia, with an inadequate supply of arginine to sustain metabolic functions such as insulin secretion. Exogenous arginine administration restores a normal insulin secretory response.

Masked GAD65Ab(DPD) are strongly associated with preserved β-cell functional reserve among patients with KPD. Absence of GAD65Ab(DPD) reactivity is associated with 2 HLA class II susceptibility haplotypes for autoimmune type 1 diabetes.