Complete long-term recovery of beta-cell function in autoimmune type 1 diabetes after insulin treatment.

HISTORY AND EXAMINATION — A 13-year-old Caucasian boy (BMI 26.4 kg/m) presented with 3 weeks’ history of polyuria, polydipsia, and weight loss. His serum glucose (26.8 mmol/l), HbA1c (9.4%, normal 3.2–5.5) and fructosamine (628 mol/l, normal 205–285) levels were highly elevated (Fig. 1), and urinalysis showed glucosuria ( ) and ketonuria ( ) . He was HLA-DRB1* 0101,*0901, DRB4*01, DQA1*0101,03, and DQB1*0303,0501. Plasma Cpeptide, determined at a blood glucose of 17.0 mmol/l, was low (0.18 nmol/l). His previous history was unremarkable, and he did not take any medication. The patient received standard treatment with insulin, fluid, and electrolyte replacement and diabetes education. After an uneventful clinical course he was discharged on multiple-injection insulin therapy (total 0.9 units kg 1 day ) after 10 days. Subsequently, insulin doses were gradually reduced to 0.3 units kg 1 day , and insulin treatment was completely stopped after 11 months. Without further treatment, HbA1c and fasting glucose levels remained normal throughout the entire follow-up of currently 4.5 years. During oral glucose tolerance testing performed 48 months after diagnosis, he had normal fasting and 2-h levels of glucose (3.7 and 5.6 mmol/l, respectively), insulin (60.5 and 217.9 pmol/l, respectively), and C-peptide (0.36 and 0.99 nmol/l, respectively). His insulin sensitivity, as determined by insulin sensitivity index (composite) and homeostasis model assessment, was normal, and BMI remained unchanged. Serum autoantibodies to GAD65, insulin autoantibody-2, insulin, and islet cell antibodies were initially positive but showed a progressive decline or loss during follow-up. INVESTIGATION — T-cell antigen recognition and cytokine profiles were studied using a library of 21 preproinsulin (PPI) peptides (2). In the patient’s peripheral blood mononuclear cells (PBMCs), a high cumulative interleukin (IL)-10) secretion (201 pg/ml) was observed in response to PPI peptides, with predominant recognition of PPI44–60 and PPI49–65, while interferon (IFN)secretion was undetectable. In contrast, in PBMCs from a cohort of 12 type 1 diabetic patients without long-term remission (2), there was a dominant IFNresponse but low IL-10 secretion to PPI. Analysis of CD4 T–helper cell subsets revealed that IL-10 secretion was mostly attributable to the patient’s naı̈ve/recently activated CD45RA cells, while a strong IFNresponse was observed in CD45RA cells. CD45RA T-cells have been associated with regulatory T-cell function in diabetes, potentially capable of suppressing