Linear Loss of Insulin Secretory Capacity During the Last Six Months Preceding IDDM: No effect of antiedematous therapy with ketotifen

Abstract

OBJECTIVE To investigate the effect of an antiedematous therapy with the histamine antagonist ketotifen on β-cell function in late prediabetes. RESEARCH DESIGN AND METHODS In a randomized double-blind placebo-controlled study, ketotifen was administered for 3 months to 9 islet cell antibody positive (ICA⁺) prediabetic patients with a first-phase insulin response (FPIR) below the 2.5th percentile to preserve residual β-cell function. Patients were followed by intravenous glucose tolerance tests (IVGTTs) every 4—6 weeks for determination of FPIR, HbA₁, ICAs, and insulin autoantibodies. In 5 patients, the immune activation state was followed by determination of serum levels of tumor necrosis factor-α (TNF-α), (β₂-microglobulin, and C-reactive protein (CRP). RESULTS Seven of nine patients developed diabetes within one year of followup. Irrespective of treatment with ketotifen, a slow and linear decline (P < 0.05) of 1 + 3-min insulin values was observed in sequential IVGTTs in those 7 patients who developed insulin-dependent diabetes mellitus (IDDM) during follow-up. The 2 other patients showed wide fluctuations of the insulin response with a threefold increase of initial insulin levels. HbAi did not correlate with FPIR. Fasting blood glucose increased significantly during the study (P < 0.05). Individual levels of serum TNF-α, CRP, and β₂-microglobulin did not change during the study. CONCLUSIONS The study could not demonstrate preservation of β-cell function by ketotifen in the late stage before manifestation of clinical diabetes. Manifestation is preceded in the last 6 months by a steady loss of the FPIR without rapid deterioration immediately before diagnosis and without signs of increased immune activity.