OBJECTIVE - Neonatal diabetes mellitus (NDM) can be caused by gain-of-function ATP-sensitive K + (K ATP) channel mutations. This realization has led to sulfonylurea therapy replacing insulin injections in many patients. In a murine model of K ATP-dependent NDM, hyperglycemia and consequent loss of β-cells are both avoided by chronic sulfonylurea treatment. Interestingly, K ATPmutations may underlie remitting-relapsing, transient, or permanent forms of the disease in different patients, but the reason for the different outcomes is unknown. RESEARCH DESIGN AND METHODS - To gain further insight into disease progression and outcome, we examined the effects of very early intervention by injecting NDM mice with high-dose glibenclamide for only 6 days, at the beginning of disease onset, then after the subsequent progression with measurements of blood glucose, islet function, and insulin sensitivity. RESULTS - Although ∼70% of mice developed severe diabetes after treatment cessation, ∼30% were essentially cured, maintaining near-normal blood glucose until killed. Another group of NDM mice was initiated on oral glibenclamide (in the drinking water), and the dose was titrated daily, to maintain blood glucose <200 mg/dL. In this case, ∼30% were also essentially cured; they were weaned from the drug after ∼4 weeks and again subsequently maintained near-normal blood glucose. These cured mice maintain normal insulin content and were more sensitive to insulin than control mice, a compensatory mechanism that together with basal insulin secretion may be sufficient to maintain near-normal glucose levels. CONCLUSIONS - At least in a subset of animals, early sulfonylurea treatment leads to permanent remission of NDM. These cured animals exhibit insulin-hypersensitivity. Although untreated NDM mice rapidly lose insulin content and progress to permanently extremely elevated blood glucose levels, early tight control of blood glucose may permit this insulin-hypersensitivity, in combination with maintained basal insulin secretion, to provide longterm remission.