title: Acute sulfonylurea therapy at disease onset can cause permanent remission of KATP-induced diabetes.
abstract: 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(ATP) mutations may underlie remitting-relapsing, transient, or permanent forms of the disease in different patients, but the reason for the different outcomes is unknown.
  
  
  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 long-term remission.
authors.affiliation: Department of Cell Biology and Physiology, and Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Maria Sara
authors.initials: MS
authors.lastname: Remedi
authors.forename: Sophia E
authors.initials: SE
authors.lastname: Agapova
authors.forename: Arpita K
authors.initials: AK
authors.lastname: Vyas
authors.forename: Paul W
authors.initials: PW
authors.lastname: Hruz
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
mesh_terms: D000818:Animals; D001786:Blood Glucose; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005905:Glyburide / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000378:metabolism; D054086:KATP Channels / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D013453:Sulfonylurea Compounds / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D054086:KATP Channels; D013453:Sulfonylurea Compounds; D005947:Glucose; D005905:Glyburide