Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations

Ewan R. Pearson, Isabelle Flechtner, Pal R. Njolstad, Maciej T. Malecki, Sarah E. Flanagan, Brian Larkin, Frances M. Ashcroft, Iwar Klimes, Ethel Codner, Violeta Iotova, Annabelle S. Slingerland, Julian Shield, Jean-Jacques Robert, Jens J. Holst, Penny M. Clark, Sian Ellard, Oddmund Sovik, Michel Polak, Andrew T. Hattersley

    Research output: Contribution to journalArticlepeer-review

    701 Citations (Scopus)

    Abstract

    NOTE: THE SPECIAL CHARACTERS IN THIS ABSTRACT CANNOT BE DISPLAYED CORRECTLY ON THIS PAGE. PLEASE REFER TO THE PUBLISHER'S WEBSITE FOR AN ACCURATE DISPLAY. Background Heterozygous activating mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (KATP) channel, cause 30 to 58 percent of cases of diabetes diagnosed in patients under six months of age. Patients present with ketoacidosis or severe hyperglycemia and are treated with insulin. Diabetes results from impaired insulin secretion caused by a failure of the beta-cell KATP channel to close in response to increased intracellular ATP. Sulfonylureas close the KATP channel by an ATP-independent route. Methods We assessed glycemic control in 49 consecutive patients with Kir6.2 mutations who received appropriate doses of sulfonylureas and, in smaller subgroups, investigated the insulin secretory responses to intravenous and oral glucose, a mixed meal, and glucagon. The response of mutant KATP channels to the sulfonylurea tolbutamide was assayed in xenopus oocytes. Results A total of 44 patients (90 percent) successfully discontinued insulin after receiving sulfonylureas. The extent of the tolbutamide blockade of KATP channels in vitro reflected the response seen in patients. Glycated hemoglobin levels improved in all patients who switched to sulfonylurea therapy (from 8.1 percent before treatment to 6.4 percent after 12 weeks of treatment, P<0.001). Improved glycemic control was sustained at one year. Sulfonylurea treatment increased insulin secretion, which was more highly stimulated by oral glucose or a mixed meal than by intravenous glucose. Exogenous glucagon increased insulin secretion only in the presence of sulfonylureas. Conclusions Sulfonylurea therapy is safe in the short term for patients with diabetes caused by KCNJ11 mutations and is probably more effective than insulin therapy. This pharmacogenetic response to sulfonyl ureas may result from the closing of mutant KATP channels, thereby increasing insulin secretion in response to incretins and glucose metabolism. (ClinicalTrials.gov number, NCT00334711.)
    Original languageEnglish
    Pages (from-to)467-477
    Number of pages11
    JournalNew England Journal of Medicine
    Volume355
    Issue number5
    DOIs
    Publication statusPublished - 3 Aug 2006

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