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Previous Volume 355:467-477 August 3, 2006 Number 5 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Supplementary Material Editorial by Sperling, M. A. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background Heterozygous activating mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (K_ATP) 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 K_ATP channel to close in response to increased intracellular ATP. Sulfonylureas close the K_ATP 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 K_ATP 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 K_ATP 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 sulfonylureas may result from the closing of mutant K_ATP channels, thereby increasing insulin secretion in response to incretins and glucose metabolism. (ClinicalTrials.gov number, NCT00334711 [ClinicalTrials.gov] .)

Source Information

From the Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter (E.R.P., S.E.F., A.S.S, S.E., A.T.H.); the Division of Medicine and Therapeutics, University of Dundee, Dundee (E.R.P.); University Laboratory of Physiology, Oxford, (B.L., F.M.A.); the Department of Child Health, University of Bristol, Bristol (J.S.); and University Hospital Birmingham, Birmingham (P.M.C.) — all in the United Kingdom; the Faculty of Medicine, René Descartes University, Pediatric Endocrinology and Diabetology, Necker Enfants Malades Hospital, Paris (I.F., J-J.R., M.P.); the Department of Clinical Medicine, University of Bergen (P.R.N., O.S.), and the Department of Pediatrics, Haukeland University Hospital (P.R.N.) — both in Bergen, Norway; the Department of Metabolic Diseases, Jagiellonian University, Medical College, Krakow, Poland (M.T.M.); Diabgene, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovak Republic (I.K.); Institute of Maternal and Child Research, School of Medicine, University of Chile, Santiago (E.C.); Medical University, Varna, Bulgaria (V.I.); the Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands (A.S.S.); and the Department of Medical Physiology, the Panum Institute, University of Copenhagen, Copenhagen (J.J.H.).

Drs. Pearson, Flechtner, and Njølstad contributed equally to this article.

Address reprint requests to Dr. Hattersley at the Peninsula Medical School, Barrack Rd., Exeter EX2 5DW, United Kingdom, or at andrew.hattersley{at}pms.ac.uk.

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