Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations.
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].).
Pearson
Ewan R
ER
Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, United Kingdom.
Flechtner
Isabelle
I
Njølstad
Pål R
PR
Malecki
Maciej T
MT
Flanagan
Sarah E
SE
Larkin
Brian
B
Ashcroft
Frances M
FM
Klimes
Iwar
I
Codner
Ethel
E
Iotova
Violeta
V
Slingerland
Annabelle S
AS
Shield
Julian
J
Robert
Jean-Jacques
JJ
Holst
Jens J
JJ
Clark
Penny M
PM
Ellard
Sian
S
Søvik
Oddmund
O
Polak
Michel
M
Hattersley
Andrew T
AT
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D015331:Cohort Studies; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005905:Glyburide / Q000009:adverse effects / Q000627:therapeutic use*; D006442:Glycated Hemoglobin / Q000032:analysis; D006579:Heterozygote; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin / Q000627:therapeutic use; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009154:Mutation; D015221:Potassium Channels / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000494:pharmacology; D064233:Sulfonylurea Receptors; D014044:Tolbutamide / Q000494:pharmacology; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D005905:Glyburide; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; D014044:Tolbutamide; D000099161:Kcnj11 Channel