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

Ewan R Pearson; Isabelle Flechtner; Pål R Njølstad; 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 Juul Holst; Penny M Clark; Sian Ellard; Oddmund Søvik; Michel Polak; Andrew T Hattersley; Neonatal Diabetes International Collaborative Group

doi:10.1056/NEJMoa061759

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

Ewan R Pearson, Isabelle Flechtner, Pål R Njølstad, 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 Juul Holst, Penny M Clark, Sian Ellard, Oddmund Søvik, Michel Polak, Andrew T Hattersley, Neonatal Diabetes International Collaborative Group

Endocrinology and Metabolism

720 Citations (Scopus)

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].).

Original language	English
Journal	New England Journal of Medicine
Volume	355
Issue number	5
Pages (from-to)	467-77
Number of pages	11
ISSN	0028-4793
DOIs	https://doi.org/10.1056/NEJMoa061759
Publication status	Published - 3 Aug 2006

Keywords

ATP-Binding Cassette Transporters
Cohort Studies
Diabetes Mellitus
Female
Glyburide
Hemoglobin A, Glycosylated
Heterozygote
Humans
Hypoglycemic Agents
Infant
Infant, Newborn
Insulin
Insulin-Secreting Cells
Male
Mutation
Potassium Channels
Potassium Channels, Inwardly Rectifying
Receptors, Drug
Sulfonylurea Compounds
Sulfonylurea Receptors
Tolbutamide

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1056/NEJMoa061759

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Pearson, E. R., Flechtner, I., Njølstad, P. R., Malecki, M. T., Flanagan, S. E., Larkin, B., Ashcroft, F. M., Klimes, I., Codner, E., Iotova, V., Slingerland, A. S., Shield, J., Robert, J-J., Holst, J. J., Clark, P. M., Ellard, S., Søvik, O., Polak, M., Hattersley, A. T., & Neonatal Diabetes International Collaborative Group (2006). Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. New England Journal of Medicine, 355(5), 467-77. https://doi.org/10.1056/NEJMoa061759

Pearson, ER, Flechtner, I, Njølstad, PR, Malecki, MT, Flanagan, SE, Larkin, B, Ashcroft, FM, Klimes, I, Codner, E, Iotova, V, Slingerland, AS, Shield, J, Robert, J-J, Holst, JJ, Clark, PM, Ellard, S, Søvik, O, Polak, M, Hattersley, AT & Neonatal Diabetes International Collaborative Group 2006, 'Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations', New England Journal of Medicine, vol. 355, no. 5, pp. 467-77. https://doi.org/10.1056/NEJMoa061759

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title = "Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations",

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].).",

keywords = "ATP-Binding Cassette Transporters, Cohort Studies, Diabetes Mellitus, Female, Glyburide, Hemoglobin A, Glycosylated, Heterozygote, Humans, Hypoglycemic Agents, Infant, Infant, Newborn, Insulin, Insulin-Secreting Cells, Male, Mutation, Potassium Channels, Potassium Channels, Inwardly Rectifying, Receptors, Drug, Sulfonylurea Compounds, Sulfonylurea Receptors, Tolbutamide",

author = "Pearson, {Ewan R} and Isabelle Flechtner and Nj{\o}lstad, {P{\aa}l R} and Malecki, {Maciej T} and Flanagan, {Sarah E} and Brian Larkin and Ashcroft, {Frances M} and Iwar Klimes and Ethel Codner and Violeta Iotova and Slingerland, {Annabelle S} and Julian Shield and Jean-Jacques Robert and Holst, {Jens Juul} and Clark, {Penny M} and Sian Ellard and Oddmund S{\o}vik and Michel Polak and Hattersley, {Andrew T} and {Neonatal Diabetes International Collaborative Group}",

year = "2006",

month = aug,

day = "3",

doi = "10.1056/NEJMoa061759",

language = "English",

volume = "355",

pages = "467--77",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "5",

}

TY - JOUR

T1 - Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations

AU - Pearson, Ewan R

AU - Flechtner, Isabelle

AU - Njølstad, Pål R

AU - Malecki, Maciej T

AU - Flanagan, Sarah E

AU - Larkin, Brian

AU - Ashcroft, Frances M

AU - Klimes, Iwar

AU - Codner, Ethel

AU - Iotova, Violeta

AU - Slingerland, Annabelle S

AU - Shield, Julian

AU - Robert, Jean-Jacques

AU - Holst, Jens Juul

AU - Clark, Penny M

AU - Ellard, Sian

AU - Søvik, Oddmund

AU - Polak, Michel

AU - Hattersley, Andrew T

AU - Neonatal Diabetes International Collaborative Group

PY - 2006/8/3

Y1 - 2006/8/3

N2 - 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].).

AB - 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].).

KW - ATP-Binding Cassette Transporters

KW - Cohort Studies

KW - Diabetes Mellitus

KW - Female

KW - Glyburide

KW - Hemoglobin A, Glycosylated

KW - Heterozygote

KW - Humans

KW - Hypoglycemic Agents

KW - Infant

KW - Infant, Newborn

KW - Insulin

KW - Insulin-Secreting Cells

KW - Male

KW - Mutation

KW - Potassium Channels

KW - Potassium Channels, Inwardly Rectifying

KW - Receptors, Drug

KW - Sulfonylurea Compounds

KW - Sulfonylurea Receptors

KW - Tolbutamide

U2 - 10.1056/NEJMoa061759

DO - 10.1056/NEJMoa061759

M3 - Journal article

C2 - 16885550

SN - 0028-4793

VL - 355

SP - 467

EP - 477

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 5

ER -

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

Abstract

Keywords

UN SDGs

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