Cited by 658Pancreatic function and diabetesIon channel regulation and functionDiabetes and associated disorders

Activating Mutations in the ABCC8 Gene in Neonatal Diabetes Mellitus

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Babenko, Andrey P., Polak, Michel, Cavé, Hélène, Busiah, Kanetee, Czernichow, Paul, Scharfmann, Raphael, Bryan, Joseph, Aguilar-Bryan, Lydia, Vaxillaire, Martine, Froguel, Philippe·2006·New England Journal of Medicine

Abstract

BACKGROUND: The ATP-sensitive potassium (K(ATP)) channel, composed of the beta-cell proteins sulfonylurea receptor (SUR1) and inward-rectifying potassium channel subunit Kir6.2, is a key regulator of insulin release. It is inhibited by the binding of adenine nucleotides to subunit Kir6.2, which closes the channel, and activated by nucleotide binding or hydrolysis on SUR1, which opens the channel. The balance of these opposing actions determines the low open-channel probability, P(O), which controls the excitability of pancreatic beta cells. We hypothesized that activating mutations in ABCC8, which encodes SUR1, cause neonatal diabetes. METHODS: We screened the 39 exons of ABCC8 in 34 patients with permanent or transient neonatal diabetes of unknown origin. We assayed the electrophysiologic activity of mutant and wild-type K(ATP) channels. RESULTS: We identified seven missense mutations in nine patients. Four mutations were familial and showed vertical transmission with neonatal and adult-onset diabetes; the remaining mutations were not transmitted and not found in more than 300 patients without diabetes or with early-onset diabetes of similar genetic background. Mutant channels in intact cells and in physiologic concentrations of magnesium ATP had a markedly higher P(O) than did wild-type channels. These overactive channels remained sensitive to sulfonylurea, and treatment with sulfonylureas resulted in euglycemia. CONCLUSIONS: Dominant mutations in ABCC8 accounted for 12 percent of cases of neonatal diabetes in the study group. Diabetes results from a newly discovered mechanism whereby the basal magnesium-nucleotide-dependent stimulatory action of SUR1 on the Kir pore is elevated and blockade by sulfonylureas is preserved.

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Crossref · 10.1056/nejmoa055068

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  • Neonatal diabetes due to Kir6.2 or SUR1 mutations can be treated with high-dose sulfonylureas despite being insulin dependent.

    “can be treated with high-dose sulfonylureas despite being insulin dependent also provide a compelling case for genetic evaluation of monogenic diabetes with therapeutic and prognostic implications ( 2 – 6 ).”

    From β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment (2014) · cites this paper as [5]

    The Clinical Studies and Diabetes sections report that patients with SUR1 mutations switched from insulin to sulfonylureas at doses at the high end of, or above, recommended adult doses. The Discussion reports sulfonylurea efficacy for Kir6.2 mutations, but does not establish the high-dose qualifier for those patients. It also says genetic testing has implications for counseling and therapy. (LLM, conf=0.86)

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  • Neonatal diabetes is most commonly due to activating mutations in genes encoding the ATP-sensitive potassium channel subunits Kir6.2 or SUR1.

    “Findings that neonatal diabetes is most commonly due to activating mutations in genes encoding the ATP-sensitive potassium channel subunits Kir6.2 or SUR1”

    From β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment (2014) · cites this paper as [5]

    The Methods report KCNJ11 mutations, which affect Kir6.2, in 18% of the study group and chromosome 6q24 abnormalities in 34%. The Abstract reports ABCC8 mutations, which affect SUR1, in 12%. The paper supports that mutations in either channel subunit can cause neonatal diabetes, but its figures do not support calling them the most common cause overall. (LLM, conf=0.90)

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Authors
Babenko, A. P., Polak, M., Cavé, H., Busiah, K., Czernichow, P., Scharfmann, R., Bryan, J., Aguilar-Bryan, L., Vaxillaire, M., & Froguel, P.
Affiliations
  • Baylor College of Medicine (US)
  • Hôpital Necker-Enfants Malades (FR)
  • Hôpital Robert-Debré (FR)
  • Centre National de la Recherche Scientifique (FR)
Venue
New England Journal of Medicine
Published
2006-08-03
Volume
355
Issue
5
Pages
456-466
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
OpenAlex
W2155078339
Cited by
655
References
33
Citations by year
2026: 11 · 2025: 16 · 2024: 15 · 2023: 27 · 2022: 20 · 2021: 32 · 2020: 28 · 2019: 33 · 2018: 32 · 2017: 29 · 2016: 37 · 2015: 33 · 2014: 42 · 2013: 42 · 2012: 26
FWCI
51.85
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • HAL (submittedVersion, other-oa)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (DK44311, DK52771, R01DK044311, R01DK052771)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
ABCC8, neonatal diabetes, SUR1, Kir6.2, ATP-sensitive potassium channels, activating mutations, missense mutations, open probability, type 2 diabetes
MeSH terms
Kcnj11 Channel, Birth Weight, Developmental Disabilities, Diabetes Mellitus, Female, Heterozygote, Humans, Hypoglycemic Agents, Infant, Newborn, Male, Pedigree, Receptors, Drug, Sulfonylurea Compounds, Tolbutamide, Potassium Channels, ATP-Binding Cassette Transporters, Mutation, Missense, Potassium Channels, Inwardly Rectifying, Diabetes Complications, Insulin-Secreting Cells, Sulfonylurea Receptors

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