Role of KATP Channels in Glucose-Regulated Glucagon Secretion and Impaired Counterregulation in Type 2 Diabetes
Open accessAbstract
Glucagon, secreted by pancreatic islet α cells, is the principal hyperglycemic hormone. In diabetes, glucagon secretion is not suppressed at high glucose, exacerbating the consequences of insufficient insulin secretion, and is inadequate at low glucose, potentially leading to fatal hypoglycemia. The causal mechanisms remain unknown. Here we show that α cell KATP-channel activity is very low under hypoglycemic conditions and that hyperglycemia, via elevated intracellular ATP/ADP, leads to complete inhibition. This produces membrane depolarization and voltage-dependent inactivation of the Na(+) channels involved in action potential firing that, via reduced action potential height and Ca(2+) entry, suppresses glucagon secretion. Maneuvers that increase KATP channel activity, such as metabolic inhibition, mimic the glucagon secretory defects associated with diabetes. Low concentrations of the KATP channel blocker tolbutamide partially restore glucose-regulated glucagon secretion in islets from type 2 diabetic organ donors. These data suggest that impaired metabolic control of the KATP channels underlies the defective glucose regulation of glucagon secretion in type 2 diabetes.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 49 · Cited by 225
- Authors
- Zhang, Q., Ramracheya, R., Lahmann, C., Tarasov, A., Bengtsson, M., Braha, O., Braun, M., Brereton, M., Collins, S., Galvanovskis, J., Gonzalez, A., Groschner, L. N., Rorsman, N. J. G., Salehi, A., Travers, M. E., Walker, J. N., Gloyn, A. L., Gribble, F., Johnson, P. R. V., Reimann, F., Ashcroft, F. M., & Rorsman, P.
- Affiliations
- Churchill Hospital (GB)
- University of Oxford (GB)
- Addenbrooke's Hospital (GB)
- Corresponding author
- Ashcroft, Frances M.
- Rorsman, Patrik
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 18
- Issue
- 6
- Pages
- 871-882
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3851686
- OpenAlex
- W2161741963
- Cited by
- 225
- References
- 49
- Citations by year
- 2026: 13 · 2025: 16 · 2024: 9 · 2023: 23 · 2022: 15 · 2021: 26 · 2020: 23 · 2019: 15 · 2018: 21 · 2017: 16 · 2016: 17 · 2015: 18 · 2014: 13
- FWCI
- 15.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (095101, 084655, 095531/Z/11/Z, 095531, 088357)
- Biomedical Research Council
- NIHR Oxford Biomedical Research Centre
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- ATP-sensitive potassium channels, glucagon secretion, type 2 diabetes, alpha cells, glucose regulation, hypoglycemia, counterregulation, ATP/ADP ratio, membrane depolarization, calcium influx, action potential, tolbutamide, metabolic inhibition, islets
- MeSH terms
- Kcnj11 Channel, Adenosine Triphosphate, Animals, Calcium, Diabetes Mellitus, Type 2, Exocytosis, Glucagon, Glucose, Humans, Membrane Potentials, Mutation, Tissue Donors, Tolbutamide, Calcium Channels, Patch-Clamp Techniques, Potassium Channels, Inwardly Rectifying, Glucagon-Secreting Cells, Mice, KATP Channels, In Vitro Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
