Glucose modulation of ATP-sensitive K-currents in wild-type, homozygous and heterozygous glucokinase knock-out mice
Open accessAbstract
One type of maturity-onset diabetes of the young (MODY2) is caused by mutations in the glucokinase gene, a key glycolytic enzyme in the beta cell and liver. Glucose fails to stimulate insulin secretion in mice in which the glucokinase gene has been selectively knocked out in the beta cell. We tested the hypothesis that this effect results from defective metabolic regulation of beta cell ATP-sensitive potassium (K(ATP)) channels. Glucose had little effect on K(ATP) currents in homozygous (-/-) mice but inhibited K(ATP) currents in wild-type (+/+) and heterozygous (+/-) mice with EC50 of 3.2 mM and 5.5 mM, respectively, in newborn animals, and of 4.7 mM and 9.9 mM, respectively, in 1.5-year-old mice. Glucose (20 mmol/l) did not affect the resting membrane potential of -/- beta cells but depolarised wild-type and + /- beta cells and induced electrical activity. In contrast, 20 mmol/l ketoisocaproic acid or 0.5 mmol/ l tolbutamide depolarised all three types of beta-cell. These results support the idea that defective glycolytic metabolism, produced by a loss (-/- mice) or reduction (+/- mice) of glucokinase activity, leads to defective K(ATP) channel regulation and thereby to the selective loss, or reduction, of glucose-induced insulin secretion.
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In whole-cell recordings, the maximum KATP conductance when ATP has washed out is around 2 nS/pF; in perforated patch it is ~1 nS/pF in single β-cells exposed to glucose-free solution; in β-cells within freshly isolated islets it ranges between 0.25 and 0.4 nS/pF.
“In whole-cell recordings, the maximum KATP conductance, measured when ATP has washed out of the cell, is around 2 nS/pF (573). When measured in the perforated patch configuration (where cytosolic ATP levels are undisturbed) it is ~1 nS/pF in single β-cells exposed to glucose-free solution (584, 631). In β-cells within freshly isolated pancreatic islets, it is significantly lower and ranges between”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [584]
The electrophysiology methods and Fig. 2 caption describe perforated-patch recordings from isolated β-cells with a glucose-free control solution; Fig. 5 reports currents normalized to cell capacitance. The passages do not give the claimed ~1 nS/pF conductance. The 2 nS/pF whole-cell value is attached to a different citation in the citing sentence, and this paper does not report the stated range for β-cells within freshly isolated islets. (LLM, conf=0.76)
Experimental — accuracy not yet measuredIn both whole-cell and perforated-patch preparations, glucose produces a concentration-dependent reduction of whole-cell KATP conductance that is half-maximal at 3-4 mM glucose.
“In both preparations, glucose produces a concentration-dependent reduction of the whole-cell conductance which, when expressed as a fraction of that in the absence of glucose, is half-maximal at 3-4 mM glucose (26, 212, 584, 674, 762).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [584]
The Results report concentration-dependent inhibition of KATP current in neonatal wild-type beta cells, with an EC50 of 3.2 mmol/l; the Statistical analysis section says conductance was expressed relative to glucose-free controls (pages unavailable in our copy). The paper also describes both recording configurations, but it does not report a 3–4 mmol/l EC50 for standard whole-cell recordings. Its EC50 values differ for heterozygous and older cells, so the quoted range cannot be applied to all cells studied. (LLM, conf=0.86)
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“Depolarization then induces voltage-gated Ca channels to open, triggering vesicle fusion and release (Sakura et al. 1998).”
Background
- Authors
- Sakura, H., Ashcroft, S. J. H., Terauchi, Y., Kadowaki, T., & Ashcroft, F. M.
- Affiliations
- University of Oxford (GB)
- John Radcliffe Hospital (GB)
- The University of Tokyo (JP)
- Venue
- Diabetologia
- Published
- 1998-05-27
- Volume
- 41
- Issue
- 6
- Pages
- 654-659
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2036370893
- Cited by
- 48
- References
- 0
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2022: 3 · 2020: 1 · 2018: 2 · 2017: 2 · 2013: 2 · 2012: 1
- FWCI
- 2.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Topics
- Health Sciences › Medicine › Surgery › 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 › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- glucokinase, ATP-sensitive potassium channels, beta-cell insulin secretion, maturity-onset diabetes of the young, MODY2, tolbutamide, glycolytic metabolism
- MeSH terms
- Adenosine Triphosphate, Animals, Animals, Newborn, Diabetes Mellitus, Type 2, Eukaryotic Cells, Glucokinase, Glucose, Heterozygote, Homozygote, Hypoglycemic Agents, Islets of Langerhans, Keto Acids, Membrane Potentials, Mutation, Tolbutamide, Potassium Channels, Mice, Knockout, Mice
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