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Cited by 105Pancreatic function and diabetesIon channel regulation and functionDiabetes and associated disorders

Expression of an activating mutation in the gene encoding the KATP channel subunit Kir6.2 in mouse pancreatic β cells recapitulates neonatal diabetes

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Girard, Christophe A., Wunderlich, F. Thomas, Shimomura, Kenju, Collins, Stephan, Kaizik, Stephan, Proks, Peter, Abdulkader, Fernando, Clark, Anne +11 more·2008·Journal of Clinical Investigation
DOI 10.1172/jci35772PMC PMC2613450
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Abstract

Neonatal diabetes is a rare monogenic form of diabetes that usually presents within the first six months of life. It is commonly caused by gain-of-function mutations in the genes encoding the Kir6.2 and SUR1 subunits of the plasmalemmal ATP-sensitive K+ (KATP) channel. To better understand this disease, we generated a mouse expressing a Kir6.2 mutation (V59M) that causes neonatal diabetes in humans and we used Cre-lox technology to express the mutation specifically in pancreatic beta cells. These beta-V59M mice developed severe diabetes soon after birth, and by 5 weeks of age, blood glucose levels were markedly increased and insulin was undetectable. Islets isolated from beta-V59M mice secreted substantially less insulin and showed a smaller increase in intracellular calcium in response to glucose. This was due to a reduced sensitivity of KATP channels in pancreatic beta cells to inhibition by ATP or glucose. In contrast, the sulfonylurea tolbutamide, a specific blocker of KATP channels, closed KATP channels, elevated intracellular calcium levels, and stimulated insulin release in beta-V59M beta cells, indicating that events downstream of KATP channel closure remained intact. Expression of the V59M Kir6.2 mutation in pancreatic beta cells alone is thus sufficient to recapitulate the neonatal diabetes observed in humans. beta-V59M islets also displayed a reduced percentage of beta cells, abnormal morphology, lower insulin content, and decreased expression of Kir6.2, SUR1, and insulin mRNA. All these changes are expected to contribute to the diabetes of beta-V59M mice. Their cause requires further investigation.

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  • In 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 [212]

    The results (p. 3) report half-maximal glucose inhibition at 3 mM in wild-type β cells, and Figure 6 (p. 7) shows those whole-cell currents were recorded using perforated patches and expressed relative to glucose-free current. The paper does not establish the same value in a separate whole-cell preparation; it reports an IC50 above 20 mM for mutant β cells. (LLM, conf=0.88)

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  • The KATP current of dispersed β-cells is not fully inhibited until glucose reaches ~20 mM.

    “Similarly, the KATP current of dispersed β-cells is not fully inhibited until glucose reaches ~20 mM (212, 674) (Figure 2C).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [212]

    Figure 6 (p. 7) reports glucose-dependent KATP currents in isolated mouse β-cells. The accompanying text (p. 3) says the mutant cells’ glucose-inhibition IC50 was greater than 20 mM, versus 3 mM in wild-type cells. Thus the paper supports incomplete inhibition at 20 mM in mutant cells, but not the claim that dispersed β-cell currents generally become fully inhibited at about 20 mM. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • This would explain why glucose-induced [Ca2+]i responses in some β-cells (~40%) from mice expressing a gain-of-function KATP channel mutation were not synchronized across the islet.

    “This would explain why although some β-cells (~40%) in islets from mice expressing a gain-of-function KATP channel mutation displayed glucose-induced [Ca2+]i responses, these were not synchronized across the islet (212).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [212]

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Research works printed but not linked: 1

  1. [35]Mao, X., Fujiwara, Y., and Orkin, S.H. 1999. Improved reporter strain for monitoring Cre recombinase-mediated DNA excisions in mice. Proc. Natl. Acad. Sci. U. S. A. 96 :5037-5042.

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Authors
Girard, C. A., Wunderlich, F. T., Shimomura, K., Collins, S., Kaizik, S., Proks, P., Abdulkader, F., Clark, A., Ball, V., Zubcevic, L., Bentley, L., Clark, R., Church, C., Hugill, A., Galvanovskis, J., Cox, R., Rorsman, P., Brüning, J. C., & Ashcroft, F. M.
Affiliations
  • University of Oxford (GB)
  • University of Cologne (DE)
  • Churchill Hospital (GB)
  • Universidade de São Paulo (BR)
  • Mary Lyon Centre at MRC Harwell (GB)
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2008-12-08
Volume
119
Issue
1
Pages
80-90
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci35772
PMC
PMC2613450
OpenAlex
W2091267031
Cited by
105
References
3
Citations by year
2026: 2 · 2025: 2 · 2023: 2 · 2022: 3 · 2021: 7 · 2020: 4 · 2019: 6 · 2018: 12 · 2017: 4 · 2016: 7 · 2015: 4 · 2014: 10 · 2013: 7 · 2012: 6
FWCI
9.79
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (publishedVersion)
  • HAL (submittedVersion)
Funders
  • Wellcome Trust (084655)
  • Royal Society
  • University of Oxford
  • European Commission (LSHM-CT-2006-518153)
  • Deutsche Forschungsgemeinschaft
  • Medical Research Council
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 › Genetics › Diabetes and associated disorders
Keywords
neonatal diabetes, Kir6.2, ATP-sensitive potassium channels, gain-of-function mutations, pancreatic beta cells, SUR1, mouse model, insulin secretion, intracellular calcium, tolbutamide, ATP inhibition, monogenic diabetes
MeSH terms
Kcnj11 Channel, Adenosine Triphosphate, Animals, Calcium, Diabetes Mellitus, Disease Models, Animal, Female, Humans, Hypoglycemic Agents, Infant, Newborn, Male, Mice, Transgenic, Mutation, Tolbutamide, Patch-Clamp Techniques, Protein Subunits, Potassium Channels, Inwardly Rectifying, Insulin-Secreting Cells, Mice

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