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Cited by 36Pancreatic function and diabetesDiabetes and associated disordersDiabetes Treatment and Management

The diabetic β‐cell: hyperstimulated vs. hyperexcited

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Nichols, C. G., Remedi, M. S.·2012·Diabetes, Obesity and Metabolism
DOI 10.1111/j.1463-1326.2012.01655.xPMC PMC3712635
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Abstract

Hyperglycaemia has multiple effects on β‐cells, some clearly prosecretory, including hyperplasia and elevated insulin content, but eventually, a ‘glucotoxic’ effect which leads to pancreatic β‐cell dysfunction, reduced β‐cell mass and insulin deficiency, is an important part of diabetes pathophysiology. Myriad underlying cellular and molecular processes could lead to such dysfunction. High glucose will stimulate glycolysis and oxidative phosphorylation, which will in turn increase β‐cell membrane excitability through K ATP channel closure. Chronic hyperexcitability will then lead to persistently elevated [Ca 2+ ] i , a key trigger to insulin secretion. Thus, at least a part of the consequence of ‘hyperstimulation’ by glucose has been suggested to be a result of ‘hyperexcitability’ and chronically elevated [Ca 2+ ] i . This link is lost when the [glucose], K ATP ‐channel activity link is broken, either pharmacologically or genetically. In isolated islets, such studies reveal that hyperexcitability causes a largely reversible chronic loss of insulin content, but in vivo chronic hyperexcitability per se does not lead to β‐cell death or loss of insulin content. On the other hand, chronic inexcitability in vivo leads to systemic diabetes and consequential β‐cell death, even while [Ca 2+ ] i remains low.

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  • Loss-of-function mutations in KATP channel genes cause congenital hyperinsulinism because they result in permanent membrane depolarization and persistent insulin release.

    “Loss-of-function mutations cause congenital hyperinsulinism because they result in permanent membrane depolarization and persistent insulin release (479, 644, 681).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [479]

    The Human Diseases section (page unavailable) identifies loss-of-function mutations in KATP genes as major causes of congenital hyperinsulinism. The Glucose Stimulation section links KATP inhibition to membrane depolarization and insulin secretion, but the Chronic Hyperexcitability section reports that severe or prolonged loss of KATP activity can instead reduce insulin secretion. Thus, permanent depolarization with persistent insulin release is too categorical. (LLM, conf=0.88)

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Authors
Nichols, C. G., & Remedi, M. S.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Nichols, C. G.
ORCID
Venue
Diabetes, Obesity and Metabolism
Publisher
Wiley
Published
2012-08-28
Volume
14
Issue
s3
Pages
129-135
ISSN
  • 1462-8902 (ISSN-L)
  • 1463-1326
DOI
10.1111/j.1463-1326.2012.01655.x
PMC
PMC3712635
OpenAlex
W2109296305
Cited by
36
References
6
Citations by year
2026: 2 · 2025: 2 · 2024: 3 · 2023: 5 · 2022: 4 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 4 · 2015: 3 · 2014: 3 · 2013: 3
FWCI
0.56
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Diabetes Obesity and Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5p60dk020579-35)
  • National Institute of Diabetes and Digestive and Kidney Diseases (5P60 DK020579, R01DK069445, P60-DK-020579, P30DK020579, DK-69445)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
beta-cell dysfunction, glucotoxicity, hyperglycemia, hyperstimulation, ATP-sensitive potassium channels, intracellular calcium, insulin secretion, beta-cell death, beta-cell mass, insulin deficiency, islets
MeSH terms
Animals, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Glucose, Glycolysis, Humans, Hyperglycemia, Insulin, Mice, Transgenic, Oxidative Phosphorylation, Insulin-Secreting Cells, Mice, KATP Channels

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