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Cited by 73Pancreatic function and diabetesCellular transport and secretionCalcium signaling and nucleotide metabolism

Progression of Diet-Induced Diabetes in C57BL6J Mice Involves Functional Dissociation of Ca2+ Channels From Secretory Vesicles

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Collins, Stephan C., Hoppa, Michael B., Walker, Jonathan N., Amisten, Stefan, Abdulkader, Fernando, Bengtsson, Martin, Fearnside, Jane, Ramracheya, Reshma +5 more·2010·Diabetes
DOI 10.2337/db09-0791PMC PMC2857899
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Abstract

OBJECTIVE: The aim of the study was to elucidate the cellular mechanism underlying the suppression of glucose-induced insulin secretion in mice fed a high-fat diet (HFD) for 15 weeks. RESEARCH DESIGN AND METHODS: C57BL6J mice were fed a HFD or a normal diet (ND) for 3 or 15 weeks. Plasma insulin and glucose levels in vivo were assessed by intraperitoneal glucose tolerance test. Insulin secretion in vitro was studied using static incubations and a perfused pancreas preparation. Membrane currents, electrical activity, and exocytosis were examined by patch-clamp technique measurements. Intracellular calcium concentration ([Ca2+]i) was measured by microfluorimetry. Total internal reflection fluorescence microscope (TIRFM) was used for optical imaging of exocytosis and submembrane depolarization-evoked [Ca2+]i. The functional data were complemented by analyses of histology and gene transcription. RESULTS: After 15 weeks, but not 3 weeks, mice on HFD exhibited hyperglycemia and hypoinsulinemia. Pancreatic islet content and β-cell area increased 2- and 1.5-fold, respectively. These changes correlated with a 20–50% reduction of glucose-induced insulin secretion (normalized to insulin content). The latter effect was not associated with impaired electrical activity or [Ca2+]i signaling. Single-cell capacitance and TIRFM measurements of exocytosis revealed a selective suppression (>70%) of exocytosis elicited by short (50 ms) depolarization, whereas the responses to longer depolarizations were (500 ms) less affected. The loss of rapid exocytosis correlated with dispersion of Ca2+ entry in HFD β-cells. No changes in gene transcription of key exocytotic protein were observed. CONCLUSIONS: HFD results in reduced insulin secretion by causing the functional dissociation of voltage-gated Ca2+ entry from exocytosis. These observations suggest a novel explanation to the well-established link between obesity and diabetes.

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  • Ca2+ channel clustering is absent following chronic exposure to palmitate or in glucose-intolerant high-fat-fed mice.

    “Interestingly, Ca2+ channel clustering is absent following chronic exposure to palmitate (a diabetogenic condition) or in glucose-intolerant high-fat-fed mice (123).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [123]

    The Discussion (page unavailable) says Ca2+ entry becomes more diffuse in high-fat-fed β-cells, suggesting less efficient channel clustering; the Results report glucose intolerance in the high-fat-fed mice. The Discussion also says that findings after more than 72 hours of palmitate exposure were similar. It does not establish that clustering is absent in either condition, so the claim is stronger than the source. (LLM, conf=0.88)

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Authors
Collins, S. C., Hoppa, M. B., Walker, J. N., Amisten, S., Abdulkader, F., Bengtsson, M., Fearnside, J., Ramracheya, R., Toye, A. A., Zhang, Q., Clark, A., Gauguier, D., & Rorsman, P.
Affiliations
  • Churchill Hospital (GB)
  • Universidade de São Paulo (BR)
  • Centre for Human Genetics (GB)
Corresponding author
Collins, Stephan C.
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2010-02-11
Volume
59
Issue
5
Pages
1192-1201
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db09-0791
PMC
PMC2857899
OpenAlex
W2165080214
Cited by
73
References
3
Citations by year
2026: 3 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 6 · 2020: 2 · 2019: 1 · 2018: 5 · 2017: 4 · 2016: 6 · 2015: 7 · 2014: 9 · 2013: 14 · 2012: 4
FWCI
8.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Scientific Electronic Library Online (São Paulo Research Foundation, Latin American and Caribbean Center on Health Sciences Information, Conselho Nacional de Desenvolvimento Científico e Tecnológico) (publishedVersion)
Funders
  • Wellcome Trust (057733/Z/99/A)
  • European Commission
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
diet-induced diabetes, high-fat diet, beta-cell dysfunction, insulin secretion, exocytosis, voltage-gated calcium channels, calcium influx, pancreatic islets, obesity, hyperglycemia, hypoinsulinemia, C57BL/6J mice
MeSH terms
Animals, Diabetes Mellitus, Type 2, Dietary Fats, Exocytosis, Flow Cytometry, Immunohistochemistry, Insulin, Male, Mice, Inbred C57BL, Microscopy, Fluorescence, Calcium Channels, Glucose Intolerance, Secretory Vesicles, Insulin-Secreting Cells, Mice

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