Cited by 32Pancreatic function and diabetesDiabetes Treatment and ManagementMitochondrial Function and Pathology

Modelling of dysregulated glucagon secretion in type 2 diabetes by considering mitochondrial alterations in pancreatic α-cells

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Grubelnik, Vladimir, Markovič, Rene, Lipovšek, Saška, Leitinger, Gerd, Gosak, Marko, Dolenšek, Jurij, Valladolid-Acebes, Ismael, Berggren, Per-Olof +3 more·2020·Royal Society Open Science

Abstract

Type 2 diabetes mellitus (T2DM) has been associated with insulin resistance and the failure of β-cells to produce and secrete enough insulin as the disease progresses. However, clinical treatments based solely on insulin secretion and action have had limited success. The focus is therefore shifting towards α-cells, in particular to the dysregulated secretion of glucagon. Our qualitative electron-microscopy-based observations gave an indication that mitochondria in α-cells are altered in Western-diet-induced T2DM. In particular, α-cells extracted from mouse pancreatic tissue showed a lower density of mitochondria, a less expressed matrix and a lower number of cristae. These deformities in mitochondrial ultrastructure imply a decreased efficiency in mitochondrial ATP production, which prompted us to theoretically explore and clarify one of the most challenging problems associated with T2DM, namely the lack of glucagon secretion in hypoglycaemia and its oversecretion at high blood glucose concentrations. To this purpose, we constructed a novel computational model that links α-cell metabolism with their electrical activity and glucagon secretion. Our results show that defective mitochondrial metabolism in α-cells can account for dysregulated glucagon secretion in T2DM, thus improving our understanding of T2DM pathophysiology and indicating possibilities for new clinical treatments.

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Authors
Grubelnik, V., Markovič, R., Lipovšek, S., Leitinger, G., Gosak, M., Dolenšek, J., Valladolid-Acebes, I., Berggren, P.-O., Stožer, A., Perc, M., & Marhl, M.
Affiliations
  • University of Maribor (SI)
  • Medical University of Graz (AT)
  • The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, 171 76 Stockholm, Sweden
  • Karolinska University Hospital (SE)
  • China Medical University (TW)
Corresponding author
  • Perc, Matjaž
  • Marhl, Marko
Venue
Royal Society Open Science
Published
2020-01
Volume
7
Issue
1
Pages
191171
ISSN
2054-5703 (ISSN-L)
OpenAlex
W3000903374
Cited by
32
References
85
Citations by year
2026: 1 · 2025: 5 · 2024: 2 · 2023: 3 · 2022: 7 · 2021: 9 · 2020: 4 · 2018: 1
FWCI
5.25
Type
journal article
Language
en
Open access
Locations
  • Royal Society Open Science (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Novo Nordisk Fonden (NNF18OC0033826)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
type 2 diabetes, glucagon secretion, alpha cells, mitochondrial dysfunction, mitochondrial ultrastructure, mitochondrial ATP production, hypoglycemia, hyperglycemia, computational model, Western diet

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