Modelling of dysregulated glucagon secretion in type 2 diabetes by considering mitochondrial alterations in pancreatic α-cells
Open accessAbstract
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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A relatively large set of mathematical models were developed with focus on glucagon secretion at cellular level.
“A relatively large set of mathematical models were developed with focus on glucagon secretion at cellular level (12–21).”
From Mathematical Model of Glucagon Kinetics for the Assessment of Insulin-Mediated Glucagon Inhibition During an Oral Glucose Tolerance Test (2021) · cites this paper as [12]
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Calcium imaging in intact mouse acinar cells in acute pancreas tissue slices
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The relationship between physical activity and diabetes in middle-aged and elderly people
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Critical slowing down indicators in synchronous period-doubling for salamander flicker vision
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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
- ORCID
- Venue
- Royal Society Open Science
- Publisher
- The Royal Society
- Published
- 2020-01
- Volume
- 7
- Issue
- 1
- Pages
- 191171
- ISSN
- 2054-5703 (ISSN-L)
- PMC
- PMC7029933
- 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
- gold
- doi.org
- 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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