PMID- 32218947 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200928 IS - 2054-5703 (Print) IS - 2054-5703 (Electronic) IS - 2054-5703 (Linking) VI - 7 IP - 1 DP - 2020 Jan TI - Modelling of dysregulated glucagon secretion in type 2 diabetes by considering mitochondrial alterations in pancreatic alpha-cells. PG - 191171 LID - 10.1098/rsos.191171 [doi] LID - 191171 AB - Type 2 diabetes mellitus (T2DM) has been associated with insulin resistance and the failure of beta-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 alpha-cells, in particular to the dysregulated secretion of glucagon. Our qualitative electron-microscopy-based observations gave an indication that mitochondria in alpha-cells are altered in Western-diet-induced T2DM. In particular, alpha-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 alpha-cell metabolism with their electrical activity and glucagon secretion. Our results show that defective mitochondrial metabolism in alpha-cells can account for dysregulated glucagon secretion in T2DM, thus improving our understanding of T2DM pathophysiology and indicating possibilities for new clinical treatments. CI - (c) 2020 The Authors. FAU - Grubelnik, Vladimir AU - Grubelnik V AD - Faculty of Electrical Engineering and Computer Science, University of Maribor, 2000 Maribor, Slovenia. FAU - Markovic, Rene AU - Markovic R AD - Faculty of Electrical Engineering and Computer Science, University of Maribor, 2000 Maribor, Slovenia. AD - Faculty of Natural Sciences and Mathematics, University of Maribor, 2000 Maribor, Slovenia. FAU - Lipovsek, Saska AU - Lipovsek S AD - Faculty of Natural Sciences and Mathematics, University of Maribor, 2000 Maribor, Slovenia. AD - Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia. AD - Faculty of Chemistry and Chemical Engineering, University of Maribor, 2000 Maribor, Slovenia. AD - Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria. FAU - Leitinger, Gerd AU - Leitinger G AD - Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria. FAU - Gosak, Marko AU - Gosak M AD - Faculty of Natural Sciences and Mathematics, University of Maribor, 2000 Maribor, Slovenia. AD - Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia. FAU - Dolensek, Jurij AU - Dolensek J AD - Faculty of Natural Sciences and Mathematics, University of Maribor, 2000 Maribor, Slovenia. AD - Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia. FAU - Valladolid-Acebes, Ismael AU - Valladolid-Acebes I AD - The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, 171 76 Stockholm, Sweden. FAU - Berggren, Per-Olof AU - Berggren PO AD - The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, 171 76 Stockholm, Sweden. FAU - Stozer, Andraz AU - Stozer A AD - Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia. FAU - Perc, Matjaz AU - Perc M AD - Faculty of Natural Sciences and Mathematics, University of Maribor, 2000 Maribor, Slovenia. AD - Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan. AD - Complexity Science Hub Vienna, 1080 Vienna, Austria. FAU - Marhl, Marko AU - Marhl M AD - Faculty of Natural Sciences and Mathematics, University of Maribor, 2000 Maribor, Slovenia. AD - Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia. AD - Faculty of Education, University of Maribor, 2000 Maribor, Slovenia. LA - eng SI - figshare/10.6084/m9.figshare.c.4810635 SI - Dryad/10.5061/dryad.9n2k1vk PT - Journal Article DEP - 20200122 PL - England TA - R Soc Open Sci JT - Royal Society open science JID - 101647528 PMC - PMC7029933 OTO - NOTNLM OT - diabetes OT - free fatty acid OT - glucagon OT - mitochondrial dysfunction OT - pancreatic alpha-cell COIS- M.P. was a member of the Royal Society Open Science Editorial Board at the time of submission and publication of this paper, but was not involved in the assessment of the manuscript. EDAT- 2020/03/29 06:00 MHDA- 2020/03/29 06:01 PMCR- 2020/01/22 CRDT- 2020/03/29 06:00 PHST- 2019/07/15 00:00 [received] PHST- 2019/12/16 00:00 [accepted] PHST- 2020/03/29 06:00 [entrez] PHST- 2020/03/29 06:00 [pubmed] PHST- 2020/03/29 06:01 [medline] PHST- 2020/01/22 00:00 [pmc-release] AID - rsos191171 [pii] AID - 10.1098/rsos.191171 [doi] PST - epublish SO - R Soc Open Sci. 2020 Jan 22;7(1):191171. doi: 10.1098/rsos.191171. eCollection 2020 Jan.