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Islet bioenergetic efficiency is regulated by nutrients
Stockholm University, Faculty of Science, The Wenner-Gren Institute . (Jan Nedergaard)
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background and aims

Excessive or unbalanced nutrient intake may cause diabetes. A growing body of evidence points to that mitochondrial dysfunction plays an important role in

Materials and methods

To enable the study we developed a high-throughput islet respirometry approach based on the XF24 platform, originally designed to study monolayers of cells. By applying drugs that act on the respiratory chain we can estimate the level of fuel-stimulated, uncoupled (reflecting proton leak), maximal as well as non-mitochondrial respiration under various conditions. Islets were derived from wildtype and high fat diet fed C57Bl6/J mice as well as from human donors.

β-cell dysfunction. The reason for this is likely that mitochondria stand in the center of nutrient metabolism. In this study we tested the hypothesis that islets from diabetic animals have defect mitochondrial respiratory function. Results

We found that due to increased proton leak, islets from diabetic high fat diet fed animals exhibit lower respiratory efficiency as compared to animals fed control chow. Examining the regulation of the leak we found that fuels that stimulate insulin secretion also increase uncoupled respiration, and that this may be mediated by reactive oxygen species. Moreover, dissecting the molecular mechanism, we show that the adenine nucleotide transporter contributes to one-third of the leak while uncoupling protein 2 and permeability transition pore appear not to contribute. Finally, we examined a cohort of human islets and found lower levels of uncoupled respiration as compared to mouse islets. However, as in the mouse islets glucose challenge induced increase in uncoupled respiration. Interestingly, there was a trend towards lower oxygen consumption rates in islets from obese donors.


Islets have relative high levels of proton leak, which is regulated by cellular fuels and reactive oxygen species. Adenine nucleotide transporter but not uncoupling protein 2 or permeability transition pore appears to contribute to the observed uncoupled respiration. Interestingly, levels of uncoupled respiration increase in a diabetes animal model. In theory, tuning islet mitochondrial efficiency may represent a therapeutic target.

Keyword [en]
mitochondria, islets, diabetes
National Category
Research subject
URN: urn:nbn:se:su:diva-39343OAI: diva2:319508
Available from: 2010-05-18 Created: 2010-05-18 Last updated: 2010-08-04Bibliographically approved
In thesis
1. Mitochondrial form and function in pancreatic β-cells and brown adipocytes
Open this publication in new window or tab >>Mitochondrial form and function in pancreatic β-cells and brown adipocytes
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis is focused on the role of mitochondria in pancreatic β-cells and brown adipose tissue (BAT). Two main aspects of mitochondria were explored; mitochondrial functional efficiency and the interrelationship between mitochondrial shape and function.

Mitochondria in β-cells were found to exhibit heterogeneity in mitochondrial membrane potential. This functional diversity decreased when cells were challenged with glucose stimuli, suggesting that at higher fuel levels low-activity mitochondria are recruited into a pool of high-activity mitochondria. Glucolipotoxic conditions increased the functional diversity suggesting that this may be of importance for diabetes pathophysiology.

To examine mitochondrial efficiency in intact islets a high throughput islet respirometry method was developed. Due to increased uncoupling, islets from a diabetic animal model exhibit lower respiratory efficiency. Glucose, free fatty acids and amino acids all decreased respiratory efficiency. A large portion of the respiratory efficiency was mediated by reactive oxygen species and the adenine nucleotide translocase.

In β-cells mitochondria were found to undergo cycles of fusion and fission. During glucolipotoxicity mitochondria fragmented and lost their fusion ability. Knock down of the fission protein Fis1 rescued the β-cells from glucolipotoxic induced cell death. BAT mitochondria also showed fusion and fission. The mitochondrial dynamics proteins Mfn2 and Drp1 were shown to strongly affect BAT mitochondrial morphology. In response to a combination of adrenergic and free fatty acid stimuli mitochondria drastically changed from long filamentous structures to fragmented spheres. Inhibiting fission by the negative form of Drp1 decreased BAT response to adrenergic stimuli by half.

In conclusion, mitochondrial efficiency may be of importance for normal as well as compromised β-cell and islet function. Mitochondrial morphology appears critical for mitochondrial function in β-cells and BAT.

Place, publisher, year, edition, pages
The Wenner-Gren Institute,Stockholm University, 2010. 70 p.
mitochondria, beta cells, brown adipose tissue, diabetes, obesity
National Category
Research subject
urn:nbn:se:su:diva-39336 (URN)978-91-7447-095-6 (ISBN)
Public defence
2010-06-14, hörsal Fb107, Frescati backe, Svante Arrhenius väg 21 A, Stockholm, 10:00 (English)
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.Available from: 2010-05-23 Created: 2010-05-18 Last updated: 2010-08-04Bibliographically approved

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