Isolated human islets require hyperoxia to maintain islet mass, metabolism, and function

Komatsu, Hirotake; Kang, Dong Hyun; Medrano, Leonard; Barriga, Alyssa; Mendez, Daniel; Rawson, Jeffrey; Omori, Keiko; Ferreri, Kevin; Yu, Hongyu; Kandeel, Fouad; Mullen, Yoko

doi:10.1016/j.bbrc.2016.01.110

Cited by 36 publications

(48 citation statements)

References 16 publications

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“…A discrepancy between studies could be due to differences in oxygen concentrations between studies as well as other factors; here we tested for effects after 24 h, whereas the published report (Komatsu et al. ) tested after 7 days of oxygen exposure. Also, base‐line viability status of islets may have differed.…”

Section: Discussionmentioning

confidence: 97%

“…Komatsu et al. () reported a positive effect by hyperoxia (tested up to 50% oxygen) on the viability of human islets. Using rat islets, we did not detect any positive effects of culture at 30 or 40% oxygen (unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

“…More serious and irreversible effects could be envisaged after an extended exposure time to hyperoxia, something which was not tested here. Komatsu et al (2016) reported a positive effect by hyperoxia (tested up to 50% oxygen) on the viability of human islets. Using rat islets, we did not detect any positive effects of culture at 30 or 40% oxygen (unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

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Hyperoxia reduces insulin release and induces mitochondrial dysfunction with possible implications for hyperoxic treatment of neonates

et al. 2017

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We previously showed that hyperoxia in vitro negatively affects beta cells of the rat. Here, we tested for possible clinical significance as well as mitochondrial interactions by hyperoxia, using human islets (function and viability), INS‐1 832/13 cells (mitochondrial metabolism), and mouse neonates (effects in vivo). Lastly, we assessed relevant parameters in a cohort of individuals born preterm and then exposed to hyperoxia. Human islets and INS‐1 832/13 cells were exposed to 24 h of hyperoxia (90–92% oxygen). Mouse neonates were subjected to 5 days of continuous hyperoxia. Individuals born preterm were evaluated in terms of glucose homeostasis and beta cell function by HbA1c and the HOMA2 formula. In human islets, hyperoxia significantly reduced glucose‐stimulated insulin secretion by 42.2 ± 5.3% and viability assessed by MTT by 22.5 ± 5.4%. Hyperoxia down‐regulated mitochondrial complex II by 21 ± 5% and upregulated complex III by 26 ± 10.1% and complex IV by 37 ± 10.6%. Partly similar effects on mitochondrial complexes were found in hyperoxia‐exposed INS‐1 832/13 cells. Exposure to hyperoxia swiftly reduced oxygen consumption in these cells and increased mitochondrial uncoupling. Hyperoxia transiently but significantly reduced insulin release in mouse neonates. Individuals born preterm displayed higher HbA1c versus controls, as well as insulin resistance. Thus, hyperoxia exerts negative effects in vitro on human beta cells and results indicate inhibitory effects on insulin secretion in vivo in mouse neonates. Negative effects may be lessened by the demonstrated swift and profound mitochondrial adaptability. Our findings open the possibility that hyperoxia could negatively affect beta cells of preterm human neonates.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Hyperoxia reduces insulin release and induces mitochondrial dysfunction with possible implications for hyperoxic treatment of neonates

et al. 2017

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“…The effect of oxygen on islets has been investigated by multiple researchers. Globally, severe hypoxia, akin to the oxygen environment transplanted islets initially encounter, has been shown to negatively impact islet yield, viability, and functionality . However, moderate hypoxia may have a beneficial effect on islet function …”

Section: Introductionmentioning

confidence: 99%

“…Globally, severe hypoxia, akin to the oxygen environment transplanted islets initially encounter, has been shown to negatively impact islet yield, viability, and functionality. [9][10][11] However, moderate hypoxia may have a beneficial effect on islet function. 12 Research into the effect(s) of how these single parameters individually impact pancreatic tissue attributes has enriched the diabetes community.…”

Section: Introductionmentioning

confidence: 99%

A factorial design to identify process parameters affecting whole mechanically disrupted rat pancreata in a perfusion bioreactor

Sharp

Spitters

Vermette

2017

Biotechnology Progress

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Few studies report whole pancreatic tissue culture, as it is a difficult task using traditional culture methods. Here, a factorial design was used to investigate the singular and combinational effects of flow, dissolved oxygen concentration (D.O.) and pulsation on whole mechanically disrupted rat pancreata in a perfusion bioreactor. Whole rat pancreata were cultured for 72 h under defined bioreactor process conditions. Secreted insulin was measured and histological (haematoxylin and eosin (H&E)) as well as immunofluorescent insulin staining were performed and quantified. The combination of flow and D.O. had the most significant effect on secreted insulin at 5 h and 24 h. The D.O. had the biggest effect on tissue histological quality, and pulsation had the biggest effect on the number of insulin-positive structures. Based on the factorial design analysis, bioreactor conditions using high flow, low D.O., and pulsation were selected to further study glucose-stimulated insulin secretion. Here, mechanically disrupted rat pancreata were cultured for 24 h under these bioreactor conditions and were then challenged with high glucose concentration for 6 h and high glucose + IBMX (an insulin secretagogue) for a further 6 h. These cultures secreted insulin in response to high glucose concentration in the first 6 h, however stimulated-insulin secretion was markedly weaker in response to high glucose concentration + IBMX thereafter. After this bioreactor culture period, higher tissue metabolic activity was found compared to that of non-bioreacted static controls. More insulin- and glucagon-positive structures, and extensive intact endothelial structures were observed compared to non-bioreacted static cultures. H&E staining revealed more intact tissue compared to static cultures. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 34:432-444, 2018.

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Identification of Compounds Protecting Pancreatic Islets against Oxidative Stress using a 3D Pseudoislet Screening Platform

Rademakers,

Sthijns,

Paulino da Silva Filho

et al. 2023

Advanced Biology

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Oxidative stress leads to a lower success rate of clinical islet transplantation. Here, FDA‐approved compounds are screened for their potential to decrease oxidative stress and to protect or enhance pancreatic islet viability and function. Studies are performed on in vitro “pseudoislet” spheroids, which are pre‐incubated with 1280 different compounds and subjected to oxidative stress. Cell viability and oxidative stress levels are determined using a high‐throughput fluorescence microscopy pipeline. Initial screening on cell viability results in 59 candidates. The top ten candidates are subsequently screened for their potential to decrease induced oxidative stress, and eight compounds efficient reduction of induced oxidative stress in both alpha and beta cells by 2550%. After further characterization, the compound sulfisoxazole is found to be the most capable of reducing oxidative stress, also at short pre‐incubation times, which is validated in primary human islets, where low oxidative stress levels and islet function are maintained. This study shows an effective screening strategy with 3D cell aggregates based on cell viability and oxidative stress, which leads to the discovery of several compounds with antioxidant capacity. The top candidate, sulfisoxazole is effective after a 30 min pre‐incubation, maintains baseline islet function, and may help alleviate oxidative stress in pancreatic islets.

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Isolated human islets require hyperoxia to maintain islet mass, metabolism, and function

Cited by 36 publications

References 16 publications

Hyperoxia reduces insulin release and induces mitochondrial dysfunction with possible implications for hyperoxic treatment of neonates

Hyperoxia reduces insulin release and induces mitochondrial dysfunction with possible implications for hyperoxic treatment of neonates

A factorial design to identify process parameters affecting whole mechanically disrupted rat pancreata in a perfusion bioreactor

Identification of Compounds Protecting Pancreatic Islets against Oxidative Stress using a 3D Pseudoislet Screening Platform

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