| 1. |
- Bauer, S, et al.
(författare)
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Functional coupling of human pancreatic islets and liver spheroids on-a-chip: Towards a novel human ex vivo type 2 diabetes model
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 14620-
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Tidskriftsartikel (refereegranskat)abstract
- Human in vitro physiological models studying disease and drug treatment effects are urgently needed as more relevant tools to identify new drug targets and therapies. We have developed a human microfluidic two-organ-chip model to study pancreatic islet–liver cross-talk based on insulin and glucose regulation. We have established a robust co-culture of human pancreatic islet microtissues and liver spheroids maintaining functional responses up to 15 days in an insulin-free medium. Functional coupling, demonstrated by insulin released from the islet microtissues in response to a glucose load applied in glucose tolerance tests on different days, promoted glucose uptake by the liver spheroids. Co-cultures maintained postprandial glucose concentrations in the circulation whereas glucose levels remained elevated in both single cultures. Thus, insulin secreted into the circulation stimulated glucose uptake by the liver spheroids, while the latter, in the absence of insulin, did not consume glucose as efficiently. As the glucose concentration fell, insulin secretion subsided, demonstrating a functional feedback loop between the liver and the insulin-secreting islet microtissues. Finally, inter-laboratory validation verified robustness and reproducibility. Further development of this model using tools inducing impaired glucose regulation should provide a unique in vitro system emulating human type 2 diabetes mellitus.
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| 2. |
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| 3. |
- Bokvist, K, et al.
(författare)
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Co-localization of L-type Ca2+ channels and insulin-containing secretory granules and its significance for the initiation of exocytosis in mouse pancreatic B-cells
- 1995
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Ingår i: EMBO Journal. - 1460-2075. ; 14:1, s. 50-57
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Tidskriftsartikel (refereegranskat)abstract
- We have monitored L-type Ca2+ channel activity, local cytoplasmic Ca2+ transients, the distribution of insulin-containing secretory granules and exocytosis in individual mouse pancreatic B-cells. Subsequent to the opening of the Ca2+ channels, exocytosis is initiated with a latency < 100 ms. The entry of Ca2+ that precedes exocytosis is unevenly distributed over the cell and is concentrated to the region with the highest density of secretory granules. In this region, the cytoplasmic Ca2+ concentration is 5- to 10-fold higher than in the remainder of the cell reaching concentrations of several micromolar. Single-channel recordings confirm that the L-type Ca2+ channels are clustered in the part of the cell containing the secretory granules. This arrangement, which is obviously reminiscent of the 'active zones' in nerve terminals, can be envisaged as being favourable to the B-cell as it ensures that the Ca2+ transient is maximal and restricted to the part of the cell where it is required to rapidly initiate exocytosis whilst at the same time minimizing the expenditure of metabolic energy to subsequently restore the resting Ca2+ concentration.
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| 4. |
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| 5. |
- Mir-Coll, J, et al.
(författare)
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Human Islet Microtissues as an In Vitro and an In Vivo Model System for Diabetes
- 2021
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 22:4
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Tidskriftsartikel (refereegranskat)abstract
- Loss of pancreatic β-cell function is a critical event in the pathophysiology of type 2 diabetes. However, studies of its underlying mechanisms as well as the discovery of novel targets and therapies have been hindered due to limitations in available experimental models. In this study we exploited the stable viability and function of standardized human islet microtissues to develop a disease-relevant, scalable, and reproducible model of β-cell dysfunction by exposing them to long-term glucotoxicity and glucolipotoxicity. Moreover, by establishing a method for highly-efficient and homogeneous viral transduction, we were able to monitor the loss of functional β-cell mass in vivo by transplanting reporter human islet microtissues into the anterior chamber of the eye of immune-deficient mice exposed to a diabetogenic diet for 12 weeks. This newly developed in vitro model as well as the described in vivo methodology represent a new set of tools that will facilitate the study of β-cell failure in type 2 diabetes and would accelerate the discovery of novel therapeutic agents.
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| 6. |
- Rorsman, Patrik, et al.
(författare)
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Ion channels, electrical activity and insulin secretion
- 1994
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Ingår i: Diabete & metabolisme. - 0338-1684. ; 20:2, s. 138-145
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Tidskriftsartikel (refereegranskat)abstract
- The insulin-secreting pancreatic beta cell is electrically excitable and changes in the membrane potential play an important role in coupling the metabolism of glucose (and other nutrient secretagogues) to the discharge of the insulin-containing granule. The application of the patch-clamp technique, which permits the recordings of the minute currents associated with the opening of individual ion channels, to pancreatic islet cells has revolutionized our understanding of the beta cell electrophysiology. Here we review some of the recent progress in the field. The properties of functionally important ion channels are described and their possible roles are discussed.
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