The Beta Cell in Its Cluster: Stochastic Graphs of Beta Cell Connectivity in the Islets of Langerhans

Striegel, Deborah A.; Hara, Manami; Periwal, Vipul

doi:10.1371/journal.pcbi.1004423

Cited by 24 publications

(21 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This value was used to calculate the cell density in an islet ( Table 1 ). Because beta and alpha cells are the dominant cells in human islets [ 29 , 30 ], the OCR obtained from beta and alpha cell lines were used for the simulation. The measured OCR was 4.38 × 10 −3 pmol/min/cell in a single INS-1 cell (a beta cell line), similar to 4.12 × 10 −3 pmol/min/cell measured in a single NIT-1 cell (another beta cell-line).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Oxygen environment and islet size are the primary limiting factors of isolated pancreatic islet survival

et al. 2017

View full text Add to dashboard Cite

BackgroundType 1 diabetes is an autoimmune disease that destroys insulin-producing beta cells in the pancreas. Pancreatic islet transplantation could be an effective treatment option for type 1 diabetes once several issues are resolved, including donor shortage, prevention of islet necrosis and loss in pre- and post-transplantation, and optimization of immunosuppression. This study seeks to determine the cause of necrotic loss of isolated islets to improve transplant efficiency.MethodologyThe oxygen tension inside isolated human islets of different sizes was simulated under varying oxygen environments using a computational in silico model. In vitro human islet viability was also assessed after culturing in different oxygen conditions. Correlation between simulation data and experimentally measured islet viability was examined. Using these in vitro viability data of human islets, the effect of islet diameter and oxygen tension of the culture environment on islet viability was also analyzed using a logistic regression model.Principal findingsComputational simulation clearly revealed the oxygen gradient inside the islet structure. We found that oxygen tension in the islet core was greatly lower (hypoxic) than that on the islet surface due to the oxygen consumption by the cells. The hypoxic core was expanded in the larger islets or in lower oxygen cultures. These findings were consistent with results from in vitro islet viability assays that measured central necrosis in the islet core, indicating that hypoxia is one of the major causes of central necrosis. The logistic regression analysis revealed a negative effect of large islet and low oxygen culture on islet survival.Conclusions/SignificanceHypoxic core conditions, induced by the oxygen gradient inside islets, contribute to the development of central necrosis of human isolated islets. Supplying sufficient oxygen during culture could be an effective and reasonable method to maintain isolated islets viable.

show abstract

Section: Resultsmentioning

confidence: 99%

“…Interestingly, the estimated single cell volume calculated using our method was similar to that calculated by another method previously published [ 15 ]. We did not calculate the volume differences among different cell types in the islet because the beta and alpha cells are the dominant cell types in the islet [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Oxygen environment and islet size are the primary limiting factors of isolated pancreatic islet survival

et al. 2017

View full text Add to dashboard Cite

show abstract

“…2Ab (beta-cells in green, alpha-cells in red and delta-cells in blue). The coordinate data are used to count the number of each endocrine cell type within islets, and for further analysis of cellular composition and geographic islet architecture (such as for mathematical modeling 25 26 27 28 29 ). Sequential analysis by the Image analysis macro is outlined in Fig.…”

Section: Resultsmentioning

confidence: 99%

Stereological analyses of the whole human pancreas

Poudel

Fowler

Zielinski

et al. 2016

Sci Rep

Self Cite

View full text Add to dashboard Cite

The large size of human tissues requires a practical stereological approach to perform a comprehensive analysis of the whole organ. We have developed a method to quantitatively analyze the whole human pancreas, as one of the challenging organs to study, in which endocrine cells form various sizes of islets that are scattered unevenly throughout the exocrine pancreas. Furthermore, the human pancreas possesses intrinsic characteristics of intra-individual variability, i.e. regional differences in endocrine cell/islet distribution, and marked inter-individual heterogeneity regardless of age, sex and disease conditions including obesity and diabetes. The method is built based on large-scale image capture, computer-assisted unbiased image analysis and quantification, and further mathematical analyses, using widely-used software such as Fiji/ImageJ and MATLAB. The present study includes detailed protocols of every procedure as well as all the custom-written computer scripts, which can be modified according to specific experimental plans and specimens of interest.

show abstract

“…For example, does the degree of suppression of glucagon secretion by high glucose correlate with the number of δ‐cells, the number of δ‐to‐α contacts, or graph theory measures of connectivity and centrality (Striegel et al . )? The limiting factor in answering these questions is our sample size – we only have six human islet architectures.…”

Section: Discussionmentioning

confidence: 99%

δ‐cells and β‐cells are electrically coupled and regulate α‐cell activity via somatostatin

Briant

Reinbothe

Spiliotis

et al. 2017

The Journal of Physiology

126

120

View full text Add to dashboard Cite

Key points We used a mouse expressing a light‐sensitive ion channel in β‐cells to understand how α‐cell activity is regulated by β‐cells.Light activation of β‐cells triggered a suppression of α‐cell activity via gap junction‐dependent activation of δ‐cells.Mathematical modelling of human islets suggests that 23% of the inhibitory effect of glucose on glucagon secretion is mediated by β‐cells via gap junction‐dependent activation of δ‐cells/somatostatin secretion. AbstractGlucagon, the body's principal hyperglycaemic hormone, is released from α‐cells of the pancreatic islet. Secretion of this hormone is dysregulated in type 2 diabetes mellitus but the mechanisms controlling secretion are not well understood. Regulation of glucagon secretion by factors secreted by neighbouring β‐ and δ‐cells (paracrine regulation) have been proposed to be important. In this study, we explored the importance of paracrine regulation by using an optogenetic strategy. Specific light‐induced activation of β‐cells in mouse islets expressing the light‐gated channelrhodopsin‐2 resulted in stimulation of electrical activity in δ‐cells but suppression of α‐cell activity. Activation of the δ‐cells was rapid and sensitive to the gap junction inhibitor carbenoxolone, whereas the effect on electrical activity in α‐cells was blocked by CYN 154806, an antagonist of the somatostatin‐2 receptor. These observations indicate that optogenetic activation of the β‐cells propagates to the δ‐cells via gap junctions, and the consequential stimulation of somatostatin secretion inhibits α‐cell electrical activity by a paracrine mechanism. To explore whether this pathway is important for regulating α‐cell activity and glucagon secretion in human islets, we constructed computational models of human islets. These models had detailed architectures based on human islets and consisted of a collection of >500 α‐, β‐ and δ‐cells. Simulations of these models revealed that this gap junctional/paracrine mechanism accounts for up to 23% of the suppression of glucagon secretion by high glucose.

show abstract

The Beta Cell in Its Cluster: Stochastic Graphs of Beta Cell Connectivity in the Islets of Langerhans

Cited by 24 publications

References 57 publications

Oxygen environment and islet size are the primary limiting factors of isolated pancreatic islet survival

Oxygen environment and islet size are the primary limiting factors of isolated pancreatic islet survival

Stereological analyses of the whole human pancreas

δ‐cells and β‐cells are electrically coupled and regulate α‐cell activity via somatostatin

Contact Info

Product

Resources

About