Role of islet structure and cellular interactions in the control of insulin secretion

Kelly, Catriona; McClenaghan, Neville H.; Flatt, Peter R.

doi:10.4161/isl.3.2.14805

Cited by 63 publications

(54 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such effects were associated with reductions in both islet and b-cell areas, whereas a-cell area was increased, reflecting resistance of glucagon secreting cells to cytotoxicity as well as observed increase in a-cell proliferation. Destruction of b-cells with loss of normal paracrine inhibition by insulin may also contribute in this regard (Kelly et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Responses of GLP1-secreting L-cells to cytotoxicity resemble pancreatic β-cells but not α-cells

Vasu

Moffett

McClenaghan

et al. 2014

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Little is known about responses of intestinal L-cells to chemical or cytokine-mediated attack and how these compare with pancreatic b-or a-cells. Administration of streptozotocin to mice induced severe diabetes, islet lymphocytic infiltration, increased a-cell proliferation and decreased numbers of b-and L-cells. In vitro, streptozotocin and cytokines reduced cell viability with higher lethal dose 50 values for a-TC1 cells. mRNA expression of Glut2 was lower and Cat was greater in GLUTag and a-TC1 cells compared with MIN6 cells. Cytotoxins affected the transcription of genes involved in secretion in GLUTag and MIN6 cells. They are also involved in upregulation of antioxidant defence enzymes, transcription of NfkB and Nos2, and production of nitrite in all cell types. Cytotoxin-induced DNA damage and apoptosis were apparent in all cells, but a-TC1 cells were less severely affected. Thus, responses of GLP1-secreting L-cells to cytotoxicity resemble b-cells, whereas a-cells are resistant due to differences in the expression of genes involved in cytotoxicity or antioxidant defence.

show abstract

Section: Discussionmentioning

confidence: 99%

Responses of GLP1-secreting L-cells to cytotoxicity resemble pancreatic β-cells but not α-cells

Vasu

Moffett

McClenaghan

et al. 2014

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

show abstract

“…MIN-6 ␤ cells, because of their propensity to cluster and form pseudoislets, are a proven model for investigations of the role of cell-to-cell contact in insulin secretion (2,5). MIN-6 cells cultured on NL-2-expressing HEK293 cells secreted 2.9-fold more insulin under basal glucose conditions and 3.3-fold more insulin under stimulatory glucose conditions than MIN-6 cells co-cultured with control-transfected HEK293 cells ( Fig.…”

Section: Presence Of Nl-2 and Nl-2 Binding Partner On ␤ Cell Surface-mentioning

confidence: 99%

“…We next tested whether soluble neuroligin, in a parallel manner, interferes with insulin secretion. In addition to rat islets, MIN-6 cells were employed for these experiments due to their tendency to cluster into pseudoislets and their proven utility as a model for investigations of ␤ cell-to-␤ cell interactions (2,5).…”

Section: Presence Of Nl-2 and Nl-2 Binding Partner On ␤ Cell Surface-mentioning

confidence: 99%

“…In contrast to the very large body of work concerning the intracellular signaling pathways and protein machinery controlling insulin secretion by ␤ cells, only two transcellular interactions that play a direct role in normal insulin secretion have been identified. The first is the coupling of adjacent ␤ cells by connexin36 channels (1,4,5). The gap junctions thus formed decrease basal secretion and enable the intraislet synchronization of insulin release necessary for normal glucose-stimulated insulin secretion (4,6).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Transcellular Neuroligin-2 Interactions Enhance Insulin Secretion and Are Integral to Pancreatic β Cell Function

Suckow

Zhang

Egodage

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:The synaptic protein neuroligin-2 is present on the pancreatic ␤ cell surface and affects insulin secretion. Results: Insulin secretion increases when ␤ cells contact adjacent cells expressing neuroligin; soluble neuroligin inhibits secretion. Conclusion: Clustered neuroligin-2 enhances insulin secretion in a transcellular manner, likely by promoting secretory microdomain formation. Significance: Transcellular protein-protein interactions paralleling the transsynaptic interactions that drive synapse formation may guide ␤ cell functional maturation.

show abstract

“…Thus, the normal b-cell secretory response in islets depends on intra-islet coordinated signaling cross talk and communication with adjacent cells (Meda et al 1979, Halban et al 1987, Palti et al 1996, Vozzi et al 1995, Squires et al 2000, Serre-Beinier et al 2002. This has prompted much research into the formation of functional islet-like structures, termed 'pseudoislets', aimed to better understand islet function and provide artificial islets that will function normally when transplanted to an in vivo environment (Kelly et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Configuration of electrofusion-derived human insulin-secreting cell line as pseudoislets enhances functionality and therapeutic utility

Guo-Parke¹,

McCluskey²,

Kelly³

et al. 2012

Journal of Endocrinology

Self Cite

View full text Add to dashboard Cite

Formation of pseudoislets from rodent cell lines has provided a particularly useful model to study homotypic islet cell interactions and insulin secretion. This study aimed to extend this research to generate and characterize, for the first time, functional human pseudoislets comprising the recently described electrofusion-derived insulin-secreting 1.1B4 human b-cell line. Structural pseudoislets formed readily over 3-7 days in culture using ultra-low-attachment plastic, attaining a static size of 100-200 mm in diameter, corresponding to w6000 b cells. This was achieved by decreases in cell proliferation and integrity as assessed by BrdU ELISA, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, and lactate dehydrogenase assays. Insulin content was comparable between monolayers and pseudoislets. However, pseudoislet formation enhanced insulin secretion by 1 . 7-to 12 . 5-fold in response to acute stimulation with glucose, amino acids, incretin hormones, or drugs compared with equivalent cell monolayers. Western blot and RT-PCR showed expression of key genes involved in cell communication and the stimulus-secretion pathway. Expression of E-Cadherin and connexin 36 and 43 was greatly enhanced in pseudoislets with no appreciable connexin 43 protein expression in monolayers. Comparable levels of insulin, glucokinase, and GLUT1 were found in both cell populations. The improved secretory function of human 1.1B4 cell pseudoislets over monolayers results from improved cellular interactions mediated through gap junction communication. Pseudoislets comprising engineered electrofusion-derived human b cells provide an attractive model for islet research and drug testing as well as offering novel therapeutic application through transplantation.

show abstract

Role of islet structure and cellular interactions in the control of insulin secretion

Cited by 63 publications

References 54 publications

Responses of GLP1-secreting L-cells to cytotoxicity resemble pancreatic β-cells but not α-cells

Responses of GLP1-secreting L-cells to cytotoxicity resemble pancreatic β-cells but not α-cells

Transcellular Neuroligin-2 Interactions Enhance Insulin Secretion and Are Integral to Pancreatic β Cell Function

Configuration of electrofusion-derived human insulin-secreting cell line as pseudoislets enhances functionality and therapeutic utility

Contact Info

Product

Resources

About