Calcineurin/NFAT signaling in the β‐cell: From diabetes to new therapeutics

@article{Heit2007CalcineurinNFATSI,
  title={Calcineurin/NFAT signaling in the $\beta$‐cell: From diabetes to new therapeutics},
  author={Jeremy J. Heit},
  journal={BioEssays},
  year={2007},
  volume={29}
}
  • J. Heit
  • Published 1 October 2007
  • Biology, Medicine
  • BioEssays
Pancreatic β‐cells in the islet of Langerhans produce the hormone insulin, which maintains blood glucose homeostasis. Perturbations in β‐cell function may lead to impairment of insulin production and secretion and the onset of diabetes mellitus. Several essential β‐cell factors have been identified that are required for normal β‐cell function, including six genes that when mutated give rise to inherited forms of diabetes known as Maturity Onset Diabetes of the Young (MODY). However, the… 
β‐Cell preservation and regeneration in diabetes by modulation of β‐cell Ca2+ homeostasis
TLDR
Down‐regulation of the Na/Ca exchanger leads to various changes in β‐cell function that are opposite to the major abnormalities seen in diabetes, providing a unique model for the prevention and treatment of β‐ cell dysfunction in diabetes and following islet transplantation.
Cellular responses of novel human pancreatic β-cell line, 1.1B4 to hyperglycemia
TLDR
Significant changes in cellular responses and gene expression are revealed in novel human pancreatic 1.1B4 β cells exposed to hyperglycemia, illustrating the usefulness of this novel human-derived cell line for studying human β-cell biology and diabetes.
Na/Ca Exchanger a Druggable Target to Promoteb-Cell ProliferationandFunction
TLDR
It is shown that Ncx1 inactivation also increases b-cell proliferation in 2-year-old mice and that NCX1 inhibition in adult mice by four small molecules of the benzoxyphenyl family stimulates b- Cell proliferation both in vitro and in vivo, and that Na/Ca exchange is a druggable target to stimulate b- cell function and proliferation.
Na+/Ca2+ Exchanger a Druggable Target to Promote β-Cell Proliferation and Function
TLDR
Specificβ-cell inhibition of Na+/Ca2+ exchange by phenoxybenzamyl derivatives may represent an innovative approach to promote β-cell regeneration in diabetes and improve the efficiency of pancreatic islet transplantation for the treatment of the disease.
Calcineurin/Nuclear Factor of Activated T Cells and MAPK Signaling Induce TNF-α Gene Expression in Pancreatic Islet Endocrine Cells*
TLDR
The data show that glucose and IL-1β can activate signaling pathways, which control induction and repression of cytokines in pancreatic endocrine cells, and by these mechanisms, pancreatic β cells themselves may contribute to islet inflammation and their own immunological destruction in the pathogenesis of diabetes.
Unique Cellular and Mitochondrial Defects Mediate FK506-Induced Islet &bgr;-Cell Dysfunction
TLDR
At pharmacologically relevant concentrations, FK506 decreases insulin secretion and reduces mitochondrial density and function without changing apoptosis rates, suggesting that posttransplantation diabetes induced by FK505 may be mediated by its effects on mitochondrial function.
In vivo imaging of β-cell function reveals glucose-mediated heterogeneity of β-cell functional development
TLDR
It is revealed that the heterogeneity of β-cell functional development in vivo occurred as two waves propagating from the islet mantle to the core, coordinated by islet vascularization.
Role of Wnt signaling pathways in type 2 diabetes mellitus.
TLDR
It was found that Wnt/c-Jun N-terminal kinase signaling was closely associated with insulin resistance, inflammatory response, and pancreatic β-cell and endothelial dysfunction, indicating a strong correlation between Wnt signaling pathways and T2DM.
Heterozygous Inactivation of the Na/Ca Exchanger Increases Glucose-Induced Insulin Release, β-Cell Proliferation, and Mass
TLDR
Downregulation of the Na/Ca exchanger leads to an increase inβ-cell function, proliferation, mass, and resistance to physiologic stress, namely to various changes in β- cell function that are opposite to the major abnormalities seen in type 2 diabetes.
...
...

References

SHOWING 1-10 OF 96 REFERENCES
Calcineurin/NFAT signalling regulates pancreatic β-cell growth and function
TLDR
Calcineurin/NFAT signalling regulates multiple factors that control growth and hallmark β-cell functions, revealing unique models for the pathogenesis and therapy of diabetes.
Insulin - producing cells derived from stem cells: recent progress and future directions
TLDR
The different approaches that have been used to obtain insulin‐producing cells from embryonic and adult stem cells are summarized, and the main problems that hamper the clinical applications of this technology are summarized.
Molecular Control of Cell Cycle Progression in the Pancreatic β-Cell
TLDR
In this review, the molecular details of cell cycle control as they relate to the pancreatic beta-cell are reviewed and can serve as a common basis and also a roadmap for those interested in developing novel strategies for enhancing beta- cell replication and improving insulin production in animal models as well as in human pancreatic Beta-cells.
INHIBITION OF GLUCOSE‐STIMULATED INSULIN RELEASE FROM βTC3 CELLS AND RODENT ISLETS BY AN ANALOG OF FK506
TLDR
The effects of an analog of a newer agent termed L-683, 590 on insulin secretion by an islet tumor line, βTC3, and rat islets are studied, and the effects of this drug to those of cyclosporine are compared, since both cause similar immunosuppression.
Inhibition of human insulin gene transcription by the immunosuppressive drugs cyclosporin A and tacrolimus in primary, mature islets of transgenic mice.
TLDR
The high potency of cyclosporin A and tacrolimus in normal islets suggests that inhibition of insulin gene transcription by cyclospora A and Tacrolima is clinically important and is one mechanism of the diabetogenic effect of these immunosuppressive drugs.
Diabetogenic effect of cyclosporin A is mediated by interference with mitochondrial function of pancreatic B-cells.
TLDR
It is concluded that CsA alters B-cell function by inhibiting the mitochondrial PTP, which terminates the oscillatory activity that is indispensable for adequate insulin secretion.
TRANSCRIPTIONAL INHIBITION OF INSULIN BY FK506 AND POSSIBLE INVOLVEMENT OF FK506 BINDING PROTEIN‐12 IN PANCREATIC β-CELL
TLDR
Findings point to the reduction of unidentified nuclear factors for insulin mRNA transcription caused by the binding of FK506 to FKBP-12 and a subsequent inhibition of calcineurin in the β-cells.
Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation
TLDR
It is reported here that overexpression of calcineurin in Jurkat cells renders them more resistant to the effects of CsA and FK506 and augments both NFAT- and NFIL2A-dependent transcription.
Secretory defects induced by immunosuppressive agents on human pancreatic β-cells
TLDR
In vitro data are consistent with the reported in vivo diabetogenicity of CsA and FK506 and point to MMF as the ideal immunosuppressive agent from a pancreatic β-cell point of view.
Direct Effects of Cyclosporin A on Human Pancreatic β-cells
TLDR
It is concluded that CyA has a direct inhibitory effect on insulin release from human pancreatic islets with a concomitant increase in the residual insulin content.
...
...