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- Schumann, DM, et al.
(författare)
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The Fas pathway is involved in pancreatic beta cell secretory function
- 2007
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 104:8, s. 2861-2866
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic β cell mass and function increase in conditions of enhanced insulin demand such as obesity. Failure to adapt leads to diabetes. The molecular mechanisms controlling this adaptive process are unclear. Fas is a death receptor involved in β cell apoptosis or proliferation, depending on the activity of the caspase-8 inhibitor FLIP. Here we show that the Fas pathway also regulates β cell secretory function. We observed impaired glucose tolerance in Fas-deficient mice due to a delayed and decreased insulin secretory pattern. Expression of PDX-1, a β cell-specific transcription factor regulating insulin gene expression and mitochondrial metabolism, was decreased in Fas-deficient β cells. As a consequence, insulin and ATP production were severely reduced and only partly compensated for by increased β cell mass. Up-regulation of FLIP enhanced NF-κB activity via NF-κB-inducing kinase and RelB. This led to increased PDX-1 and insulin production independent of changes in cell turnover. The results support a previously undescribed role for the Fas pathway in regulating insulin production and release.
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- Speier, S, et al.
(författare)
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Cx36-mediated coupling reduces beta-cell heterogeneity, confines the stimulating glucose concentration range, and affects insulin release kinetics
- 2007
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 56:4, s. 1078-1086
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Tidskriftsartikel (refereegranskat)abstract
- We studied the effect of gap junctional coupling on the excitability of β-cells in slices of pancreas, which provide a normal environment for islet cells. The electrophysiological properties of β-cells from mice (C57Bl/6 background) lacking the gap junction protein connexin36 (Cx36−/−) were compared with heterozygous (Cx36+/−) and wild-type littermates (Cx36+/+) and with frequently used wild-type NMRI mice. Most electrophysiological characteristics of β-cells were found to be unchanged after the knockout of Cx36, except the density of Ca2+ channels, which was increased in uncoupled cells. With closed ATP-sensitive K+ (KATP) channels, the electrically coupled β-cells of Cx36+/+ and Cx36+/− mice were hyperpolarized by the membrane potential of adjacent, inactive cells. Additionally, the hyperpolarization of one β-cell could attenuate or even stop the electrical activity of nearby coupled cells. In contrast, β-cells of Cx36−/− littermates with blocked KATP channels rapidly depolarized and exhibited a continuous electrical activity. Absence of electrical coupling modified the electrophysiological properties of β-cells consistent with the reported increase in basal insulin release and altered the switch on/off response of β-cells during an acute drop of the glucose concentration. Our data indicate an important role for Cx36-gap junctions in modulating stimulation threshold and kinetics of insulin release.
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