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题名:A novel mechanism regulating insulin secretion involving Herpud1 in mice.
作者:WONG N; MORAHAN G; STATHOPOULOS M; PROIETTO J; ANDRIKOPOULOS S;
来源:Diabetologia. 2013 Jul;56(7):1569-76. doi: 10.1007/s00125-013-2908-y. Epub 2013 [ IF= 6.49 ] ]
URL :10.1007/s00125-013-2908-y
日期:20130830
摘要:AIMS/HYPOTHESIS: Type 2 diabetes results from beta cell dysfunction after
prolonged physiological stress, which causes oversecretion of insulin. We
recently found that insulin hypersecretion is mediated by at least two genes.
Among mouse models of type 2 diabetes, the DBA/2 mouse strain is more susceptible
to diabetes than is the C57BL/6J (B6J) strain. One distinctive feature of the
DBA/2 mouse is that it hypersecretes insulin, independent of changes in insulin
sensitivity; we identified Nnt as a gene responsible for this trait. METHODS: To
identify the other gene(s) affecting insulin hypersecretion, we tested a panel of
recombinant inbred BXD strains, which have different combinations of B6 and DBA/2
alleles. RESULTS: We found that 25% of the BXD strains hypersecreted insulin in
response to glucose. Microarray profiling of islets from high- and low-secretor
strains showed that at least four genes were differentially expressed. One gene
was consistently underexpressed in islets from both DBA/2 and the high-secretor
BXD strains. This gene (Herpud1 or Herp) encodes the 54 kDa endoplasmic reticulum
stress-inducible protein (HERP) that resides in the integral endoplasmic
reticulum membrane. To test directly whether Herpud1 can interact with Nnt,
Herpud1 was either knocked down or overexpressed in MIN6 cells. These results
showed that when Herpud1 was suppressed, Nnt expression was reduced, while
overexpression of Herpud1 led to increased Nnt expression. Furthermore, Herpud1
suppression resulted in significantly decreased glucose-stimulated insulin
secretion in the DBA/2 islets but not B6J islets. CONCLUSIONS/INTERPRETATION: We
conclude that Herpud1 regulates insulin secretion via control of Nnt expression.

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