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题名:The Type 2 Diabetes-Associated Gene Ide Is Required for Insulin Secretion and Suppression of alpha-Synuclein Levels in beta-Cells.
作者:STENEBERG P; BERNARDO L; EDFALK S; LUNDBERG L; BACKLUND F; OSTENSON CG; EDLUND H;
来源:Diabetes. 2013 Jun;62(6):2004-14. doi: 10.2337/db12-1045. Epub 2013 Jan 24. [ IF= 8.29 ] ]
URL :10.2337/db12-1045
日期:20130702
摘要:Genome-wide association studies have identified several type 2 diabetes (T2D)
risk loci linked to impaired beta-cell function. The identity and function of the
causal genes in these susceptibility loci remain, however, elusive. The HHEX/IDE
T2D locus is associated with decreased insulin secretion in response to oral
glucose stimulation in humans. Here we have assessed beta-cell function in Ide
knockout (KO) mice. We find that glucose-stimulated insulin secretion (GSIS) is
decreased in Ide KO mice due to impaired replenishment of the releasable pool of
granules and that the Ide gene is haploinsufficient. We also show that autophagic
flux and microtubule content are reduced in beta-cells of Ide KO mice. One
important cellular role for IDE involves the neutralization of amyloidogenic
proteins, and we find that alpha-synuclein and IDE levels are inversely
correlated in beta-cells of Ide KO mice and T2D patients. Moreover, we provide
evidence that both gain and loss of function of alpha-synuclein in beta-cells in
vivo impair not only GSIS but also autophagy. Together, these data identify the
Ide gene as a regulator of GSIS, suggest a molecular mechanism for beta-cell
degeneration as a consequence of Ide deficiency, and corroborate and extend a
previously established important role for alpha-synuclein in beta-cell function.

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