The Type 2 Diabetes-Associated Gene Ide Is Required for Insulin Secretion and Suppression of alpha-Synuclein Levels in beta-Cells
2013 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, no 6, 2004-2014 p.Article in journal (Refereed) Published
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 a-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 a-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 a-synuclein in beta-cell function.
Place, publisher, year, edition, pages
2013. Vol. 62, no 6, 2004-2014 p.
Cell and Molecular Biology Endocrinology and Diabetes
IdentifiersURN: urn:nbn:se:umu:diva-76787DOI: 10.2337/db12-1045ISI: 000319845000030OAI: oai:DiVA.org:umu-76787DiVA: diva2:637162