The Type 2 Diabetes–Associated Gene Ide Is Required for Insulin Secretion and Suppression of α-Synuclein Levels in β-Cells
| Autor: | Helena Edlund, Lisandro M. D. Bernardo, Lisa Lundberg, Fredrik Backlund, Claes-Göran Östenson, Pär Steneberg, Sara Edfalk |
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| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_specialty
Endocrinology Diabetes and Metabolism Blotting Western Regulator Stimulation In Vitro Techniques Biology Insulysin Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Insulin-Secreting Cells Internal medicine Internal Medicine medicine Animals Humans Cells Cultured Loss function Original Research 030304 developmental biology Mice Knockout Alpha-synuclein 0303 health sciences Autophagy Immunohistochemistry Blot Endocrinology Islet Studies Diabetes Mellitus Type 2 chemistry alpha-Synuclein Haploinsufficiency 030217 neurology & neurosurgery |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | Genome-wide association studies have identified several type 2 diabetes (T2D) risk loci linked to impaired β-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 β-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 β-cells of Ide KO mice. One important cellular role for IDE involves the neutralization of amyloidogenic proteins, and we find that α-synuclein and IDE levels are inversely correlated in β-cells of Ide KO mice and T2D patients. Moreover, we provide evidence that both gain and loss of function of α-synuclein in β-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 β-cell degeneration as a consequence of Ide deficiency, and corroborate and extend a previously established important role for α-synuclein in β-cell function. |
| Databáze: | OpenAIRE |
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