Abstract
Mutations in human Gli-similar (GLIS) 3 protein cause neonatal diabetes. The GLIS3 gene region has also been identified as a susceptibility risk locus for both type 1 and type 2 diabetes. GLIS3 plays a role in the generation of pancreatic beta cells and in insulin gene expression, but there is no information on the role of this gene on beta cell viability and/or susceptibility to immune- and metabolic-induced stress. GLIS3 knockdown (KD) in INS-1E cells, primary FACS-purified rat beta cells, and human islet cells decreased expression of MafA, Ins2, and Glut2 and inhibited glucose oxidation and insulin secretion, confirming the role of this transcription factor for the beta cell differentiated phenotype. GLIS3 KD increased beta cell apoptosis basally and sensitized the cells to death induced by pro-inflammatory cytokines (interleukin 1β + interferon-γ) or palmitate, agents that may contribute to beta cell loss in respectively type 1 and 2 diabetes. The increased cell death was due to activation of the intrinsic (mitochondrial) pathway of apoptosis, as indicated by cytochrome c release to the cytosol, Bax translocation to the mitochondria and activation of caspases 9 and 3. Analysis of the pathways implicated in beta cell apoptosis following GLIS3 KD indicated modulation of alternative splicing of the pro-apoptotic BH3-only protein Bim, favouring expression of the pro-death variant BimS via inhibition of the splicing factor SRp55. KD of Bim abrogated the pro-apoptotic effect of GLIS3 loss of function alone or in combination with cytokines or palmitate. The present data suggest that altered expression of the candidate gene GLIS3 may contribute to both type 1 and 2 type diabetes by favouring beta cell apoptosis. This is mediated by alternative splicing of the pro-apoptotic protein Bim and exacerbated formation of the most pro-apoptotic variant BimS.
Highlights
The Kruppel-like zinc finger protein Gli-similar (GLIS) 3 plays a critical role in pancreatic development, and loss-of-function mutations in this transcription factor lead to a syndrome characterized by neonatal diabetes, hypothyroidism and other congenital dysfunctions [1,2]
Genome-wide association studies have identified a large number of associations between specific loci and the two main forms of diabetes, namely type 1 and type 2 diabetes, but the mechanisms by which these candidate genes predispose to diabetes remain to be clarified
The GLIS3 gene region has been identified as a susceptibility risk locus for both type 1 and type 2 diabetes—it is the only locus showing association with both forms of diabetes and the regulation of blood glucose
Summary
The Kruppel-like zinc finger protein Gli-similar (GLIS) 3 plays a critical role in pancreatic development, and loss-of-function mutations in this transcription factor lead to a syndrome characterized by neonatal diabetes, hypothyroidism and other congenital dysfunctions [1,2]. Genome-wide association studies in large numbers of individuals with type 1 (T1D) or type 2 (T2D) diabetes indicated that common variants near GLIS3 gene are associated with both forms of diabetes [3,4,5,6,7], making GLIS3 one of the few candidate genes for both T1D and T2D It remains to be proven, that susceptibility alleles for T1D and T2D decrease expression of GLIS3 in pancreatic beta cells. GLIS3 deficient mice have a major decrease in beta cell mass and develop neonatal diabetes [9,10] These mice have decreased expression of several key transcription factors required for the endocrine development of the pancreas, i.e. Neurogenin, NeuroD1, MafA and Pdx1 [9,10]. GLIS3 synergizes with the beta cell transcription factors Pdx, MafA and NeuroD1, increasing insulin promoter activity, besides directly regulating the expression
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