Transcriptional network of β-cell compensation in the face of obesity induced insulin resistance

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In obesity-related insulin resistance, pancreatic islets compensate for chronic insulin insensitivity by expanding β-cell mass and increasing insulin secretory capacity. In a previous study, we identified sex-determining region Y-box (SOX) 6 as a down-regulated transcription factor in obesity-related insulin resistant animals. We also showed that SOX6 directly binds with pancreatic-duodenal homeobox factor 1 (PDX1) and negatively regulates glucose-stimulated insulin secretion. Based on the role of PDX1 in the development and proliferation of β-cells, insulin/insulin-like growth factor signaling pathways and the onset of type 2 diabetes, we suggested that the attenuated expression of SOX6 may contribute to β-cell adaptation in obesity-related insulin resistance. To further define the role of SOX6 in obesity-related insulin resistance, we analyzed the effects of SOX6 expression on cell proliferation. SiRNA mediated knockdown of SOX6 significantly stimulated cell proliferation, whereas induced SOX6 expression resulted in the inhibition of cell growth. In the present paper, we demonstrate the mechanism by which SOX6 suppresses cell proliferation. Our current studies reveal that SOX6 binds with β-catenin and recruits histone deacetylase 1 for suppression of cyclin D1 promoter activities induced by β-catenin. Together with the stimulation of glucose-stimulated insulin secretion, the induced cell proliferation by attenuation of SOX6 expression may account for the hyperinsulinemia and hyperplasia characteristic of insulin resistance.