ABSTRACT
Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion, but the mechanisms underlying insulin secretion failure are not completely understood. Here, we show that a set of co-expressed genes, which is enriched for genes with islet-selective open chromatin, is associated with T2D. These genes are perturbed in T2D and have a similar expression pattern to that of dedifferentiated islets. We identify Sox5 as a regulator of the module. Sox5 knockdown induces gene expression changes similar to those observed in T2D and diabetic animals and has profound effects on insulin secretion, including reduced depolarization-evoked Ca2+-influx and ß-cell exocytosis. SOX5 overexpression reverses the expression perturbations observed in a mouse model of T2D, increases the expression of key ß-cell genes and improves glucose-stimulated insulin secretion in human islets from donors with T2D. We suggest that human islets in T2D display changes reminiscent of dedifferentiation and highlight SOX5 as a regulator of ß-cell phenotype and function.
Subject(s)
Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 2/metabolism , Insulin-Secreting Cells/metabolism , SOXD Transcription Factors/metabolism , Animals , Calcium/metabolism , Calcium Channels/metabolism , Chromatin/metabolism , Exocytosis , Female , Gene Expression Regulation , Humans , Insulin/metabolism , Islets of Langerhans/metabolism , Male , Mice , Mice, Inbred C57BL , Oligonucleotide Array Sequence Analysis , Phenotype , Phlorhizin/chemistry , RNA, Small Interfering/metabolism , Rats , Valproic Acid/chemistryABSTRACT
The CAG repeat in the androgen receptor (AR) has been widely studied in association with male infertility, but the results are conflicting. In a recent meta-analysis, infertile men had <1 repeat longer CAG stretch than fertile men when analysed in a linear regression model assuming that AR function diminishes with increasing CAG length. However, in vitro, a non-linear activity pattern was recently demonstrated so that ARs containing short and long stretches, respectively, displayed lower activity than the AR of median length. These results prompted us to explore the possible association between CAG number and male infertility risk in a stratified manner on the basis of data from the mentioned meta-analysis and subjects from our clinical unit. The study population included 3915 men, 1831 fertile and 2084 infertile. Data were divided into three categories: CAG<22, CAG 22-23 (reference) and CAG>23 and analysed in a binary logistic regression model. Men with CAG<22 and CAG>23 had 20% increased odds ratio of infertility compared with carriers of the median lengths [for CAG<22: p=0.03, 95% confidence interval (CI): 1.02-1.39; for CAG>23: p=0.02, 95% CI: 1.03-1.44]. These results show that an alternative model to a linear one for the genotype-phenotype association in relation to AR CAG repeats is likely, as lengths close to the median confine lowest risk of infertility.
