Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Malmö, Sweden
Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Malmö, Sweden.
Diabetes. 2017 Dec;66(12):3013-3028. doi: 10.2337/db17-0311. Epub 2017 Sep 7.
Dysregulation of gene expression in islets from patients with type 2 diabetes (T2D) might be causally involved in the development of hyperglycemia, or it could develop as a consequence of hyperglycemia (i.e., glucotoxicity). To separate the genes that could be causally involved in pathogenesis from those likely to be secondary to hyperglycemia, we exposed islets from human donors to normal or high glucose concentrations for 24 h and analyzed gene expression. We compared these findings with gene expression in islets from donors with normal glucose tolerance and hyperglycemia (including T2D). The genes whose expression changed in the same direction after short-term glucose exposure, as in T2D, were considered most likely to be a consequence of hyperglycemia. Genes whose expression changed in hyperglycemia but not after short-term glucose exposure, particularly those that also correlated with insulin secretion, were considered the strongest candidates for causal involvement in T2D. For example, , , , and were downregulated in donors with hyperglycemia and correlated positively with insulin secretion, suggesting a protective role, whereas was upregulated in hyperglycemia and correlated negatively with insulin secretion, suggesting a potential pathogenic role. This study provides a catalog of gene expression changes in human pancreatic islets after exposure to glucose.
2 型糖尿病（T2D）患者胰岛中的基因表达失调可能与高血糖的发生有关，也可能是高血糖（即糖毒性）的结果。为了将可能与发病机制有关的基因与可能继发于高血糖的基因区分开来，我们将供体胰岛暴露于正常或高葡萄糖浓度下 24 小时，并分析基因表达。我们将这些发现与来自糖耐量正常和高血糖（包括 T2D）供体的胰岛的基因表达进行了比较。那些在短期葡萄糖暴露后表达方向相同的基因（如在 T2D 中）被认为最有可能是高血糖的结果。那些在高血糖中表达发生变化但在短期葡萄糖暴露后没有变化的基因，特别是那些与胰岛素分泌相关的基因，被认为是与 T2D 因果关系最强的候选基因。例如，在高血糖的供体中下调，与胰岛素分泌呈正相关，提示其具有保护作用，而上调与胰岛素分泌呈负相关，提示其具有潜在的致病作用。本研究提供了人类胰腺胰岛在暴露于葡萄糖后基因表达变化的目录。
