Characterizetion of glucose-induced signal transduction and its impairment in type 2 diabete

在胰腺β细胞中，葡萄糖浓度升高不仅诱导胰岛素分泌，而且还诱导胰岛素的生物合成。细胞内信号介质包括cAMP和钙离子可能通过激活蛋白激酶A(PKA)和钙调蛋白激酶IV(CaMKIV)作用于胰岛素基因的cAMP反应元件(CRES)，从而促进胰岛素基因的表达。在这项研究中，我们研究了ATF2(Cre-Bp1)和CREM的作用，它们都属于CREB/ATF家族，并在胰腺β-细胞中表达。当ATF2在分离的大鼠胰岛中表达时，葡萄糖诱导的胰岛素基因表达增强，而CREB抑制其表达。CaMKIV可激活ATF2的反式激活结构域，而PKA不能激活ATF2的反式激活结构域。苏氨酸的三个残基对CaMKIV的激活起重要作用。CREM有几种异构体。我们发现了四种新的在胰岛表达的异构体。CREM的P和Q结构域与TATA结合蛋白和TAF130相互作用，对葡萄糖诱导的胰岛素表达具有重要作用。这些研究表明，Cre对葡萄糖诱导的胰岛素基因表达具有重要的转录调控作用。

In pancreatic β-cells, elevated glucose concentration induces not only insulin secretion but also insulin biosynthesis. Intracellular signal mediators including cAMP and calcium ion might act on cAMP responsive elements (CREs) of insulin gene through activation of protein kinase A (PKA) and calmodulin kinase IV (CaMKIV) and increase the expression of insulin gene. In this study, we examined the effects of ATF2 (CRE-BP1) and CREM, both of which belong to the CREB/ATF family and are expressed in pancreatic β-cells. When ATF2 was expressed in isolated rat pancreatic islets, glucose-induced insulin gene expression was augmented, while CREB repressed it. The transactivation domain of ATF2 was activated by CaMKIV but not by PKA. Three residues of threonine were important for the activation by CaMKIV. There are several isorforms of CREM. We found four novel isoforms expressed in pancreatic islets. P and Q domains of CREM were important for glucose-induced insulin expression, interacting with TATA-binding protein and TAF130. These studies demonstrate that transcriptional regulation via CRE is important for glucose-induced insulin gene expression.