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Differential synthesis and action of TGFβ superfamily ligands in mouse and rat islets

机译:TGFβ超家族配体在小鼠和大鼠胰岛中的差异合成和作用

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摘要

Members of the TGFβ superfamily, including activins and TGFβ, modulate glucose-stimulated insulin secretion (GSIS) in vitro using rat islets while genetic manipulations that reduce TGFβ superfamily signaling in vivo in mice produced hypoplastic islets and/or hyperglycemia. Moreover, deletion of Fstl3, an antagonist of activin and myostatin, resulted in enlarged islets and β-cell hyperplasia. These studies suggest that endogenous TGFβ superfamily ligands regulate β-cell generation and/or function. To test this hypothesis, we examined endogenous TGFβ ligand synthesis and action in isolated rat and mouse islets. We found that activin A, TGFβ1, and myostatin treatment enhanced rat islet GSIS but none of the ligands tested enhanced GSIS in mouse islets. However, follistatin inhibited GSIS, consistent with a role for endogenous TGFβ superfamily ligands in regulating insulin secretion. Endogenous expression of TGFβ superfamily members was different in rat and mouse islets with myostatin being highly expressed in mouse islets and not detectable in rats. These results indicate that TGFβ superfamily members directly regulate islet function in a species-specific manner while the ligands produced by islets differ between mice and rats. The lack of in vitro actions of ligands on mouse islets may be mechanical or result from species-specific actions of these ligands.
机译:TGFβ超家族的成员,包括激活素和TGFβ,利用大鼠胰岛在体外调节葡萄糖刺激的胰岛素分泌(GSIS),而在小鼠体内降低TGFβ超家族信号的基因操作产生了发育不良的胰岛和/或高血糖症。此外,缺失Fstl3(激活素和肌生长抑制素的拮抗剂)会导致胰岛增大和β细胞增生。这些研究表明内源性TGFβ超家族配体调节β细胞的产生和/或功能。为了验证这一假设,我们研究了内源性TGFβ配体的合成及其在离体大鼠和小鼠胰岛中的作用。我们发现激活素A,TGFβ1和肌生长抑制素处理可增强大鼠胰岛GSIS,但没有一个被测配体可增强小鼠胰岛GSIS。然而,卵泡抑素抑制GSIS,这与内源性TGFβ超家族配体在调节胰岛素分泌中的作用一致。 TGFβ超家族成员的内源表达在大鼠和小鼠胰岛中是不同的,其中肌生长抑制素在小鼠胰岛中高表达并且在大鼠中不可检测。这些结果表明,TGFβ超家族成员以物种特异性的方式直接调节胰岛功能,而小鼠和大鼠之间由胰岛产生的配体不同。配体对小鼠胰岛缺乏体外作用可能是机械性的,也可能是由于这些配体的物种特异性作用所致。

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