Department of Internal Medicine, State University of Campinas, Campinas, 13081-970 São Paulo, Brazil.
Endocrinology. 2012 Dec;153(12):5760-9. doi: 10.1210/en.2012-1496. Epub 2012 Sep 28.
Insulin resistance is present in obesity and in type 2 diabetes and is associated with islet cell hyperplasia and hyperinsulinemia, but the driving forces behind this compensatory mechanism are incompletely understood. Previous data have suggested the involvement of an unknown circulating insulin resistance-related β-cell growth factor. In this context, looking for candidates to be a circulating factor, we realized that hepatocyte growth factor (HGF) is a strong candidate as a link between insulin resistance and increased mass of islets/hyperinsulinemia. Our approach aimed to show a possible cause-effect relationship between increase in circulating HGF levels and compensatory islet hyperplasia/hyperinsulinemia by showing the strength of the association, whether or not is a dose-dependent response, the temporality, consistency, plausibility, and reversibility of the association. In this regard, our data showed: 1) a strong and consistent correlation between HGF and the compensatory mechanism in three animal models of insulin resistance; 2) HGF increases β-cell mass in a dose-dependent manner; 3) blocking HGF shuts down the compensatory mechanisms; and 4) an increase in HGF levels seems to precede the compensatory response associated with insulin resistance, indicating that these events occur in a sequential mode. Additionally, blockages of HGF receptor (Met) worsen the impaired insulin-induced insulin signaling in liver of diet-induced obesity rats. Overall, our data indicate that HGF is a growth factor playing a key role in islet mass increase and hyperinsulinemia in diet-induced obesity rats and suggest that the HGF-Met axis may have a role on insulin signaling in the liver.
胰岛素抵抗存在于肥胖和 2 型糖尿病中，与胰岛细胞增生和高胰岛素血症有关，但这种代偿机制的驱动力尚不完全清楚。先前的数据表明，一种未知的循环胰岛素抵抗相关的β细胞生长因子参与其中。在这种情况下，我们寻找候选的循环因子，意识到肝细胞生长因子（HGF）是作为胰岛素抵抗和胰岛质量增加/高胰岛素血症之间联系的一个强有力的候选因子。我们的方法旨在通过显示循环 HGF 水平增加与代偿性胰岛增生/高胰岛素血症之间可能存在的因果关系，来证明这种关联的强度，无论是否存在剂量依赖性反应、时间性、一致性、合理性和可逆转性。在这方面，我们的数据显示：1）在三种胰岛素抵抗动物模型中，HGF 与代偿机制之间存在强烈而一致的相关性；2）HGF 以剂量依赖性方式增加β细胞质量；3）阻断 HGF 可关闭代偿机制；4）HGF 水平的升高似乎先于与胰岛素抵抗相关的代偿反应，表明这些事件以顺序模式发生。此外，HGF 受体（Met）的阻断会加重饮食诱导肥胖大鼠肝脏中胰岛素诱导的胰岛素信号受损。总的来说，我们的数据表明，HGF 是一种在饮食诱导肥胖大鼠中增加胰岛质量和高胰岛素血症中起关键作用的生长因子，并表明 HGF-Met 轴可能在肝脏的胰岛素信号中起作用。
