Tomas Eva, Stanojevic Violeta, Habener Joel F
Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Boston, MA 02114, United States.
Regul Pept. 2011 Apr 11;167(2-3):177-84. doi: 10.1016/j.regpep.2011.01.003. Epub 2011 Jan 21.
Uncontrolled hepatic glucose production (gluconeogenesis), and glycogenolysis, is a major contributor to the fasting hyperglycemia associated with type 2 diabetes. Here we report the discovery of a C-terminal nonapeptide (FIAWLVKGRamide) derived from GLP-1 that suppresses glucose production and oxidative stress in isolated mouse hepatocytes. The nonapeptide, GLP-1(28-36)amide, was reported earlier to be a major product derived from the cleavage of GLP-1 by the endopeptidase NEP 24.11.
Hepatocytes were isolated from the livers of normal and diet-induced obese mice. We find that the GLP-1(28-36)amide nonapeptide rapidly enters isolated mouse hepatocytes by GLP-1 receptor-independent mechanisms, and targets to mitochondria where it inhibits gluconeogenesis and oxidative stress.
These findings suggest that GLP-1 not only acts on a cell surface G-protein coupled receptor activating kinase-regulated signaling pathways, but a small C-terminal peptide derived from GLP-1 also enters cells, targets mitochondria, and exerts insulin-like actions by modulating oxidative phosphorylation. GLP-1(28-36)amide, or a peptide mimetic derived there from, might prove to be a useful treatment for fasting hyperglycemia and metabolic syndrome in type 2 diabetes.
不受控制的肝脏葡萄糖生成（糖异生）和糖原分解是导致2型糖尿病患者空腹血糖升高的主要因素。在此，我们报告了一种源自胰高血糖素样肽-1（GLP-1）的C末端九肽（FIAWLVKGR酰胺）的发现，该九肽可抑制分离的小鼠肝细胞中的葡萄糖生成和氧化应激。该九肽，即GLP-1(28 - 36)酰胺，此前被报道为内肽酶NEP 24.11切割GLP-1产生的主要产物。
从正常小鼠和饮食诱导的肥胖小鼠肝脏中分离肝细胞。我们发现GLP-1(28 - 36)酰胺九肽通过不依赖GLP-1受体的机制迅速进入分离的小鼠肝细胞，并靶向线粒体，在那里它抑制糖异生和氧化应激。
这些发现表明，GLP-1不仅作用于细胞表面的G蛋白偶联受体激活激酶调节的信号通路，而且源自GLP-1的一个小的C末端肽也能进入细胞，靶向线粒体，并通过调节氧化磷酸化发挥胰岛素样作用。GLP-1(28 - 36)酰胺或由此衍生的肽模拟物可能被证明是治疗2型糖尿病空腹血糖升高和代谢综合征的有效药物。
