Gao Huashan, Zhao Qian, Song Ziwei, Yang Zhaocong, Wu You, Tang Shanshan, Alahdal Murad, Zhang Yanfeng, Jin Liang
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
College of Chemistry and Chemical Engineering, Pingdingshan University, Pingdingshan, China.
FASEB J. 2017 Aug;31(8):3527-3539. doi: 10.1096/fj.201700002R. Epub 2017 May 1.
It is well known that glucagon-like peptide 1 (GLP-1) has antidiabetic action. It has 2 distinct functions, an insulinotropic effect dependent on GLP-1 receptor (GLP-1R) and an insulinomimetic effect independent of GLP-1R. However, use of GLP-1 is limited by its short half-life. Therefore, our lab designed PGLP-1, a novel 2-function candidate peptide as a potential substitute. Using a streptozotocin-induced hyperglycemic mouse model, we demonstrated and that PGLP-1 had insulinotropic actions dependent on GLP-1R and insulinomimetic functions independent of GLP-1R. PGLP-1 treatment increased islet β-cell mass, plasma insulin, and C-peptide levels and Ki-67-immunoreactive β-cell numbers, verifying that PGLP-1 can work as a short GLP-1R agonist, similar to commercially available exendin-4. Additionally, PGLP-1 improved insulin sensitivity, inhibited gluconeogenesis by increasing expression of AMPK and receptor subfamily 0, group B, member 2 (SHP), and inhibited body weight loss by inhibiting β-oxidation, suggesting that PGLP-1 had insulinomimetic action. Taken together, these data indicated that PGLP-1, as a dual-function peptide, improved glycemic control and inhibited body weight loss, suggesting it could be useful for type 1 diabetes mellitus patients as an adjunctive therapy to insulin.-Gao, H., Zhao, Q., Song, Z., Yang, Z., Wu, Y., Tang, S., Alahdal, M., Zhang, Y., Jin, L. PGLP-1, a novel long-acting dual-function GLP-1 analog, ameliorates streptozotocin-induced hyperglycemia and inhibits body weight loss.
众所周知，胰高血糖素样肽1（GLP-1）具有抗糖尿病作用。它有两种不同的功能，一种是依赖胰高血糖素样肽1受体（GLP-1R）的促胰岛素分泌作用，另一种是不依赖GLP-1R的胰岛素模拟作用。然而，GLP-1的使用受到其短半衰期的限制。因此，我们实验室设计了PGLP-1，一种新型的双功能候选肽作为潜在替代品。使用链脲佐菌素诱导的高血糖小鼠模型，我们证明PGLP-1具有依赖GLP-1R的促胰岛素分泌作用和不依赖GLP-1R的胰岛素模拟功能。PGLP-1治疗增加了胰岛β细胞质量、血浆胰岛素和C肽水平以及Ki-67免疫反应性β细胞数量，证实PGLP-1可以作为一种短效GLP-1R激动剂发挥作用，类似于市售的艾塞那肽-4。此外，PGLP-1改善了胰岛素敏感性，通过增加AMPK和受体亚家族0、B组、成员2（SHP）的表达抑制糖异生，并通过抑制β氧化抑制体重减轻，表明PGLP-1具有胰岛素模拟作用。综上所述，这些数据表明，PGLP-1作为一种双功能肽，改善了血糖控制并抑制了体重减轻，表明它作为胰岛素的辅助治疗对1型糖尿病患者可能有用。-高，H.，赵，Q.，宋，Z.，杨，Z.，吴，Y.，唐，S.，阿拉达尔，M.，张，Y.，金，L.PGLP-1，一种新型长效双功能GLP-1类似物，改善链脲佐菌素诱导的高血糖并抑制体重减轻。
