人胰高血糖素样肽-1的研究与应用进展

doi:10.13560/j.cnki.biotech.bull.1985.2016.06.006

摘要/Abstract

摘要： 糖尿病的成因非常复杂，迄今为止，人们仍没有找到根治糖尿病的有效方法。尽管市面上销售和治疗糖尿病的化药不断涌现，但这些化药在降糖的同时，不可避免带来许多毒副作用，同时也并不能延缓一些糖尿病并发症的发展。人体自身分泌的胰高血糖素样肽-1(GLP-1)是一种小分子的多肽，长度仅有30个氨基酸，它属于葡萄糖浓度依赖型的，既可以特异性有效降低血糖浓度，又不会产生任何不良反应，加上GLP-1多重功效的发挥，使其成为II型糖尿病治疗的一个研究热点。要将GLP-1应用于临床，亟待解决它在体内的半衰期非常短的难题。因此，综述国内外对GLP-1的研究探索与应用的最新进展情况，旨在为研究人员和医务工作者在GLP-1相关药物研发上提供借鉴。

关键词: 糖尿病, 胰高血糖素样肽-1, 降血糖, 药物研发, 临床应用

Abstract: The cause of Diabetes mellitus is very complex，so far，the effective measures to completely cure diabetes have not been found yet. The chemical drugs for the treatment of diabetes in market continuously emerge，and these drugs may lower the blood sugar，but concurrently，they will inevitably lead to many toxic side effects，and cannot delay the development of diabetes complications. Human glucagon-likepPeptide -1(GLP-1)is a small polypeptide with 30 amino acids，which is potent to reduce blood sugar in a glucose-dependent manner without any adverse reactions，in addition to the multiple functions of GLP-1，it becomes a research hotspot in curing the diabetes II. However，to realize its clinical application，it is urgent to solve the problem of its short half-life in vivo. Hence，the reviews of the latest progress on the research and clinical application of GLP-1 in China and abroad on the basis of previous studies will provide reference for the researchers and medical workers in the development of GLP-1 relevant drugs.

Key words: Diabetes mellitus, glucagon-like peptide-1, lowering blood sugar, drug development, clinical application

许芳芳, 王楠, 李刚强, 刘德虎. 人胰高血糖素样肽-1的研究与应用进展[J]. 生物技术通报, 2016, 32(6): 30-37.

XU Fang-fang, WANG Nan, LI Gang-qiang, LIU De-hu. Research and Application Progress on Human Glucagon-like Peptide-1[J]. Biotechnology Bulletin, 2016, 32(6): 30-37.

参考文献

[1] Talchai C, Xuan S, Lin HV, et al. Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure[J]. Cell, 2012, 150(6)：1223-1234.
[2] DeFronzo RA. From the triumvirate to the ominous octet：a new paradigm for the treatment of type 2 diabetes mellitus[J]. Diabetes, 2009, 58(4)：773-795.
[3] Weir GC, Bonner-Weir S. Five stages of evolving beta-cell dysfunction during progression to diabetes[J]. Diabetes, 2004, 53(suppl 3)：16-21.
[4] Cryer P E, Davis SN, Shamoon H. Hypoglycemia in diabetes[J]. Diabetes Care, 2003, 26(6)：1902-1912.
[5] Zunz E, La Barre J. Contributions à l'étude des variations physiologiques de la sécrétion interne du pancréas[J]. Arch Physiol Biochem, 1929, 31(2)：162-179.
[6] Mcintyre N, Holdsworth C, Turner D. Intestinal factors in the control of insulin secretion[J]. The Journal of Clinical Endocrinology and Metabolism, 1965, 25(10)：1317-1324.
[7] Perley MJ, Kipnis DM. Plasma insulin responses to oral and intravenous glucose：studies in normal and diabetic subjects[J]. Journal of Clinical Investigation, 1967, 46(12)：1954.
[8] Nauck M, St?ckmann F, Ebert R, et al. Reduced incretin effect in type 2(non-insulin-dependent)diabetes[J]. Diabetologia, 1986, 29(1)：46-52.
[9] Darleen AS, David AD. Physiology of proglucagon peptides：role of glucagon and GLP-1 in health and disease[J]. Physiological Reviews, 2015, 95(2)：513-548.
[10] Wu TZ, Rayner CK, Horowitz M. Incretins[J]. Handbook of Experimental Pharmacology, 2015, 233：137-171.
[11] Ahrén B. Sensory nerves contribute to insulin secretion by glucagon-like peptide-1 in mice[J]. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2004, 286(2)：269-272.
[12] Flamez D, Van Breusegem A, Scrocchi LA, et al. Mouse pancreatic beta-cells exhibit preserved glucose competence after disruption of the glucagon-like peptide-1 receptor gene[J]. Diabetes, 1998, 47(4)：646-652.
[13] Drucker DJ. The biology of incretin hormones[J]. Cell Metab, 2006, 3(3)：153-165.
[14] Suzuki A, Nakauchi H, Taniguchi H. Glucagon-like peptide 1(1-37)converts intestinal epithelial cells into insulin-producing cells[J]. Proceedings of the National Academy of Sciences, 2003, 100(9)：5034-5039.
[15] 单忠艳. GLP-1类似物在糖尿病治疗中的作用[J]. 药品评价, 2009, 6(12)：500-501.
[16] Zander M, Madsbad S, Madsen JL, et al. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes：a parallel-group study[J]. The Lancet, 2002, 359(9309)：824-830.
[17] Yamamoto H, Kishi T, Lee CE, et al. Glucagon-like peptide-1-responsive catecholamine neurons in the area postrema link peripheral glucagon-like peptide-1 with central autonomic control sites[J]. The Journal of Neuroscience, 2003, 23(7)：2939-2946.
[18] Baggio LL, Drucker DJ. Biology of incretins：GLP-1 and GIP[J]. Gastroenterology, 2007, 132(6)：2131-2157.
[19] 郭莉霞, 刘建辉, 陈刚, 等. 胰高血糖素样肽1类似物调节胰岛素分泌细胞增殖和功能的细胞信号通路研究进展[J]. 中国药理学与毒理学杂志, 2009, 23(4)：308-311.
[20] 蔡德海, 宋光明, 丁全福. 利拉鲁肽人GLP-1类似物2型糖尿病的新疗法[J]. 河北医学, 2010, 16(2)：230-232.
[21] 左翼, 黄静, 卞慧芳, 等. 人胰高血糖素样肽-1 串联体的克隆及其表达[J]. 华东师范大学学报：自然科学版, 2006(4)：110-114.
[22] Hou JH, Yan RX, Ding DF, et al. Oral administration of a fusion protein containing eight GLP-1 analogues produced in Escherichia coli BL21(DE3)in streptozotocin-induced diabetic rats[J]. Biotechnol Lett, 2007, 29(10)：1439-1446.
[23] 窦文芳, 张莲芬, 雷楗勇, 等. 人胰高糖素样肽-1及其突变体在毕赤酵母中的表达与生物活性研究[J]. 生物技术通报, 2008(6)：139-143.
[24] 陈其亮, 窦文芳, 雷楗勇, 等. 重组胰高糖素样肽-1 融合蛋白的纯化及其活性测定[J]. 生物技术通报, 2008(6)：147-151.
[25] 李现丽, 窦文芳, 张晓梅, 等. 融合蛋白(GLP-1_A2G)2-HSA的分离纯化及其活性评价[J]. 药物生物技术, 2010, 17(6)：487-492.
[26] 吴日, 马超, 李晓丹, 等. 长效促胰岛素降糖酵母的构建及其对糖尿病模型小鼠的治疗效果[J]. 遗传, 2015, 37(2)：183-191.
[27] Jomori T, Hayashi Y, Makino M, et al. GLP-1 derivative and use thereof[J]Diabetes, 2008, 57：409.
[28] Wu YL, Huang J, Xu J, et al. Addition of a cysteine to glucagon-like peptide-1(GLP-1)conjugates GLP-1 to albumin in serum and prolongs GLP-1 action in vivo[J]. Regul Pept, 2010, 164(2)：83-89.
[29] 金明飞. 口服胰高血糖素样肽-1的筛选和应用研究[D]. 上海：华南师范大学, 2008.
[30] Yasuda H, Tada Y, Hayashi Y, et al. Expression of the small peptide GLP-1 in transgenic plants[J]. Transgenic Research, 2005, 14：677-684.
[31] Yasuda H, Hayashi Y, Jomori T, et al. The correlation between expression and localization of a foreign gene product in rice endosperm[J]. Plant Cell Physiol, 2006, 47(6)：756-763.
[32] Brandsma M, Wang X, Diao H, et al. A proficient approach to the production of therapeutic Glucagon-Like Peptide-1(GLP-1)in transgenic plants[J]. The Open Biotechnology Journal, 2009, 3：57-66.