促性腺激素释放激素及其受体在糖尿病大鼠肠道、胰腺中表达的研究
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摘要
有研究表明药理剂量的促性腺激素释放激素(GnRH)类似物即可导致糖代谢紊乱,而在与葡萄糖代谢密切相关的消化系统又广泛存在GnRH及其受体。肠道和胰腺合成分泌的GnRH是否与葡萄糖代谢有关,其是否会以自分泌或旁分泌的方式作用于肠道和胰腺GnRH受体(GnRH-R),并通过影响肠道吸收、运动功能或调节其他肠道激素如:胰高血糖素、胰高血糖素样多肽-1(GLP-1)等的分泌而对葡萄糖代谢产生影响,这些问题尚有待探讨。
目的:
探讨肠道和胰腺的GnRH及其受体、胰高血糖素原(PG)和GLP-1受体在糖尿病病理状态下的变化,肠道、胰腺GnRH及其受体、胰高血糖素原和GLP-1受体的表达之间的相关性,为进一步研究GnRH类似物在临床应用中出现的葡萄糖代谢紊乱的机制以及糖尿病的病理生理过程奠定基础。
方法:
采用免疫组织化学方法观察了自发性2型糖尿病GK大鼠肠道和胰腺GnRH及其受体蛋白的表达及分布特点,并采用实时荧光定量PCR方法,研究了GK大鼠及正常Wistar大鼠GnRH及其受体、胰高血糖素原和GLP-1受体的mRNA在不同肠段和胰腺在灌服葡萄糖(2 g/kg)后3 h时的表达差异。
结果:
1、免疫组织化学染色显示糖尿病GK大鼠空肠、回肠、结肠和胰腺均有GnRH及GnRH-R表达,且其分布特点与正常大鼠相一致。
2、糖尿病大鼠空肠GnRH、GnRH-R、胰高血糖素原和GLP-1受体的mRNA相对表达量均低于正常大鼠(P<0.05)。
3、糖尿病大鼠回肠GnRH mRNA表达量低于正常大鼠(P<0.05),回肠GnRH-R、胰高血糖素原和GLP-1受体的mRNA表达量在两组间差异无统计学意义。
4、糖尿病大鼠结肠GLP-1受体mRNA相对表达量显著低于正常大鼠(P<0.05),而结肠GnRH及其受体和胰高血糖素原的mRNA表达量在两组间差异无统计学意义。
5、糖尿病大鼠胰腺胰高血糖素原和GLP-1受体mRNA相对表达量显著低于正常大鼠(P<0.05),而胰腺GnRH和GnRH-R mRNA表达量在两组间差异无统计学意义。
6、大鼠空肠GnRH mRNA表达量与胰高血糖素原mRNA的表达量呈正相关(r=0.883,P<0.05),大鼠空肠GnRH mRNA相对表达量与其空腹血糖、OGTT 3h血糖值均呈负相关(r=-0.72和r=-0.82,P<0.05),大鼠回肠GnRH mRNA相对表达量与其OGTT 3h血糖值呈负相关(r=-0.9,P<0.05),大鼠空肠GnRH-R与GLP-1受体mRNA相对表达量呈正相关(r=0.91,P<0.05)。
结论:
糖尿病大鼠肠道和胰腺GnRH及其受体免疫阳性物质分布与正常大鼠相一致。糖尿病大鼠部分肠道GnRH及其受体mRNA在灌服葡萄糖(2 g/kg)后3 h时下调,大鼠空肠GnRH与胰高血糖素原mRNA的表达量,以及空肠、回肠的GnRH mRNA水平与OGTT 3 h血糖值均呈现较好的相关性,提示空肠和回肠的GnRH可能与葡萄糖代谢关系密切,其相关机制有待进一步研究。
Some studies showed that the treatment dosage of GnRH analogues can lead to disorders of glucoregulation. GnRH and its receptor showed widespread expression in digestive system, which is highly related to glucoregulation. Whether GnRH secreted by intestine and pancreas were related to glucoregulation, and whether they could influence glucoregulation by acting on GnRH receptor in intestine and pancreas through effecting intestinal absorption and motor function, or regulating secretion of other gastro-intestinal hormones, such as glucagon, glucagon-like peptid-1, all these issues need to investigate.
Objective:
The objectives of this study were to study the change of the expression of GnRH, GnRH receptor, proglucagon and GLP-1 receptor in intestine and pancreas in diabetic rat, and to seek the relationships among the expression of GnRH, GnRH receptor, proglucagon and GLP-1 receptor in intestine and pancreas. The results of it will lay foundation for further study of the mechanism of glucoregulation disorders caused by GnRH analogues in clinical application and of the pathophysiology of diabetes.
Methods:
Immunohistochemical method was used to show the protein expression and the distribution of GnRH and its receptor in GK rats. Real-time quantitative PCR was used to detect the change of the mRNA expression of GnRH, GnRH receptor, proglucagon and GLP-1 receptor at the time of 3 h after intragastrical administration of glucose (2 g/kg) between spontaneous type 2 diabetic GK rats and normal Wistar rats.
Results:
1. Immunohistochemical staining showed GnRH and GnRH receptor expression in diabetic GK rats has the same distribution characteristics as in normal rats.
2. The relative mRNA levels of GnRH, GnRH receptor, proglucagon and the GLP-1 receptor in jejunum were lower in diabetic rats than those in normal rats (P<0.05).
3. The relative level of GnRH mRNA in ileum was lower in diabetic rats than this in normal rats (P<0.05), while there were no significant difference of the relative mRNA levels of GnRH receptor, proglucagon and the GLP-1 receptor in ileum between diabetic rats and normal rats.
4. The relative mRNA levels of GLP-1 receptor in colon were lower in diabetic rats than those in normal rats (P<0.05), when there were no significant difference of the relative mRNA levels of GnRH, GnRH receptor and proglucagon in colon between diabetic rats and normal rats.
5. The relative mRNA levels of proglucagon and the GLP-1 receptor in pancreas were lower in diabetic rats than those in normal rats (P<0.05), while there were no significant difference of the relative mRNA levels of GnRH and GnRH receptor in pancreas between diabetic rats and normal rats.
6. A significant positive correlation between the expression of GnRH mRNA and proglucagaon mRNA was observed in rat’s jejunum (r=0.883, P<0.05). A significant negative correlation between the expression of GnRH mRNA in jejunum and blood glucose level was observed in fasting and OGTT 3 h rats (r=-0.72 and r=-0.82,P<0.05). A significant negative correlation between the expression of GnRH mRNA in ileum and blood glucose level was observed in OGTT 3 h rats (r=-0.9, P<0.05), while the level of GnRH-R mRNA was significant positive correlation with GLP-1R mRNA level in rat’s jejunum (r=0.91, P<0.05).
Conclusion:
Immunohistochemical staining showed GnRH and GnRH-R expression in diabetic GK rats have same distribution characteristics as normal rats. The expressions of GnRH and GnRH-R at the time of 3 h after intragastrical administration of glucose (2 g/kg) were downregulated in parts of intestine in diabetic rats. A positive correlation between the GnRH mRNA and proglucagaon mRNA level was observed in rat’s jejunum, while a significant negative correlation between GnRH mRNA level and blood glucose level in OGTT 3 h rats was observed in jejunum, ileum. These suggested GnRH secreted by jejunum and ileum may be related to glucoregulation and the mechanism will be explored further.
目的:
探讨肠道和胰腺的GnRH及其受体、胰高血糖素原(PG)和GLP-1受体在糖尿病病理状态下的变化,肠道、胰腺GnRH及其受体、胰高血糖素原和GLP-1受体的表达之间的相关性,为进一步研究GnRH类似物在临床应用中出现的葡萄糖代谢紊乱的机制以及糖尿病的病理生理过程奠定基础。
方法:
采用免疫组织化学方法观察了自发性2型糖尿病GK大鼠肠道和胰腺GnRH及其受体蛋白的表达及分布特点,并采用实时荧光定量PCR方法,研究了GK大鼠及正常Wistar大鼠GnRH及其受体、胰高血糖素原和GLP-1受体的mRNA在不同肠段和胰腺在灌服葡萄糖(2 g/kg)后3 h时的表达差异。
结果:
1、免疫组织化学染色显示糖尿病GK大鼠空肠、回肠、结肠和胰腺均有GnRH及GnRH-R表达,且其分布特点与正常大鼠相一致。
2、糖尿病大鼠空肠GnRH、GnRH-R、胰高血糖素原和GLP-1受体的mRNA相对表达量均低于正常大鼠(P<0.05)。
3、糖尿病大鼠回肠GnRH mRNA表达量低于正常大鼠(P<0.05),回肠GnRH-R、胰高血糖素原和GLP-1受体的mRNA表达量在两组间差异无统计学意义。
4、糖尿病大鼠结肠GLP-1受体mRNA相对表达量显著低于正常大鼠(P<0.05),而结肠GnRH及其受体和胰高血糖素原的mRNA表达量在两组间差异无统计学意义。
5、糖尿病大鼠胰腺胰高血糖素原和GLP-1受体mRNA相对表达量显著低于正常大鼠(P<0.05),而胰腺GnRH和GnRH-R mRNA表达量在两组间差异无统计学意义。
6、大鼠空肠GnRH mRNA表达量与胰高血糖素原mRNA的表达量呈正相关(r=0.883,P<0.05),大鼠空肠GnRH mRNA相对表达量与其空腹血糖、OGTT 3h血糖值均呈负相关(r=-0.72和r=-0.82,P<0.05),大鼠回肠GnRH mRNA相对表达量与其OGTT 3h血糖值呈负相关(r=-0.9,P<0.05),大鼠空肠GnRH-R与GLP-1受体mRNA相对表达量呈正相关(r=0.91,P<0.05)。
结论:
糖尿病大鼠肠道和胰腺GnRH及其受体免疫阳性物质分布与正常大鼠相一致。糖尿病大鼠部分肠道GnRH及其受体mRNA在灌服葡萄糖(2 g/kg)后3 h时下调,大鼠空肠GnRH与胰高血糖素原mRNA的表达量,以及空肠、回肠的GnRH mRNA水平与OGTT 3 h血糖值均呈现较好的相关性,提示空肠和回肠的GnRH可能与葡萄糖代谢关系密切,其相关机制有待进一步研究。
Some studies showed that the treatment dosage of GnRH analogues can lead to disorders of glucoregulation. GnRH and its receptor showed widespread expression in digestive system, which is highly related to glucoregulation. Whether GnRH secreted by intestine and pancreas were related to glucoregulation, and whether they could influence glucoregulation by acting on GnRH receptor in intestine and pancreas through effecting intestinal absorption and motor function, or regulating secretion of other gastro-intestinal hormones, such as glucagon, glucagon-like peptid-1, all these issues need to investigate.
Objective:
The objectives of this study were to study the change of the expression of GnRH, GnRH receptor, proglucagon and GLP-1 receptor in intestine and pancreas in diabetic rat, and to seek the relationships among the expression of GnRH, GnRH receptor, proglucagon and GLP-1 receptor in intestine and pancreas. The results of it will lay foundation for further study of the mechanism of glucoregulation disorders caused by GnRH analogues in clinical application and of the pathophysiology of diabetes.
Methods:
Immunohistochemical method was used to show the protein expression and the distribution of GnRH and its receptor in GK rats. Real-time quantitative PCR was used to detect the change of the mRNA expression of GnRH, GnRH receptor, proglucagon and GLP-1 receptor at the time of 3 h after intragastrical administration of glucose (2 g/kg) between spontaneous type 2 diabetic GK rats and normal Wistar rats.
Results:
1. Immunohistochemical staining showed GnRH and GnRH receptor expression in diabetic GK rats has the same distribution characteristics as in normal rats.
2. The relative mRNA levels of GnRH, GnRH receptor, proglucagon and the GLP-1 receptor in jejunum were lower in diabetic rats than those in normal rats (P<0.05).
3. The relative level of GnRH mRNA in ileum was lower in diabetic rats than this in normal rats (P<0.05), while there were no significant difference of the relative mRNA levels of GnRH receptor, proglucagon and the GLP-1 receptor in ileum between diabetic rats and normal rats.
4. The relative mRNA levels of GLP-1 receptor in colon were lower in diabetic rats than those in normal rats (P<0.05), when there were no significant difference of the relative mRNA levels of GnRH, GnRH receptor and proglucagon in colon between diabetic rats and normal rats.
5. The relative mRNA levels of proglucagon and the GLP-1 receptor in pancreas were lower in diabetic rats than those in normal rats (P<0.05), while there were no significant difference of the relative mRNA levels of GnRH and GnRH receptor in pancreas between diabetic rats and normal rats.
6. A significant positive correlation between the expression of GnRH mRNA and proglucagaon mRNA was observed in rat’s jejunum (r=0.883, P<0.05). A significant negative correlation between the expression of GnRH mRNA in jejunum and blood glucose level was observed in fasting and OGTT 3 h rats (r=-0.72 and r=-0.82,P<0.05). A significant negative correlation between the expression of GnRH mRNA in ileum and blood glucose level was observed in OGTT 3 h rats (r=-0.9, P<0.05), while the level of GnRH-R mRNA was significant positive correlation with GLP-1R mRNA level in rat’s jejunum (r=0.91, P<0.05).
Conclusion:
Immunohistochemical staining showed GnRH and GnRH-R expression in diabetic GK rats have same distribution characteristics as normal rats. The expressions of GnRH and GnRH-R at the time of 3 h after intragastrical administration of glucose (2 g/kg) were downregulated in parts of intestine in diabetic rats. A positive correlation between the GnRH mRNA and proglucagaon mRNA level was observed in rat’s jejunum, while a significant negative correlation between GnRH mRNA level and blood glucose level in OGTT 3 h rats was observed in jejunum, ileum. These suggested GnRH secreted by jejunum and ileum may be related to glucoregulation and the mechanism will be explored further.
引文
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51. Sakurai H, Adama BM, Adams TE. Concentration of GnRH receptor and GnRH receptor mRNA in pituitary tissue of orchidectomized sheep: effect of oestradiol, progesterone, and progestrone withdrawal. J Endocrinol, 1997, 152(1):91-98
52. Ghosh BR, Wu JC, Strahl BD, Childs GV, Miller WL. Inhibin and estradiol alter gonadotropes differentially in ovine pituitary cultures: changing gonadotrope numbers and calcium responses to gonadotropin-releasing hormone. Endocrinology, 1996, 137(11):5144-5154.
53. Tsutsumi M, Laws SC, Sealfon SC.Translational regulation of the gonadotropin-releasing hormone receptor in alpha T3-1 cells. Endocrinology, 1995, 136(3):1361-1366.
54. HolZ GG, Kuhltreiber WM, Habener JF. Pancreatic beta-cells are rendered glucose competent by the insulinotropic hormone glucagons-like peptide-1(7-37). Nature, 1993, 361(6410):362-365
55. Nauck MA, Heimesaat MM, Behle K. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulinsecretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab, 2002, 87(3):1239-1246
56. Flint A, Raben A, Ersb?ll AK, Holst JJ, Astrup A. The effect of physiological levels of glucagon-like peptide-1 on appetite, gastric emptying, energy and substrate metabolism in obesity. Int J Obes Relat Metab Disord, 2001, 25(6):781-7922
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60. Hupe-Sodmann K, McGregor GP, Bridenbaugh R, Goke B, Thole H, Zimmermann B, Voigt K. Characterisation of the processing by human neutral endopeptidase 24.11 of GLP-1 (7-36) amide and comparison of the substrate specificity of the enzyme for other glucagon-like peptides. Regul Pept, 1995, 58(3):149-156
61. Lawrence MC, Bhatt HS, Easom RA. NFAT regulates insulin gene promoter activity in response to synergistic pathways induced by glucose and glucagon-like peptide-1. Diabetes, 2002, 51(3):691-698
62. Ahren B. Sensory nerves contribute to insulin secretion by glucagon-likepeptide-1 in mice. Am J Physiol Regul Integr Comp Physiol, 2004, 286(2): R269-272
63. Drucker DJ. Glucagon-like peptide-1 and the islet beta-cell: augmentation of cell proliferation and inhibition of apoptosis. Endocrinology, 2003, 144(12): 5145-5148
64. Abraham EJ, Leech CA, Lin JC, Zulewski H, Habener JF. Insulinotropic hormone glucagon-like peptide-1 differentiation of human pancreatic islet-derived progenitor cells into insulin-producing cells. Endocrinology, 2002, 143(8): 3152-3161
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68. Schick RR, Zimmermann JP, vorm Walde T, Schusdziarra V. Peptides that regulate food intake:glucagon-like peptide 1-(7-36)amide acts at lateral and medial hypothalamic sites to suppress feeding in rats. Am J Physiol Regul Integr Comp Physiol, 2003, 284(6):1427-1435
69. Gutniak M, Orskov C, Holst JJ, Ahren B, Efendic S. Antidiabetogenic effect of glucagon-like peptide-1 (7-36) amide in normal subjects and patients with diabetes mellitus. N Engl J Med, 1992, 326(20): 1316-1322
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71. Sandhu H, Wiesenthal SR, MacDonald PE, McCall RH, Tchipashvili V, Rashid S, Satkunarajah M, Irwin DM, Shi ZQ, Brubaker PL, Wheeler MB, Vranic M, Efendic S, Giacca A. Glucagon-like peptide 1 increases insulin sensitivity in depancreatized dogs. Diabetes, 1999, 48(5):1045-1053
72. Yamamoto H, Lee CE, Marcus JN, Williams TD, Overton JM, Lopez ME, Hollenberg AN, Baggio L, Saper CB, Drucker DJ, Elmquist JK. Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons. J Clin Invest, 2002 , 110(1):43-52
73. Nystrom T, GutniakMK, Zhang Q, Zhang F,Holst JJ, Ahren B. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol EndocrinolMetab, 2004, 287(6): 1209-1215
74. ThorensB. Expression cloning of the pancreatic betacell receptor for the gluco-incretin hormone glucagon-like peptide1. Proc Natl Acad Sci, 1992, 89(18): 8641-8645
75. MStoffel M, Espinosa III R, LeBeau MM, Bell BI. Human glucagon-like peptide-1 receptor gene. Localization to chromosome band 6p21 by fluorescence in situ hybridization and linkage of a highly polymorphic simple tandem repeat DNA polymorphism to other markers on chromosome 6. Diabetes, 1993, 42(8): 1215-1218
76. Thorens B, Porret A, Buhler L, Deng SP, Morel P and Widmann C. Cloning and functional expression of the human islet GLP-1 receptor, Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor.Diabetes, 1993, 42(11):1678-1682
77. Harmar AJ. Family-B G-protein-coupled receptors. Genome Biol. 2001, 3013(2):1-10
78. Tibaduiza EC, Chen C, Beinborn MA. Small molecule ligand of the glucagon-like peptide1 receptor targetsits amino-terminal hormone binding domain. J Biol Chem, 2001,276(41):37787-37793
79. Satoh F, Beak SA, Small CJ. Characterization of human and rat glucagon-like peptide-1 receptors in the neuro intermediate lobe: lack of coupling to either stimulation or inhibition of adenylyl cyclase. Endocrinology, 2000,141(4): 1301-1309
80. Unger RH, Eisentraut AM, McCall MS, Madison LL. Measurements of endogenous glucagon in plasma and the influence of blood glucose concentration upon its secretion. J Clin Invest, 1962,41:682–689
81. Cherrington AD. Control of glucose production in vivo by insulin and glucagon. In: Jefferson LS, Cherrington AD, Goodman HM, eds. Handbook of physiology: a critical, comprehensive presentation of physiological knowledge and concepts. American Physiological Society. New York: Oxford University Press:2001, 759–785
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48. Kakar SS, Nath S, Jennes L. The inhibition of growth and down-regulation of gonadotropin-releasing hormone (GnRH) receptor in alpha T3-1 cells by GnRH agonist. Anticancer Drugs, 1997, 8(4):360-375
49. Sakakibara H, Taga M, Ikeda M, Kurogi K, Minaguchi H. Continuous stimulation of gonadotropin-releasing hormone (GnRH) receptor by GnRH agonist decreases pituitary GnRH receptor messenger ribonucleic acid concentration in immature femalerats. Endocrino J, 1996, 43(1):115-118.
50. Quinones-Jenab V, Jenab S, Ogawa S, Funabashi T, Pfaff DW.Estrogen regulation of gonadotropin-releasing hormone receptor messenger RNA in female rat pituitary tissue. Brain ResMol Brain Res, 1996, 38(2):243-250.
51. Sakurai H, Adama BM, Adams TE. Concentration of GnRH receptor and GnRH receptor mRNA in pituitary tissue of orchidectomized sheep: effect of oestradiol, progesterone, and progestrone withdrawal. J Endocrinol, 1997, 152(1):91-98
52. Ghosh BR, Wu JC, Strahl BD, Childs GV, Miller WL. Inhibin and estradiol alter gonadotropes differentially in ovine pituitary cultures: changing gonadotrope numbers and calcium responses to gonadotropin-releasing hormone. Endocrinology, 1996, 137(11):5144-5154.
53. Tsutsumi M, Laws SC, Sealfon SC.Translational regulation of the gonadotropin-releasing hormone receptor in alpha T3-1 cells. Endocrinology, 1995, 136(3):1361-1366.
54. HolZ GG, Kuhltreiber WM, Habener JF. Pancreatic beta-cells are rendered glucose competent by the insulinotropic hormone glucagons-like peptide-1(7-37). Nature, 1993, 361(6410):362-365
55. Nauck MA, Heimesaat MM, Behle K. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulinsecretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab, 2002, 87(3):1239-1246
56. Flint A, Raben A, Ersb?ll AK, Holst JJ, Astrup A. The effect of physiological levels of glucagon-like peptide-1 on appetite, gastric emptying, energy and substrate metabolism in obesity. Int J Obes Relat Metab Disord, 2001, 25(6):781-7922
57. Mojsov S, Heinrich G, W ilson IB, Ravazzola M, Orci L, Habener JF. Preproglucagon gene expression in pancreas and intestine diversifies at the level of post transcriptional processing. J Bio l Chem, 1986, 25(261): 11880-11889
58. Schirra J, Katschinski M, Weidmann C, Schafer T. Gastric emptying and release of incretin hormones after glucose ingestion in humans. J Clin Invest, 1996, 97(1):92-103
59. Deacon CF, Nauck MA, Nielsen M T, Pridal L, Willms B, Holst JJ. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes, 1995, 44(9):1126-1131
60. Hupe-Sodmann K, McGregor GP, Bridenbaugh R, Goke B, Thole H, Zimmermann B, Voigt K. Characterisation of the processing by human neutral endopeptidase 24.11 of GLP-1 (7-36) amide and comparison of the substrate specificity of the enzyme for other glucagon-like peptides. Regul Pept, 1995, 58(3):149-156
61. Lawrence MC, Bhatt HS, Easom RA. NFAT regulates insulin gene promoter activity in response to synergistic pathways induced by glucose and glucagon-like peptide-1. Diabetes, 2002, 51(3):691-698
62. Ahren B. Sensory nerves contribute to insulin secretion by glucagon-likepeptide-1 in mice. Am J Physiol Regul Integr Comp Physiol, 2004, 286(2): R269-272
63. Drucker DJ. Glucagon-like peptide-1 and the islet beta-cell: augmentation of cell proliferation and inhibition of apoptosis. Endocrinology, 2003, 144(12): 5145-5148
64. Abraham EJ, Leech CA, Lin JC, Zulewski H, Habener JF. Insulinotropic hormone glucagon-like peptide-1 differentiation of human pancreatic islet-derived progenitor cells into insulin-producing cells. Endocrinology, 2002, 143(8): 3152-3161
65. Suzuki A, Nakauchi H, Taniguchi H. Glucagon-like peptide 1(1-37) converts intestinal epithelial cells into insulin-producing cells. Proc Natl Acad Sci U S A, 2003, 100(9):5034-5039
66. Komatsu R, Matsuyama T, Nanba M, Watanabe N, Itoh H, Kona N, Tauri S. Glucagonostatic and insulinotropic action of glucagonslike peptide-1(7-36) amide. Diabetes, 1989, 38(7):902-905
67. Naslund E, Gutniak M, Skogar S, Rossner S, Hellstrom PM. Glucagon-like peptide 1 increases the period of postprandial satiety and slows gastric emptying in obese men. Am J Clin Nutr, 1998, 68(3):525-530
68. Schick RR, Zimmermann JP, vorm Walde T, Schusdziarra V. Peptides that regulate food intake:glucagon-like peptide 1-(7-36)amide acts at lateral and medial hypothalamic sites to suppress feeding in rats. Am J Physiol Regul Integr Comp Physiol, 2003, 284(6):1427-1435
69. Gutniak M, Orskov C, Holst JJ, Ahren B, Efendic S. Antidiabetogenic effect of glucagon-like peptide-1 (7-36) amide in normal subjects and patients with diabetes mellitus. N Engl J Med, 1992, 326(20): 1316-1322
70. DardevetD, MooreMC, Neal D. Insulin independent effects of GLP21 oncanine liver glucose metabolism: duration of infusion and involvement of hepatoportal region. Am J Physiol EndocrinolMetab, 2004, 287(1): E75-E81
71. Sandhu H, Wiesenthal SR, MacDonald PE, McCall RH, Tchipashvili V, Rashid S, Satkunarajah M, Irwin DM, Shi ZQ, Brubaker PL, Wheeler MB, Vranic M, Efendic S, Giacca A. Glucagon-like peptide 1 increases insulin sensitivity in depancreatized dogs. Diabetes, 1999, 48(5):1045-1053
72. Yamamoto H, Lee CE, Marcus JN, Williams TD, Overton JM, Lopez ME, Hollenberg AN, Baggio L, Saper CB, Drucker DJ, Elmquist JK. Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons. J Clin Invest, 2002 , 110(1):43-52
73. Nystrom T, GutniakMK, Zhang Q, Zhang F,Holst JJ, Ahren B. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol EndocrinolMetab, 2004, 287(6): 1209-1215
74. ThorensB. Expression cloning of the pancreatic betacell receptor for the gluco-incretin hormone glucagon-like peptide1. Proc Natl Acad Sci, 1992, 89(18): 8641-8645
75. MStoffel M, Espinosa III R, LeBeau MM, Bell BI. Human glucagon-like peptide-1 receptor gene. Localization to chromosome band 6p21 by fluorescence in situ hybridization and linkage of a highly polymorphic simple tandem repeat DNA polymorphism to other markers on chromosome 6. Diabetes, 1993, 42(8): 1215-1218
76. Thorens B, Porret A, Buhler L, Deng SP, Morel P and Widmann C. Cloning and functional expression of the human islet GLP-1 receptor, Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor.Diabetes, 1993, 42(11):1678-1682
77. Harmar AJ. Family-B G-protein-coupled receptors. Genome Biol. 2001, 3013(2):1-10
78. Tibaduiza EC, Chen C, Beinborn MA. Small molecule ligand of the glucagon-like peptide1 receptor targetsits amino-terminal hormone binding domain. J Biol Chem, 2001,276(41):37787-37793
79. Satoh F, Beak SA, Small CJ. Characterization of human and rat glucagon-like peptide-1 receptors in the neuro intermediate lobe: lack of coupling to either stimulation or inhibition of adenylyl cyclase. Endocrinology, 2000,141(4): 1301-1309
80. Unger RH, Eisentraut AM, McCall MS, Madison LL. Measurements of endogenous glucagon in plasma and the influence of blood glucose concentration upon its secretion. J Clin Invest, 1962,41:682–689
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