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代謝性疾患モデルにおけるGPR119 agonist (JTP-109192) の薬効解析
http://hdl.handle.net/10191/0002000278
http://hdl.handle.net/10191/00020002787b9e6630-0561-49ab-be0f-73b9d607b1f2
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| Item type | 学位論文 / Thesis or Dissertation(1) | |||||||
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| 公開日 | 2022-04-04 | |||||||
| タイトル | ||||||||
| タイトル | 代謝性疾患モデルにおけるGPR119 agonist (JTP-109192) の薬効解析 | |||||||
| 言語 | ja | |||||||
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| 言語 | jpn | |||||||
| 資源タイプ | ||||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_db06 | |||||||
| 資源タイプ | doctoral thesis | |||||||
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| アクセス権 | open access | |||||||
| アクセス権URI | http://purl.org/coar/access_right/c_abf2 | |||||||
| 著者 |
唯木, 洋暢
× 唯木, 洋暢
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| 抄録 | ||||||||
| 内容記述タイプ | Abstract | |||||||
| 内容記述 | Type 2 diabetes mellitus is a well-known disease with effects on several percent of the world's population being due to recent changes in lifestyle factors, including the westernization of dietary habits, excessive sugar intake, and reduced physical activity. It is known that genetic or environmental factors, or both, induce a decrease in insulin secretion and insulin resistance, leading to hyperglycemia stemming from a relative lack of insulin action. In addition to non-oral insulin, oral hypoglycemic agents are available on the market and are generally used in combination with other hypoglycemic agents as the disease progresses. The target protein, GPR119, was found to be a GPCR that is mainly expressed in small intestinal L cells and pancreatic β-cells. It has been shown in in vivo ligand studies that GPR119 promotes GLP-1 secretion in L cells and insulin secretion in β-cells via elevated cAMP. Considering that GPR119- targeted drugs enhance insulin secretion in a glucose concentration-dependent manner, they have the potential to reduce the risk of hypoglycemia, unlike SUs and other drugs that promote insulin secretion in a glucose concentration-independent manner. The SAR of GPR119 agonist and the development of JTP-109192, which was used in this study, have been previously reported by Harada and colleagues. In the present study, we first characterized the basic profile of JTP-109192 in vitro and in vivo, and found that JTP-109192 stimulated cAMP production against human, rat, and mouse GPR119 without specific difference. An examination of the effect of JTP-109192 on insulin secretion in INS-1E cells showed a glucose-dependent insulin secretion effect in the DMSO-treated group and a stimulatory effect of JTP-109192 on insulin secretion only under high glucose conditions. In the study of GLP-1 secretion in GLUTag cells, JTP-109192 promoted GLP-1 secretion in a dose dependent manner. Then, in cannulated SD rats maintained at different blood glucose levels (250 and 400 mg/dL) by the hyperglycemic clamp method, JTP-109192 promoted first- and second-phase insulin secretions in response to the increase in blood glucose level. On the other hand, JTP-109192 did not promote insulin secretion in the normoglycemic range before glucose infusion, indicating that the promotion of insulin secretion by JTP-109192 was dependent on the glucose concentration in vivo. These results suggest that JTP-109192 could be a potential candidate drug with a low risk of hypoglycemia, in contrast to existing SUs. Next, we evaluated the effects of single and repeated oral administration of JTP-109192 on glucose metabolism in ZF rats, a model of insulin resistance, to address concerns about possible tachyphylaxis to GPCR agonists, including GPR119. In addition, it is generally considered important to examine the durability of the response after repeated administration to develop a drug, regardless of the disease for which it is used. Improved glucose tolerance was demonstrated by enhanced insulin secretion after glucose administration at 16 hours following a single JTP-109192 administration and by enhanced glucose-dependent insulin secretion after repeated administration of JTP-109192 at 4 weeks. In addition, using a hyperinsulinemic euglycemic clamp method, we showed that 6 weeks of JTP-109192 administration significantly improved insulin sensitivity and suppressed hepatic glucose production. The potential of GPR119 agonist as a glucose-lowering compound was also suggested. To explore the potential of GPR119 agonist as a lipid-lowering agent, we administered JTP-109192 as a food admixture for approximately 12 weeks to SHL mice with spontaneous ApoE gene deletion. JTP-109192 for 12 weeks treatment decreased plasma TC levels, increased fecal cholesterol excretion, and reduced the area of atherosclerotic lesions. The gene expression analysis of a single dose of JTP-109192 derivative showed that Abca1, Abcg5, and Abcg8 gene expressions were increased. The former gene and the latter two genes were thought to contribute to the increase in blood HDL-C and promotion of dietary cholesterol excretion, respectively. Thus, a part of the mechanism of JTP-109192's lipid-lowering effect was clarified. In this study, possible clinical efficacy can be assessed by comparing JTP-109192 with existing drugs or by conducting a combination study. These results suggest that JTP-109192 is a promising candidate compound with multifaceted effects on metabolic diseases, as it has not only anti-diabetic but also anti-atherosclerotic effects. | |||||||
| 言語 | en | |||||||
| 学位名 | ||||||||
| 言語 | ja | |||||||
| 学位名 | 博士（農学） | |||||||
| 学位授与機関 | ||||||||
| 学位授与機関識別子Scheme | kakenhi | |||||||
| 学位授与機関識別子 | 13101 | |||||||
| 言語 | ja | |||||||
| 学位授与機関名 | 新潟大学 | |||||||
| 言語 | en | |||||||
| 学位授与機関名 | Niigata University | |||||||
| 学位授与年月日 | ||||||||
| 学位授与年月日 | 2021-03-23 | |||||||
| 学位授与番号 | ||||||||
| 学位授与番号 | 甲第4921号 | |||||||
| 学位記番号 | ||||||||
| 内容記述タイプ | Other | |||||||
| 内容記述 | 新大院博(農)第213号 | |||||||
| 言語 | ja | |||||||
