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系統識別號 U0026-3007201414175200
論文名稱(中文) Estradiol對Glucosamine引起之胰島素阻抗性的預防保護效應研究
論文名稱(英文) Investigation for the Protecting Effects of Estradiol on Glucosamine-induced Insulin Resistance
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 102
學期 2
出版年 103
研究生(中文) 康琳
研究生(英文) Lin Kang
學號 S98931102
學位類別 博士
語文別 英文
論文頁數 92頁
口試委員 指導教授-吳孟興
召集委員-許惠恆
口試委員-張峰銘
口試委員-鄭瑞棠
口試委員-蔡曜聲
口試委員-謝清河
中文關鍵字 女性賀爾蒙  葡萄糖胺  切除卵巢  胰島素阻抗性  停經 
英文關鍵字 17 β-estradiol  glucosamine  ovariectomy  insulin resistance  menopause 
學科別分類
中文摘要 第二型糖尿病以及代謝症候群是當今醫學的重要議題,而胰島素阻抗性是第二型糖尿病以及代謝症候群的重要特徵,目前已有許多文獻報告:停經後婦女發生第二型糖尿病、代謝症候群的機會比停經前婦女增加許多,表示卵巢分泌的女性賀爾蒙17 β-estradiol(E2),對於胰島素阻抗性以及胰臟β-cell的功能有保護作用。而停經後婦女也常會有退化性關節炎的問題,葡萄糖胺(glucosamine;GlcN)是這些婦女廣為使用的營養補充品,目前已有研究結果發現:葡萄糖胺不止會誘發胰島素阻抗性,更會影響胰臟β-cell的功能。但是至今仍無針對E2對葡萄糖胺引起之胰島素阻抗性的預防保護效應的相關研究。在我們的研究中發現:葡萄糖胺只有在卵巢切除的母鼠中會誘發胰島素阻抗性,而此阻抗性與骨骼肌的葡萄糖第四型運輸蛋白(glucose transport protein subtype 4; GLUT4)的表現降低,以及胰臟的胰小島(pancreatic islets)變大有關;在母鼠的胰臟組織中我們進一步發現:在只有給予葡萄糖胺或是只有卵巢切除的母鼠中,其胰小島胰島素的mRNA表現量以及螢光染色的強度會降低,而在切除卵巢並給予葡萄糖胺這一組的母鼠中,胰小島胰島素的mRNA表現量以及螢光染色的強度會降得更低;母鼠給予葡萄糖胺後,會增加其胰小島發生細胞凋亡的情形,而在切除卵巢並給予葡萄糖胺這一組的母鼠中,胰小島發生細胞凋亡的情形更為增加。以胰臟β-cell的細胞株來進一步探討E2是否能改善葡萄糖胺對於胰臟β-cell造成的功能損傷及其機轉,結果發現:葡萄糖胺會降低胰島素的分泌量,抑制細胞的鈣離子進入以及細胞膜上Kir6.2蛋白的表現,而在有E2 的情況下,這些現象都會被逆轉,而葡萄糖胺也會抑制胰臟β-cell的活性,也會誘發endoplasmic reticulum (ER) stress-associated protein的表現,而在有E2 的情況下,這些現象也都會被逆轉。我們的動物及細胞株實驗研究結果發現:E2是能改善葡萄糖胺造成的胰島素阻抗性以及對於胰臟β-cell造成的功能損傷。
英文摘要 The metabolic syndrome and type 2 diabetes mellitus (T2DM) are highly prevalent health problems in the modern era. Insulin resistance (IR) is a hallmark of T2DM and metabolic syndrome. Many literatures have shown that the higher prevalence of T2DM and metabolic syndrome in menopausal than premenopausal women is a powerful evidence that ovarian estrogen, 17 β-estradiol (E2), has protecting effects in IR and pancreatic β-cell dysfunction. Besides, many menopausal women suffered from osteoarthritis and glucosamine (GlcN) is a popular nutritional supplement used to treat osteoarthritis. Some studies have demonstrated that GlcN causes not only IR, but also β-cell dysfunction. To date, no study has investigated for the protecting effect of E2 on GlcN-induced IR. In our studies, we found that female rats do not develop IR upon GlcN treatment except after ovariectomy (OVX) and the underlying mechanisms are relevant to decreasing the expression of glucose transport protein subtype 4 (GLUT-4) in skeletal muscle and increasing the size of pancreatic islets. Besides, in pancreatic islets, we found either GlcN or ovariectomy alone reduced the mRNA expression and the staining intensity of insulin. The combination of GlcN and OVX further synergistically reduced the mRNA expression and staining intensity of insulin. GlcN alone also induced β-cell apoptosis and this adverse effect aggravated after ovariectomy. In our in vitro study, we found GlcN inhibited insulin secretion of β-cell via decreasing intracellular calcium (Ca2+) influx and Kir6.2 expression in MIN-6 cells. GlcN also decreased MIN-6 cell viability by inducing the expression of ER stress-associated proteins including C/EBP homologous protein (CHOP), phospho-protein kinase-like endoplasmic reticulum kinase (p-PERK), phospho-eukaryotic translation initiation factor 2α (p-EIF2α), and c-Jun N-terminal kinase (JNK). E2 counteracted the GlcN-induced attenuation in intracellular calcium concentration, extracellular insulin secretion, expression of Kir6.2, cell viability and the expression of ER stress-associated proteins and ICI182.780 inhibited these beneficial effects of E2. In conclusion, we demonstrated that E2 has the protecting effects for GlcN-induced IR and β-cell dysfunction in vivo and in vitro.
論文目次 Abstract I
Chinese Abstract III
Acknowledgments V
Content VII
List of figures IX
Abbreviations X
Chapter 1. Introduction 1
1.1 Estrogen, insulin resistance and pancreatic β-cell function 1
1.2 Glucosamine and insulin resistance 3
1.3 Motivation and Objectives 10
Chapter 2. Material and Methods 13
2.1 Animal model 13
2.2 Intraperitoneal glucose tolerance test (IPGTT) 15
2.3 Determination of plasma glucose and insulin level 15
2.4 Determination of insulin resistance in animals 16
2.5 Tissue preparation and measurement of islet size 16
2.6 Western Blot Analysis for glucose transport protein subtype 4 (GLUT-4) in skeletal muscle 17
2.7 Reverse transcription polymerase chain reaction for the mRNA expression of insulin in pancreas 18
2.8 Immunofluorescence stains for insulin and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) in pancreatic islets 19
2.9 Cell culture 20
Chapter 3. Results 25
3.1 Effects on body weight 25
3.2 Fasting glucose, insulin, and HOMA-IR 25
3.3 The changes in plasma glucose and insulin during IPGTT 26
3.4 HOMA-IR and glucose-insulin index in IPGTT 26
3.5 Islet sizes 27
3.6 Expression of GLUT-4 in the skeletal muscle 27
3.7 RT-PCR for the expression of insulin mRNA levels in the pancreas 27
3.8 Immunofluorescence stains for insulin and TUNEL in pancreatic islets 27
3.9 Intracellular calcium concentration and extracellular insulin secretion in MIN-6 cells 28
3.10 Western blot analysis for the expression of Kir6.2 subunits of KATP in MIN-6 cells 29
3.11 MTT assay in MIN-6 cells 29
3.12 Western blot analysis for the expression of ER stress-associated proteins, CHOP, p-PERK, p-EIF2α, and p-JUN in MIN-6 cells 30
3.13 Figures 30
Chapter 4. Discussion 43
Chapter5. Conclusion 61
Reference 63
Appendix 85

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