BỘ Y TẾ TRƢỜNG ĐẠI HỌC DƢỢC HÀ NỘI PHAN ANH ĐÀO TỔNG QUAN VỀ INCRETIN VÀ CÁC ỨNG DỤNG TRONG Y DƢỢC KHÓA LUẬN TỐT NGHIỆP DƢỢC SĨ HÀ NỘI – 2018 BỘ Y TẾ TRƢỜNG ĐẠI HỌC DƢỢC HÀ NỘI PHAN ANH ĐÀO Mã sinh viên: 1301079 TỔNG QUAN VỀ INCRETIN VÀ CÁC ỨNG DỤNG TRONG Y DƢỢC KHÓA LUẬN TỐT NGHIỆP DƢỢC SĨ Người hướng dẫn: TS Đào Thị Mai Anh Nơi thực hiện: Bộ mơn Hóa Sinh HÀ NỘI – 2018 LỜI CẢM ƠN Trong suốt thời gian thực khóa luận tốt nghiệp tơi nhận đƣợc nhiều bảo, lời khuyên hữu ích nhƣ động viên từ thầy cơ, gia đình bạn bè Lời đầu tiên, tơi xin bày tỏ lòng biết ơn sâu sắc tới giáo đáng kính TS Đào Thị Mai Anh, Bộ mơn Hóa Sinh- ngƣời tận tâm hƣớng dẫn, bảo tơi q trình thực hiện, bổ sung đóng góp ý kiến để tơi hồn thiện khóa luận Cơ dạy cho phƣơng pháp nghiên cứu khoa học hiệu quả, khơi gợi tinh thần làm việc khoa học mà bảo nhiều điều sống Tôi xin gửi lời cám ơn tới thầy cô Trƣờng Đại Học Dƣợc Hà Nội, đặc biệt thầy cô mơn Hóa Sinh, trƣờng Đại học Dƣợc Hà Nội Các thầy cô truyền đạt cho kiến thức quý báu nhƣ tạo điều kiện thuận lợi cho tơi q trình hồn thành khóa luận Tôi xin cảm ơn bạn bè anh chị ln sát cánh cho tơi góp ý chân thành hữu ích để tơi hồn thiện khóa luận Cuối cùng, tơi xin cám ơn gia đình ngƣời ln động viên, hỗ trợ tiếp thêm sức mạnh để tơi vƣợt qua khó khăn suốt thời gian thực khóa luận Hà Nội, ngày 18 tháng năm 2018 Sinh Viên Phan Anh Đào MỤC LỤC DANH MỤC CÁC KÝ HIỆU, CHỮ VIẾT TẮT DANH MỤC CÁC BẢNG DANH MỤC CÁC HÌNH ẢNH ĐẶT VẤN ĐỀ CHƢƠNG ĐẠI CƢƠNG VỀ CÁC INCRETIN 1.1 LỊCH SỬ NGHIÊN CỨU .3 1.1.1 Sự đời giả thiết trục điều hòa đƣờng ruột- insulin (entero-insular axis) 1.1.2.Nghiên cứu xác định thành phần incretin 1.1.3.Tình hình nghiên cứu incretin giai đoạn 1.2.ĐỊNH NGHĨA 1.3.PHÂN LOẠI CHƢƠNG GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE (GIP) 2.1.CẤU TRÚC PHÂN TỬ CỦA GIP 2.2 GEN MÃ HÓA CHO GIP 2.3 QÚA TRÌNH SINH TỔNG HỢP GIP 2.4 QUÁ TRÌNH BÀI TIẾT GIP VÀ CÁC YẾU TỐ ẢNH HƢỞNG .10 2.4.1 Vai trò chất dinh dƣỡng 10 2.4.2 Vai trò hormon yếu tố thần kinh 12 2.5 Q TRÌNH CHUYỂN HĨA THẢI TRỪ CỦA GIP .12 2.6 TÁC DỤNG SINH LÝ CỦA GIP .12 2.6.1 Trên tụy 13 2.6.2 Trên mô mỡ 14 2.6.3 Trên quan đƣờng tiêu hóa 15 2.6.4.Trên quan hệ tim mạch .15 2.6.5 Trên xƣơng 15 2.6.6 Trên hệ thần kinh trung ƣơng .16 2.7 CƠ CHẾ TRUYỀN TÍN HIỆU CỦA GIP 16 2.7.1 Receptor GIP 16 2.7.2 Cơ chế truyền tín hiệu chung GIP 17 2.7.3 Cơ chế tắt tín hiệu GIP 19 CHƢƠNG GLUCAGON-LIKE PEPTIDE (GLP – 1) 20 3.1 CẤU TRÚC PHÂN TỬ CỦA GLP-1 20 3.2 GEN MÃ HÓA CHO GLP-1 20 3.3 QUÁ TRÌNH SINH TỔNG HỢP GLP-1 21 3.4 QUÁ TRÌNH BÀI TIẾT GLP-1 VÀ CÁC YẾU TỐ ẢNH HƢỞNG 22 3.4.1 Vai trò chất dinh dƣỡng 23 3.4.2 Vai trò hormon yếu tố thần kinh 25 3.5 Q TRÌNH CHUYỂN HĨA THẢI TRỪ GLP-1 25 3.6 TÁC DỤNG SINH LÝ CỦA GLP-1 26 3.6.1 Trên tuyến tụy .26 3.6.2 Trên mô mỡ 27 3.6.3 Trên gan 27 3.6.4 Trên quan đƣờng tiêu hóa 27 3.6.5 Trên 28 3.6.6 Trên hệ miễn dịch 28 3.6.7 Trên hệ tim mạch 28 3.6.8 Trên xƣơng 29 3.6.9 Trên thận .29 3.6.10 Trên hệ thần kinh trung ƣơng ngoại vi 30 3.7 CƠ CHẾ TRUYỀN TÍN HIỆU CỦA GLP-1 .31 3.7.1 GLP-1 receptor .31 3.7.2 Cơ chế truyền tín hiệu chung GLP-1 .33 3.7.3 Cơ chế tắt tín hiệu GLP-1 36 CHƢƠNG VAI TRÒ CỦA CÁC INCRETIN TRONG MỘT SỐ BỆNH LÝ 37 4.1 TRONG BỆNH ĐÁI THÁO ĐƢỜNG .37 4.2 TRONG BỆNH BÉO PHÌ 39 4.3 TRONG BỆNH ALZHEIMER 40 4.4 TRONG BỆNH PARKINSON 42 4.5 TRONG HỘI CHỨNG CUSHING DO TĂNG TIẾT GIP 44 4.6 TRONG BỆNH GÃY XƢƠNG Ở PHỤ NỮ MÃN KINH 44 4.7 TRONG BỆNH THẬN .44 4.8 TRONG BỆNH GAN NHIỄM MỠ KHÔNG DO CỒN 46 4.9 TRONG BỆNH HEN CĨ LIÊN QUAN ĐẾN BÉO PHÌ 46 4.10 TRONG BỆNH KÉM HẤP THU .46 4.11 TRONG MỘT SỐ BỆNH TIM MẠCH 47 4.12 TRONG BỆNH BUỒNG TRỨNG ĐA NANG .48 4.13 TRONG BỆNH CONGENITAL HYPERINSULINISM (CHI) 48 4.14 TRONG CÁC TRƢỜNG HỢP TĂNG INSULIN QUÁ MỨC Ở NHỮNG BỆNH NHÂN THỰC HIỆN PHẪU THUẬT NỐI THÔNG RUỘT (ROUX-EN-Y GASTRIC BYPASS SURGERY) .48 CHƢƠNG CÁC LOẠI THUỐC THUỘC LIỆU PHÁP INCRETIN 50 5.1 CÁC THUỐC LIÊN QUAN ĐẾN GIP 50 5.2 CÁC THUỐC LIÊN QUAN ĐẾN GLP-1 52 5.3 CÁC THUỐC CHỦ VẬN TRÊN CẢ GIPR VÀ GLP-1R 55 5.4 CÁC CHẤT ỨC CHẾ DPP IV 56 5.5 NHÓM THUỐC CHỦ VẬN TRÊN GPR119 57 CHƢƠNG BÀN LUẬN 58 6.1 VỀ CÁC ĐẶC TÍNH HĨA SINH CỦA INCRETIN 58 6.2 VỀ VAI TRÒ ỨNG DỤNG CỦA INCRETIN TRONG Y DƢỢC 59 6.2.1 Về tiềm sử dụng incretin điều trị 59 6.2.2 Về tiềm nhóm thuốc 62 KẾT LUẬN 66 ĐỀ XUẤT 67 TÀI LIỆU THAM KHẢO DANH MỤC CÁC KÝ HIỆU, CHỮ VIẾT TẮT Tên viết tắt Tên viết tiếng Anh AC adenylate cyclase ADA American Diabetes Association Tên tiếng Việt Hiệp hội đái tháo đƣờng Mỹ AMPK AMP-activated protein kinase ATF-4 activating transcription factor-4 Bad Bcl-2-associated death promoter Bax Bcl2-associated X protein Bcl-2 B-cell lymphoma Bik Bcl2-interacting killer cAMP Cyclic adenosine monophosphate Casp-3 Caspase Casp-9 Caspase CHOP C/EBP (CCAAT/enhancer-binding protein)-homologous protein Cnr-1 Gi- coupled endocannabinoid receptor c-Raf Cellular Raf gene (rapidly accelerated fibrosarcom) CRE cAMP respond element Yếu tố đáp ứng với AMPv CREB cAMP response element binding protein Protein gắn với yếu tố đáp ứng với AMPv DPP IV ĐTĐ dipeptidyl peptidase IV protease Đái Tháo Đƣờng eIF2α eukaryote initiation factor α Epac2 cAMP-regulated guanine nucleotide exchange factor ERK Extracellular signal-regulated kinase FDA Food and Drug Administration Gadd34 growth arrest and DNA damage-inducible protein GEF II Guanine nucleotide exchange factor II GIP glucose-depepdent insulinotropic Polypeptide kích thích polypeptide tiết insulin phụ thuộc nồng độ glucose GIPR Glucose- dependent insulinotropic Receptor GIP polypeptide receptor GLP-1 glucagon-like peptide Peptid có cấu trúc tƣơng tự glucagon GLP-1R Glucagon-like peptide receptor Receptor GLP-1 GLUT Glucose transporter Kênh vận chuyển glucose GPR119/120 long chain fatty acid G-protein coupled Receptor cặp đôi với receptor 119/120 protein G acid béo chuỗi dài 119 120 IRS-2 Insulin receptor substrate KV Voltage-dependent K+ channel Kênh Kali phụ thuộc điện LPL Lipoprotein lipase MAPK Mitogen-activated protein kinase Mcl1 Myeloid cell leukemia protein NEP-24.11 Neutral endopeptidase 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(2015), "Plasma DPP4 Activities Are Associated With Osteoporosis in Postmenopausal Women With Normal Glucose Tolerance", J Clin Endocrinol Metab, 100(10), pp 3862-70 243 Xiao C., Dash S., et al (2015), "Gut Peptides Are Novel Regulators of Intestinal Lipoprotein Secretion: Experimental and Pharmacological Manipulation of Lipoprotein Metabolism", Diabetes, 64(7), pp 2310-8 ... 58 6.1 VỀ CÁC ĐẶC TÍNH HĨA SINH CỦA INCRETIN 58 6.2 VỀ VAI TRÒ ỨNG DỤNG CỦA INCRETIN TRONG Y DƢỢC 59 6.2.1 Về tiềm sử dụng incretin điều trị 59 6.2.2 Về tiềm nhóm thuốc...BỘ Y TẾ TRƢỜNG ĐẠI HỌC DƢỢC HÀ NỘI PHAN ANH ĐÀO Mã sinh viên: 1301079 TỔNG QUAN VỀ INCRETIN VÀ CÁC ỨNG DỤNG TRONG Y DƢỢC KHÓA LUẬN TỐT NGHIỆP DƢỢC SĨ Người... chế tác dụng) incretin Tổng hợp phân tích đƣợc vai trò, ứng dụng incretin lĩnh vực Y Dƣợc CHƢƠNG ĐẠI CƢƠNG VỀ CÁC INCRETIN 1.1 LỊCH SỬ NGHIÊN CỨU Lịch sử nghiên cứu incretin trình xuyên suốt từ