Type 2 diabetes mellitus patients have a markedly higher risk of developing dementia.While multiple factors contribute to this predisposition,one of these involves the increased secretion of amylin,or islet amyloid po...Type 2 diabetes mellitus patients have a markedly higher risk of developing dementia.While multiple factors contribute to this predisposition,one of these involves the increased secretion of amylin,or islet amyloid polypeptide,that accompanies the pathophysiology of type 2 diabetes mellitus.Islet amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia,including Alzheimer’s disease and vascular dementia,but the exact mechanisms underlying islet amyloid polypeptide’s causative role in dementia are unclear.In this review,we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage,ultimately leading to the clinical symptoms of dementia.We discuss the evidence for islet amyloid polypeptide deposition in the brain,islet amyloid polypeptide interaction with other amyloids implicated in neurodegeneration,neuroinflammation caused by islet amyloid polypeptide deposition,vascular damage induced by islet amyloid polypeptide accumulation,and islet amyloid polypeptide-induced cytotoxicity.There are very few therapies approved for the treatment of dementia,and of these,clinical responses have been controversial at best.Therefore,investigating new,targetable pathways is vital for identifying novel therapeutic strategies for treating dementia.As such,we conclude this review by discussing islet amyloid polypeptide accumulation as a potential therapeutic target not only in treating type 2 diabetes mellitus but as a future target in treating or even preventing dementia associated with type 2 diabetes mellitus.展开更多
Curvature is one of the most important features of lipid membranes in living cells,which significantly influences the structure of lipid membranes and their interaction with proteins.Taken the human islet amyloid poly...Curvature is one of the most important features of lipid membranes in living cells,which significantly influences the structure of lipid membranes and their interaction with proteins.Taken the human islet amyloid polypeptide(h IAPP),an important protein related to the pathogenesis of type II diabetes,as an example,we performed molecular dynamics(MD)simulations to study the interaction between the protein and the lipid structures with varied curvatures.We found that the lipids in the high curvature membrane pack loosely with high mobility.The h IAPP initially forms H-bonds with the membrane surface that anchored the protein,and then inserts into the membrane through the hydrophobic interactions between the residues and the hydrophobic tails of the lipids.h IAPP can insert into the membrane more deeply with a larger curvature and with a stronger binding strength.Our result provided important insights into the mechanism of the membrane curvature-dependent property of proteins with molecular details.展开更多
目的探讨高糖刺激下转染过表达人胰岛淀粉样多肽基因的大鼠胰岛素瘤细胞(INS-1)细胞凋亡的影响及其相关基因表达。方法应用酶联免疫吸附法(ELISA)检测高糖刺激后INS-1及转染人胰岛淀粉样多肽的INS-1细胞(h IAPP/INS-1)上清液的胰岛素水...目的探讨高糖刺激下转染过表达人胰岛淀粉样多肽基因的大鼠胰岛素瘤细胞(INS-1)细胞凋亡的影响及其相关基因表达。方法应用酶联免疫吸附法(ELISA)检测高糖刺激后INS-1及转染人胰岛淀粉样多肽的INS-1细胞(h IAPP/INS-1)上清液的胰岛素水平;利用Hoechst33258染色检测细胞凋亡百分率;采用RTPCR方法检测高糖刺激培养后的Bcl2、Bax m RNA的水平。结果高糖刺激下,与未转染人胰岛淀粉样多肽INS-1细胞相比较,h IAPP/INS-1细胞胰岛素分泌功能显著下降,凋亡细胞比例明显增加,抗凋亡基因Bcl2 m RNA表达水平下调,促凋亡基因Bax m RNA表达水平上调,Bcl2/Bax比例明显降低。结论人胰岛淀粉样多肽上调促凋亡基因表达和抑制抗凋亡基因表达可能与糖尿病的发生发展相关。展开更多
基金supported by The Mike Hogg FundBaylor College of Medicine Medical Scientist Training Program,NICHD R01HD099252(to RJP)and R01HD098131(to RJP)the NHLBI T32 HL092332(to ASB)。
文摘Type 2 diabetes mellitus patients have a markedly higher risk of developing dementia.While multiple factors contribute to this predisposition,one of these involves the increased secretion of amylin,or islet amyloid polypeptide,that accompanies the pathophysiology of type 2 diabetes mellitus.Islet amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia,including Alzheimer’s disease and vascular dementia,but the exact mechanisms underlying islet amyloid polypeptide’s causative role in dementia are unclear.In this review,we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage,ultimately leading to the clinical symptoms of dementia.We discuss the evidence for islet amyloid polypeptide deposition in the brain,islet amyloid polypeptide interaction with other amyloids implicated in neurodegeneration,neuroinflammation caused by islet amyloid polypeptide deposition,vascular damage induced by islet amyloid polypeptide accumulation,and islet amyloid polypeptide-induced cytotoxicity.There are very few therapies approved for the treatment of dementia,and of these,clinical responses have been controversial at best.Therefore,investigating new,targetable pathways is vital for identifying novel therapeutic strategies for treating dementia.As such,we conclude this review by discussing islet amyloid polypeptide accumulation as a potential therapeutic target not only in treating type 2 diabetes mellitus but as a future target in treating or even preventing dementia associated with type 2 diabetes mellitus.
基金supported by funds from the National Natural Science Foundation of China(Grants 11932017,11772054,11772055,and 11532009)supported by the Fundamental Research Funds for the Central Universities(Grant 2019QNA4060)。
文摘Curvature is one of the most important features of lipid membranes in living cells,which significantly influences the structure of lipid membranes and their interaction with proteins.Taken the human islet amyloid polypeptide(h IAPP),an important protein related to the pathogenesis of type II diabetes,as an example,we performed molecular dynamics(MD)simulations to study the interaction between the protein and the lipid structures with varied curvatures.We found that the lipids in the high curvature membrane pack loosely with high mobility.The h IAPP initially forms H-bonds with the membrane surface that anchored the protein,and then inserts into the membrane through the hydrophobic interactions between the residues and the hydrophobic tails of the lipids.h IAPP can insert into the membrane more deeply with a larger curvature and with a stronger binding strength.Our result provided important insights into the mechanism of the membrane curvature-dependent property of proteins with molecular details.
文摘目的探讨高糖刺激下转染过表达人胰岛淀粉样多肽基因的大鼠胰岛素瘤细胞(INS-1)细胞凋亡的影响及其相关基因表达。方法应用酶联免疫吸附法(ELISA)检测高糖刺激后INS-1及转染人胰岛淀粉样多肽的INS-1细胞(h IAPP/INS-1)上清液的胰岛素水平;利用Hoechst33258染色检测细胞凋亡百分率;采用RTPCR方法检测高糖刺激培养后的Bcl2、Bax m RNA的水平。结果高糖刺激下,与未转染人胰岛淀粉样多肽INS-1细胞相比较,h IAPP/INS-1细胞胰岛素分泌功能显著下降,凋亡细胞比例明显增加,抗凋亡基因Bcl2 m RNA表达水平下调,促凋亡基因Bax m RNA表达水平上调,Bcl2/Bax比例明显降低。结论人胰岛淀粉样多肽上调促凋亡基因表达和抑制抗凋亡基因表达可能与糖尿病的发生发展相关。
