Although "closed-loop" smart insulin delivery systems have been extensively investigated, the majority of them suffer from low insulin loading efficiency and slow glucose response. Here, we constructed a novel nanocomplex (NC), which was prepared by electrostatic interaction between negatively charged insulin prodrug nanoparticles (NPs) and positively charged polycaprolactone− polyethylenimine (PCL−PEI) micelles. The insulin prodrug was linked to acetalated dextran (AD) via borate ester bonds to form IAD NPs, and glucose oxidase (GOx) was encapsulated in PCL−PEI micelles. The NC was negatively charged with a high insulin grafting rate (0.473 mg/mg), and in vitro experiments revealed that IAD was sensitive to hyperglycemia and H 2 O 2 , whereas GOx significantly improved the response to glucose by altering the microenvironment to promote sustained insulin release. Furthermore, compared with free insulin and IAD NPs, subcutaneously injected NCs in diabetic rats had long-term hypoglycemic effects, showing excellent biocompatibility in vitro and in vivo, which had good potential in insulin self-regulation delivery.
Objectives: Apelin-APJ system has been implicated in the regulation of metabolic homeostasis. This study aimed to explore the genetic predisposition of the apelin-APJ system to metabolic syndrome. Materials And Methods: 1005 subjects were enrolled, including 448 metabolic syndrome patients and 557 controls. Seven single nucleotide polymorphisms, including rs909656, rs5975126, and rs3115757 of the apelin gene and rs7119375, rs10501367, rs9943582 and rs11544374 of the APJ gene, were genotyped.Results: For males, apelin-36 were higher in metabolic syndrome subjects compared with controls (p < 0.05). Apelin-36 were significantly lower in those with TT genotype of rs10501367 than those with CC and CT genotypes (p < 0.05), and fasting plasma glucose were higher in T allele carriers of rs10501367 and A allele carriers of rs7119375 compared with non-carriers (both p < 0.05). A significant difference in genotype distribution between diabetes mellitus patients and controls existed for both rs10501367 and rs7119375 (both p < 0.05). However, the association between apelin-APJ system genetic polymorphisms and metabolic syndrome was nonsignificant.For females, apelin-36 were higher in metabolic syndrome subjects compared with controls (p < 0.05). The association between apelin-APJ system genetic polymorphisms and apelin-36, fasting plasma glucose and diabetes mellitus was nonsignificant. However, carrying A allele in rs7119375 was associated with lower metabolic syndrome risk compared with non-carriers of A allele (odds ratio: 0.646, 95% confidence interval: 0.420-0.994, p = 0.043).Conclusions: The current findings revealed a gender-specific association of apelin-APJ system genetic polymorphisms with metabolic syndrome and glucose homeostasis disorders in a Han Chinese population.Oncotarget 2 www.impactjournals.com/oncotarget
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