Aims/hypothesis The loss of beta cell function is a critical factor in the development of type 2 diabetes. Glucotoxicity plays a major role in the progressive deterioration of beta cell function and development of type 2 diabetes mellitus. Here we demonstrate that microRNA (miR)-30a-5p is a key player in early-stage glucotoxicity-induced beta cell dysfunction. Methods We performed northern blots, RT-PCR and western blots in glucotoxicity-exposed primary rat islets and INS-1 cells. We also measured glucose-stimulated insulin secretion and insulin content. In vivo approaches were used to evaluate the role of miR-30a-5p in beta cell dysfunction.Results miR-30a-5p expression was increased in beta cells after exposure to glucotoxic conditions, and exogenous miR-30a-5p overexpression also induced beta cell dysfunction in vitro. miR-30a-5p directly suppressed expression of Beta2/NeuroD (also known as Neurod1) by binding to a specific binding site in its 3′-untranslated region. After restoration of Beta2/NeuroD expression by knockdown miR-30a-5p or transfection of the Beta2/NeuroD gene, beta cell dysfunction, including decreased insulin content, gene expression and glucose-stimulated insulin secretion, recovered. Glucose tolerance and beta cell dysfunction improved on direct injection of Ad-si30a-5p into the pancreas of diabetic mice. Conclusions/interpretation Our data demonstrate that miR30a-5p-mediated direct suppression of Beta2/NeuroD gene expression is an important initiation step of glucotoxicityinduced beta cell dysfunction.
MicroRNAs (miRNAs) are increasingly recognized as being involved in pancreatic cancer progression by directly regulating the expression of their targets. In this study, we showed that miR-216b-5p expression was significantly decreased in pancreatic cancer tissues and cell lines. In addition, low miR-216b-5p expression was significantly associated with large tumor size and advanced TNM stage. Meanwhile, both Kaplan-Meier and multivariate survival analysis showed that decreased miR-216b-5p expression was associated with overall survival. miR-216b-5p over-expression repressed pancreatic cancer cell proliferation and induced cell cycle arrest and cell apoptosis in vitro and inhibited tumorigenesis in vivo. The translationally controlled tumor protein (TPT1) was identified as a novel direct target of miR-216b-5p. miR-216b-5p up-regulation suppressed TPT1 expression. Moreover, TPT1 mRNA expression levels were increased in pancreatic cancer tissues, and were inversely correlated with miR-216b-5p expression. TPT1 down-regulation had similar effects as miR-216b-5p up-regulation on pancreatic cancer cell progression. The restoration of TPT1 reversed the effect of miR-216b-5p on pancreatic cancer cell progression. Furthermore, we found that miR-216b-5p up-regulation suppressed Pim-3, Cyclin B1, p-Bad and Bcl-xL protein expression. However, the effect of miR-216b-5p up-regulation was partly reversed by TPT1 up-regulation in vitro. Taken together, our findings suggested that miR-216b-5p functions as a potential tumor suppressor by regulating TPT1 in pancreatic cancer cells, and it may represent a potential therapeutic target for patients with pancreatic cancer.
Pancreatic cancer has a five-year overall survival rate <5%, a situation that has not improved since for 40 years. Diabetes mellitus including type 2 diabetes mellitus (T2D) is a suspected risk factor for the development of pancreatic cancer and nearly 45% of the pancreatic cancer cases are likely to present as new onset diabetes cases; however, the nature of association between T2D and pancreatic cancer is still controversial. In this meta-analysis, we examined the association specifically of T2D with pancreatic cancer and the influence of insulin therapy. PubMed, EMBASE, Scholar, Web of Science and Scopus databases were searched to identify clinical and patient oriented studies that examined the incidence of diabetes in pancreatic cancer patients and vice versa, over the last 10 years. All the authors independently screened the articles, and a collective decision was reached about the studies included in the meta-analysis. Parameters analyzed included, the Incidence of diabetes in pancreatic cancer patients; duration history of T2D in pancreatic cancer patients; influence of insulin therapy in T2D patients on pancreatic cancer incidence. Eleven studies with a total of 14,399 patients, of whom 4,080 were T2D-positive and 9,721 were non-diabetic were included in this meta-analysis. T2D duration history was significantly related to pancreatic cancer incidence and insulin therapy effects. In conclusion, recent-onset T2D is probably a manifestation of pancreatic cancer whereas long-term T2D is likely a risk factor for this cancer. Insulin therapy appears to decrease the incidence of pancreatic cancer.
Aim. In drug‐responsive epilepsy patients, treatment non‐compliance is a major factor in seizure recurrence, but adherence to prescribed regimens following epilepsy surgery has not been examined. We measured adherence to prescribed antiepileptic drugs (AEDs) after epilepsy surgery and investigated factors influencing treatment non‐compliance. Methods. Postsurgical epilepsy patients (n=214) were monitored for 18.1±8.1 months. Adherence was measured using the Medication Possession Ratio (MPR) self‐report questionnaire, with MPR<0.8 defined as non‐adherence. Results. According to the MPR, 58 patients (27.1%) were non‐adherent after surgery. There were no differences in demographic and clinical variables, such as age (p=0.057, t =−1.925), duration of illness (p=0.597, t=0.530), gender ratio (p=0.714, χ2=0.134), and place of residence (urban vs. rural; p=0.874, χ2=0.025), between adherent and non‐adherent patients. Moreover, adherence was not related to surgical outcome as evaluated by the Engel classification (p=0.635, χ2=1.628) or to the types of AEDs after surgery (p=0.165, χ2=6.530). The most common reasons for non‐adherence were seizure‐free status for an extended period (26.5%), forgetfulness (19.1%), and an inability to buy the drugs locally (18.6%). Conclusion. Adherence to AEDs is improved after epilepsy surgery compared to presurgical estimates, but is still a common and serious problem. Targeted postsurgical management programs and communication strategies are necessary to improve adherence to AEDs after epilepsy surgery.
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