A comparative study of the role of crocin and sitagliptin in attenuation of STZ-induced diabetes mellitus and the associated inflammatory and apoptotic changes in pancreatic β-islets

Type 1 diabetes mellitus (T1DM) describes a complex group of metabolic disorders associated with elevated blood glucose levels and increased risks of complications development. Exploring new drug therapies would reduce the increased diabetes-associated morbidity and mortality and will reduce the excessive health care costs. Crocin is the major active ingredient of saffron. In the current study, DM was induced by single intraperitoneal injection of streptozocin (50 mg/kg).DM progression was associated with a significant increase in blood glucose level with reduced insulin and increased glucagon secretion. Pancreatic malondialdehyde (MDA) content significantly escalated, while superoxide dismutase (SOD) activity, reduced glutathione (GSH) concentration, catalase activity, thioredoxin level and serum total antioxidant capacity significantly declined. This was associated with a significant increase in pancreatic caspase-3 contents and pancreatic infiltration with inflammatory cells in β-islets. Both sitagliptin and crocin significantly reduced blood glucose levels, enhanced pancreatic insulin expression and secretion and suppressed glucagon secretion with enhancement of anti-oxidant defenses and reduction of oxidative burden, with evident anti-inflammatory impacts. Interestingly, the effect of crocin on DM indices, inflammatory and apoptotic changes was comparable to that of sitagliptin; the standard oral hypoglycemic agent. Nevertheless, crocin had a superior effect compared to sitagliptin on blood sugar level, β-islets diameter and insulin immune-reactivity. In conclusion, crocin reduced blood glucose level mainly via reduction of oxidative burden, modulation of apoptotic pathway and attenuation of pancreatic inflammation.     

Sitagliptin: Anti-platelet effect in diabetes and healthy volunteers

Sitagliptin, a selective dipeptidyl peptidase-4 inhibitor drug is used to treat type-2 diabetes (T2DM). We investigated the anti-platelet activity of sitagliptin in patients with T2DM and in in vitro samples obtained from healthy humans. Patients with T2DM (27 male + 23 female) were selected and followed up before (control) and after treatment with sitagliptin for up to 3 months. Platelets were isolated from the blood of sitagliptin treated patients and controls. Patients with T2DM treated with sitagliptin for 1and 3 months, showed 10?±?2% and 30?±?5% inhibition of platelet aggregation, respectively. For the in vitro study, platelets from 10 normal humans (n?=?10) were isolated. Platelet aggregation, intracellular free calcium and tyrosine phosphorylation of multiple proteins were measured by aggregometer, spectrofluorometer and western blotting, respectively. Platelets pre-treated with 5 and 10?µg/ml of sitagliptin, showed 25?±?4% and 40?±?6% inhibition of thrombin-induced platelet aggregation, respectively. Sitagliptin decreased intracellular free calcium (2.5-fold) and tyrosine phosphorylation of multiple proteins in thrombin-induced platelet activation. Sitagliptin inhibited platelet aggregation in T2DM as well as in healthy humans. Sitagliptin has significant concentration-dependent anti-platelet activity. This activity was due to its inhibitory effect on intracellular free calcium and tyrosine phosphorylation.     

Simultaneous quantitation of metformin and sitagliptin from mouse and human dried blood spots using laser diode thermal desorption tandem mass spectrometry

A simple, rapid and robust high-throughput assay for the simultaneous analysis of metformin and sitagliptin from mouse and human dried blood spot samples using laser diode thermal desorption interfaced with atmospheric pressure chemical ionization tandem mass spectrometry (LDTD-APCI-MS/MS) was developed for use in a pharmaceutical discovery environment as an alternative to traditional plasma analysis. Analytes were extracted from dried blood spots using a simple punch disc and solvent extract procedure. Details of the method development and optimization of the instrumental parameters are presented. The method was successfully applied to spiked mouse and human dried blood spot samples. Analyte stability was determined in dried blood spots on FTA cards and as extracts of dried blood spots. The method was subsequently used to determine the oral pharmacokinetics of metformin and sitagliptin after dosing to male mice. Metformin and Sitagliptin results are compared to data generated by more traditional liquid chromatography-mass spectrometry methods. Intra-assay and inter-assay accuracy and precision across the analytes and species deviated by less than 30% at all calibration levels and less than 20% at all quality control levels.     

西格列汀对db/db糖尿病小鼠坐骨神经传导速度的影响

目的 探讨西格列汀对db/db糖尿病小鼠坐骨神经传导速度的影响.方法 将60只12周龄的db/db小鼠随机分为3组:西格列汀组、二甲双胍组、db/db组,各20只,分别给予8周西格列汀、二甲双胍、安慰剂灌胃治疗.另选取20只同周龄、同窝出生的db/m非糖尿病小鼠(对照组).治疗8周后行腹腔葡萄糖耐量试验(IPGTT),治疗前后分别测定4组小鼠的坐骨神经传导速度.结果 与db/db组比较,西格列汀和二甲双胍组治疗8周后空腹血糖显著下降(P＜0.05),而西格列汀组与二甲双胍组比较差异无统计学意义(P＞0.05).糖负荷120 min后西格列汀和二甲双胍组小鼠葡萄糖曲线下面积和胰岛素曲线下面积均显著低于db/db组(P＜0.05),但两组间差异无统计学意义(P＞0.05).西格列汀组小鼠治疗后坐骨神经传导速度显著高于db/db组和二甲双胍组(P＜0.05),而二甲双胍组与db/db组比较差异无统计学意义(P＞0.05).结论 西格列汀降低血糖的同时能提高坐骨神经传导速度,其作用独立于降糖作用.     

西格列汀对2型糖尿病大鼠心肌细胞焦亡的影响及其可能机制

目的:研究西格列汀(sitagliptin,SLT)对2型糖尿病大鼠心肌细胞焦亡的影响,并探讨其抑制糖尿病心肌病可能的作用机制。方法:建立2型糖尿病大鼠模型,并给予(3、10和30 mg/kg)和sirtuin(SIRT)家族抑制剂尼克酰胺(nicotinamide,NAM;500 mg/kg)灌胃4周。检测空腹血糖,采用免疫组织化学法和Western blot法检测心肌组织中相关蛋白表达。结果:与正常对照组相比,糖尿病大鼠心肌组织细胞SIRT3表达下调,而NLRP3表达上调(P0.05),糖尿病大鼠心肌组织发生焦亡的细胞明显增多。灌胃SLT能剂量依赖性地抑制糖尿病大鼠心肌细胞焦亡的发生,并上调SIRT3的表达,下调NLRP3蛋白表达(P0.05);SIRT3非特异性抑制剂NAM(500 mg/kg)能逆转SLT的心脏保护作用,与正常对照组相比,单独给予NAM(500 mg/kg)对正常大鼠心肌细胞SIRT3表达无明显作用,但NLRP3表达上调(P0.05),心肌组织发生焦亡的细胞增多。结论:SLT能抑制糖尿病诱导的心肌细胞焦亡,其作用机制可能涉及SIRT3/NLRP3信号途径。     

Obesity may attenuate the HbA1c‐lowering effect of sitagliptin in Japanese type 2 diabetic patients

Aims/Introduction: The aim of the present study was to assess the independent predictors of the HbA1c‐lowering effect of sitagliptin in Japanese type 2 diabetic patients. Materials and Methods: Data were retrieved from the medical records of 151 type 2 diabetic patients who had been taking sitagliptin 25 or 50 mg once daily for inadequate glycemic control for at least 12 weeks, with or without other oral hypoglycemic agents. Spearman’s rank correlation coefficients were calculated to investigate correlations between two independent continuous variables. Multiple stepwise regression analysis was used to identify independent predictors of reductions in HbA1c levels after 12 weeks of sitagliptin treatment (ΔHbA1c). Results: In all patients combined, Spearman’s rank correlation coefficients showed that ΔHbA1c was significantly correlated with baseline HbA1c alone (r = 0.371, P < 0.0001). However, multiple linear regression analysis among all patients using baseline variables revealed that the independent factors contributing to ΔHbA1c, in order of importance, were method of prescribing (P < 0.0001), baseline HbA1c (P < 0.0001), body mass index (BMI; P = 0.004), and duration of diabetes (P = 0.024). Conclusions: Our analysis may provide novel evidence that increased BMI contributes, in part, to attenuation of the HbA1c‐lowering effect of sitagliptin in Japanese type 2 diabetic patients. Analysis of a larger population over a longer period of time is warranted to confirm these findings. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00156.x, 2011)     

西格列汀与甘精胰岛素应用于二甲双胍控制不佳的 2 型糖尿病合并非酒精性脂肪性肝病的疗效及安全性比较

目的比较二甲双胍单药治疗血糖控制不佳的2型糖尿病合并非酒精性脂肪性肝病（NAFLD）患者加用二肽基肽酶-4（DPP-4）抑制剂西格列汀和基础胰岛素（甘精胰岛素）的疗效和安全性。方法二甲双胍单药治疗（≥1500mg／d,1〉6月）血糖控制不佳[7％〈糖化血红蛋白（HbAlc）≤10．0％]的2型糖尿病合并NAFLD患者55例,分为加用西格列汀组（n=33,西格列汀100mgQD）和甘精胰岛素组（n=22,QD剂量滴定）。观察治疗3月后的体重指数（BMI）、HbAlc、空腹血糖（FPG）和餐后2小时血糖（PPG）、甘油三酯（TG）、总胆固醇（Tc）、低密度脂蛋白-胆固醇（LDL-C）、高密度脂蛋白-胆固醇（HDL—C）、谷草转氨酶（AST）、谷丙转氨酶（A1月）、谷氨酰转移酶（GGT）的变化。结果与治疗前相比较,两组患者的HbAlC、FPG,PPG、TG、LDL—C、AST、ALT、GGT均明显下降（P〈0．001）,甘精胰岛素组BMI升高（P〈0．05）,西格列汀组BMI下降（P〈0．05）。治疗后与西格列汀组相比较,甘精胰岛素组低血糖事件更明显（P〈0．05）,降低FPG更显著（P〈0．05）。结论西格列汀和甘精胰岛素加用于单用Z-甲双胍治疗失败的2型糖尿病合并NAFLD患者,均能降低I-IbMC、FPG和2hi？-PG,安全性良好。     

A retrospective review of isolated gliptin-exposure cases reported to a state poison control system

Background. The dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin, saxagliptin, and linagliptin are approved by the US Food and Drug Administration in the treatment of type-2 diabetes. Given the limited published information regarding human overdoses to these medications, our goal was to characterize such exposures. Methods. A state poison system database was retrospectively reviewed for all single-agent exposures to sitagliptin, saxagliptin, and linagliptin from 2006 to 2012. Case notes were reviewed and an observational case series was constructed from the data collected including age, weight, gender, circumstances surrounding exposure, symptoms, and outcome. Patients with co-ingestants, confirmed non-exposure, unknown outcomes, or other coding errors were excluded. Results. A total of 197 cases were identified: 135 cases were excluded (123 cases were excluded due to co-ingestants and 12 cases were lost to follow-up); 62 were included for review. No patients experienced hypoglycemia. One of 19 exposed pediatric (0–9 years of age) patients experienced symptoms and was safely managed at home after one episode of emesis. No symptom was experienced following unintentional ingestion by three adolescent (10–18 years of age) patients. Forty single-agent adult exposures to gliptins were included. Thirty-seven involved non-self-harm exposures resulting from double or triple doses; all were safely managed at home without reported symptoms. The majority of these ingestions involved sitagliptin. Three self-harm-adult exposures to gliptins were included for review. All the three were evaluated in a healthcare facility. One patient experienced abdominal discomfort after ingesting 700 mg of sitagliptin and was ultimately discharged from the emergency department. The other two patients experienced no reported symptoms. Conclusion. The majority of gliptin-exposed adult and pediatric/adolescent patients were safely managed at home and when evaluated in a healthcare facility, did not require hospitalization. Intentional self-harm-adult gliptin exposures were managed in a healthcare facility but rarely resulted in hospitalization or serious morbidity at doses up to 18 times the adult therapeutic dose. Additional studies are necessary to determine precise triage guidelines for the management of gliptin overdose.     

磷酸西格列汀干预糖尿病大鼠肾脏中VEGF的表达

①目的研究磷酸西格列汀（sitagliptin phosphate,SP）对糖尿病（diabetes mellitus,DM）大鼠肾脏中血管内皮生长因子（VEGF）表达的影响。②方法用50只雄性健康SD大鼠随机分为正常对照组（Normal control,NC组）、糖尿病对照组（DM组）和糖尿病sP治疗组（SP组）,除NC组外,其余两组经腹腔注射链脲佐菌素（str eptozotocin,STZ剂量65mg／kg）制备糖尿病大鼠模型。成功后治疗组每日灌胃给予磷酸西格列汀10mg／（kg·d）,分别采集各组大鼠3、6、8周后的尿液、血液标本,通过酶联免疫吸附法（ELISA）检测肾脏中血管内皮生长因子的表达;取一侧肾组织经HE染色,光镜下观察肾脏组织的病理变化,利用全自动生化仪检测血糖、肌酐、尿素氮及24h尿蛋白。③结果与NC组比较,造膜后大鼠的血糖、血肌酐、尿素氮、24h尿蛋白定量及肾脏组织中VEGF的表达明显升高（P〈0．01）有统计学意义;SP组血肌酐、尿素氮、24h尿蛋白定量及肾脏组织VEGF的表达与DM组比较明显降低（P〈0．01）。④结论磷酸西格列汀这类新型降糖药物对肾脏有一定的保护作用,可延缓糖尿病肾病的发展。     

Comparative effects of sitagliptin and metformin in patients with type 2 diabetes mellitus: a meta-analysis

Abstract

Background:

Sitagliptin has been widely used in the treatment of type 2 diabetes mellitus (T2DM); however, the therapeutic efficacy of sitagliptin remains inconclusive in randomized controlled studies on T2DM in which metformin has served as a control.