Pharmacokinetic and pharmacodynamic study of ipragliflozin in Japanese patients with type 2 diabetes mellitus: A randomized,double-blind,placebo-controlled study

Aims

Ipragliflozin is a novel and highly selective sodium–glucose transporter 2 (SGLT2) inhibitor that reduces plasma glucose levels by enhancing urinary glucose excretion in patients with type 2 diabetes mellitus (T2DM). We examined the pharmacokinetic and pharmacodynamic characteristics of two oral doses of ipragliflozin in Japanese patients with T2DM.

Methods

In this randomized, placebo-controlled, double-blind study, patients were treated with placebo, 50 mg or 100 mg ipragliflozin once daily for 14 days. Plasma and urine pharmacodynamic parameters were measured on Days −1 and 14, and pharmacokinetic parameters on Day 14. Pharmacodynamic characteristics included area under the curve (AUC) for plasma glucose and insulin for 0–3 h (AUC_0–3h) and 0–24 h (AUC_0–24h). Pharmacokinetic characteristics included AUC_0–24h, maximum ipragliflozin concentration (C_max), and time to maximum plasma ipragliflozin concentration (t_max).

Results

Thirty patients were enrolled; 28 were included in pharmacokinetic/pharmacodynamic analyses and 30 in safety analyses. Administration of 50 and 100 mg ipragliflozin significantly reduced fasting plasma glucose, as well as the AUC_0–3h and AUC_0–24h for plasma glucose relative to placebo. Both doses of ipragliflozin also reduced AUC_0–24h for insulin, body weight, and glycoalbumin, while urinary glucose excretion increased remarkably. C_max and AUC_0–24h were 1.7- and 1.9-fold higher, respectively, in the 100-mg group than in the 50-mg group.

Conclusions

Ipragliflozin increased urinary glucose excretion and improved fasting and postprandial glucose, confirming its pharmacokinetic/pharmacodynamic properties in Japanese patients with T2DM.     

High-sensitivity C-reactive protein,low-grade systemic inflammation and type 2 diabetes mellitus: A two-sample Mendelian randomization study

Background and aims

The role of inflammation in type 2 diabetes mellitus (T2D) remains unclear. We investigated the associations of high sensitivity C-reactive protein (hsCRP) concentration with T2D and glycemic traits using two-sample Mendelian Randomization.

白细胞介素-6受体基因单核苷酸多态性及单体型与2型糖尿病的相关性研究

目的 探讨白细胞介素-6受体(IL-6R)基因单核苷酸多态性(SNP)及单体型与2型糖尿病的相关性.方法 选择入住本院的88例2型糖尿病(T2DM)患者为2型糖尿病组,以同期体检并糖耐量正常的98例健康自愿者为对照组,采用聚合酶链反应限制性片段长度多态性(PCR-RFLP)方法对IL-6R基因的2个SNP位点予以基因型检测.采用聚类分析方法分析基因多态性特征.结果 2型糖尿病组D358A基因型中A等位基因频率较对照组高,C等位基因频率较对照组降低,差异有统计学意义(P＜0.05).2型糖尿病组-183(G→A)基因型频率与等位基因频率和对照组比较,差异均无统计学意义(P＞0.05).A2-G单体型在两组中最为常见,其频率分布为0.391、0.288(P =0.053).在4种单体型中两组仅C-A1单体型的频率差异有统计学意义,分别为0.103、0.281 (P =0.001).结论 IL-6R基因第9外显子D358A(rs8192284)是种有价值的遗传性标志,C等位基因对2型糖尿病具有保护作用,携带C-A2单体型的人群较易患2型糖尿病.     

2型糖尿病并发脂肪肝的临床研究

目的探讨2型糖尿病合并脂肪肝的主要危险因素。方法采用病例对照研究的方法观察338例2型糖尿病并发脂肪肝和无脂肪肝患者的年龄、身高、体重、腰围、臀围、体重指数（BMI）、腰臀比、空腹血糖（FBG）、C肽、糖化血红蛋白（HbAlc）、谷草转氨酶（AST）、谷丙转氨酶（ALT）、总胆红素（TBIL）、直接胆红素（DBIL）、碱性磷酸酶（ALP）、γ-谷氨酰转肽酶（γ-GT）、肌酐、甘油三酯（TG）、总胆固醇（TC）、高密度脂蛋白（HDL）、低密度脂蛋白（LDL）、2 h血糖、2 h C肽等指标：多因素相关分析采用Logistic逐步回归。结果2型糖尿病并发脂肪肝组与无脂肪肝组年龄、身高、FBG、2 h血糖、HbAlc、TBIL、DBIL、ALP、肌酐、TC、LDL无显著性差异（P〉0.05）,体重、BMI、腰围、臀围、腰臀比、空腹C肽、2hC肽、AST、ALT、γ-GT、TG、HDL有显著性差异（P〈0.01）;BMI（OR=1.22）、空腹C肽（OR=2.24）与2型糖尿病并发脂肪肝呈正相关,HDL（OR=0.26）与2型糖尿病并发脂肪肝呈负相关。结论肥胖、胰岛素抵抗及脂质代谢紊乱是2型糖尿病并发脂肪肝的主要危险因素。     

2型糖尿病的抗炎治疗

胰岛素抵抗与胰岛β细胞功能障碍是2型糖尿病发病的主要病理生理基础,而炎性反应因子介导的慢性非特异性低度炎性反应状态与胰岛素抵抗及β细胞功能障碍密切相关.传统意义上的降糖药物如二甲双胍、噻唑烷二酮类药物、胰岛素、胰高血糖素样肽-1以及他汀类降脂药都具有抗炎效应.新型的抗炎药物如白细胞介素1受体拮抗剂、白藜芦醇、姜黄素等可以通过多种途径改善炎性反应状态而降低血糖.因此,针对炎性反应因子的抗炎治疗有望成为一种崭新的糖尿病治疗u方法.     

逆转糖尿病心血管转归的最新临床试验证据

糖尿病影响了世界近3亿人的生活,并使心血管疾病（CVD）的发生率增加2～3倍.伴随全球化和东西方交流,亚洲糖尿病发病率呈逐年上升趋势,且以发病年龄轻和低体重为体征[1].糖尿病在中国的发病率已接近10%,目前中国有糖尿病患者9240万,已排世界糖尿病患者人数第一位[2].     

Effect of Eicosapentaenoic acid (EPA) supplementation on cardiovascular markers in patients with type 2 diabetes mellitus: A randomized,double-blind,placebo-controlled trial

Aims

Cardiovascular complications are one of main cause of increased mortality and morbidity among Diabetes Mellitus (DM) patients. Altered metabolism of sulphur amino acids in diabetes reflected as increases in concentration of methionine and cysteine/cystine in the blood which known as a markers of Cardiovascular Diseases (CVD). The aim of present study was to determine the effect of Eicosapentaenoic acid (EPA) supplementation on sulfhydryl amino acids and Atherogenic Index of Plasma (AIP) in patients with type 2 DM (T2DM).

TAp63 is correlated with chronic inflammation in patients with newly diagnosed type 2 diabetes mellitus

Aims

To investigate TAp63 expression in patients with type 2 diabetes mellitus (T2DM) and the potential correlations between TAp63 and proinflammatory cytokines production and other clinical parameters.

利拉鲁肽对2型糖尿病患者血浆丝氨酸蛋白酶抑制剂水平的影响

目的 探讨胰高糖素样肽-1(GLP-1)类似物利拉鲁肽(Liraglutide)对2型糖尿病(T2DM)患者血浆丝氨酸蛋白酶抑制剂(Vaspin)水平的影响.方法 采用酶联免疫法测定T2DM患者及正常人Vaspin水平,分析血浆Vaspin水平与体重指数(BMI)、腰臀比(WHR)、胰岛素抵抗指数(HOMA-IR)、胰岛素分泌指数(HOMA-IS)、游离脂肪酸(FFA)等的关系,观察利拉鲁肽治疗前后T2DM患者血浆Vaspin水平变化.结果 T2DM患者血浆Vaspin水平显著高于正常人(P＜0.05).血浆Vaspin水平与空腹血糖(FPG)及糖化血红蛋白(HbA1c)呈明显正相关(r=0.35,P＜0.01和r=0.25,P＜0.05),而与DBP呈明显负相关(r=-0.25,P＜0.05),FPG、WHR分别是影响血浆Vaspin水平的独立相关因素.T2DM患者经利拉鲁肽治疗后,体重、BMI、WHR、FPG、餐后2小时血糖(2 h PG)、HbA1c均显著降低(P＜0.01),而HOMA-IS则显著增高(P＜0.01),空腹血浆Vaspin也显著增高(P＜0.05).结论 利拉鲁肽能有效改善T2DM患者糖脂代谢和胰岛素敏感性,增强胰岛β细胞功能,同时升高血浆Vaspin水平.     

Comparison of acarbose and metformin in patients with Type 2 diabetes mellitus insufficiently controlled with diet and sulphonylureas: a randomized, placebo-controlled study.

AIMS: To compare the efficacy and safety of acarbose and metformin when added to sulphonylurea therapy in diabetic patients insufficiently controlled with sulphonylureas alone. METHODS: A 12-week, single-centre, placebo-controlled study, with 89 patients randomized to receive acarbose (100 mg t.d.s.), metformin (850 mg b.d.) or placebo in addition to their sulphonylurea therapy. The study was double-blinded with respect to acarbose/placebo and single-blinded for metformin/ acarbose and metformin/placebo. Patients started a strict dietary regimen 1 week before receiving their first dose of acarbose, metformin or placebo. This regimen was individually adjusted to metabolic status and energy requirements. RESULTS: The primary endpoint, HbA1c, decreased from baseline in all three groups after 12 weeks. The decrease was greater in the two groups receiving active therapy compared with placebo (acarbose -2.3+/-0.32%; metformin -2.5+/-0.16%; placebo -1.3+/-0.34%). There was no significant difference between acarbose and metformin (P=0.65). Differences between both active therapies and placebo were statistically significant (acarbose P < or = 0.01; metformin P < or = 0.004). Reductions in body weight over the treatment period were seen in all three groups and were greatest in the acarbose group (median weight reduction: acarbose 3.5 kg; metformin, 1.0 kg; placebo 1.4 kg). There were no significant differences in the incidence of gastrointestinal side-effects between the three groups and all regimens were generally well tolerated. CONCLUSION: The results of the study demonstrate the equivalence of acarbose and metformin for improving metabolic control in patients insufficiently controlled with diet and sulphonylureas.     

2型糖尿病患者血瘦素水平与高血压的相关性研究

选择122例2型糖尿病患者,分为合并高血压组和血压正常组,各组又分别分为肥胖和非肥胖亚组.测定其体重指数(BMI)、空腹血糖(FBG)和胰岛素、糖化血红蛋白(HbA1c)及血清瘦素水平,并作相关性分析.结果显示,2型糖尿病患者高血压组与非高血压组间血清瘦素水平无差异(P＞0.05);血清瘦素水平与BMI、空腹胰岛素呈正相关关系(P＜0.01),与血压无明显相关性(P＞0.05);但在合并高血压组,血清瘦素水平与HbA1c呈负相关关系(P＜0.05).提示2型糖尿病患者的血清瘦素水平与血压无明显相关性,但合并高血压患者长时间血糖控制不良可能会导致血清瘦素水平的下降.     

Insulin degludec in Japanese patients with type 1 diabetes mellitus: A randomized controlled trial

Introduction

Insulin degludec is an ultra‐long‐acting insulin with a flat time‐action profile and duration of action >42 h. Data from several studies have shown insulin degludec to have a favorable therapeutic profile in type 1 and type 2 diabetes.

Materials and Methods

This was a 6‐week, parallel‐group, randomized controlled trial carried out in 65 Japanese patients with type 1 diabetes, previously treated with mealtime insulin aspart and either insulin glargine or neutral protamine Hagedorn insulin. Patients were randomized to receive either insulin degludec or insulin detemir, each once daily and at the same unit dose as pretrial basal insulin. During the trial, basal insulin was titrated according to a prespecified algorithm in order to achieve a fasting plasma glucose target of 80–109 mg/dL.

Results

No severe hypoglycemia occurred; there was no significant difference in confirmed hypoglycemia rates with insulin degludec and insulin detemir (rate ratio degludec/detemir 0.78; 95% confidence interval 0.45–1.34). The rate of nocturnal confirmed hypoglycemia was 69% lower with insulin degludec than with insulin detemir (rate ratio 0.31; 95% confidence interval 0.13–0.78). Final fasting plasma glucose levels were similar (insulin degludec 147 mg/dL, insulin detemir 136 mg/dL), despite differing baseline fasting plasma glucose levels.

Conclusions

In conclusion, no concerns relating to hypoglycemia or general safety were observed when initiating insulin degludec in Japanese patients with type 1 diabetes at the same unit dose as previous basal insulin. This trial was registered with ClinicalTrials.gov (no. NCT00841087).     

格列美脲联合门冬胰岛素30治疗2型糖尿病的多中心临床研究

目的 观察在接受门冬胰岛素30治疗控制不佳的2型糖尿病患者中,联合格列美脲治疗后胰岛素剂量和血糖水平的变化情况.方法 为多中心、开放、自身对照的观察性研究,入选161例2型糖尿病患者.在原门冬胰岛素30或联合2种以下非胰岛素促泌剂治疗方案基础上,联合格列美脲降糖治疗12周.结果 治疗3个胆后,患者全天各时点血糖均较基线...     

对2型糖尿病患者启动胰岛素治疗的思考

在2型糖尿病的治疗中尽早启动胰岛素治疗,是血糖达标的需要,也是保护胰岛β细胞、恢复其功能,从而延缓糖尿病进展的需要。初诊2型糖尿病患者经过3个月的生活方式干预和优化的口服降糖药物治疗血糖仍不能达标时,即应启动胰岛素治疗。对代谢紊乱严重、血糖水平较高的患者,应及时启动胰岛素强化治疗。可供选择的胰岛素治疗方案很多,各有优缺点和适应人群,临床上应当因患者而异地选择适宜的起始治疗方案。如何依据糖化血红蛋白（Hb）A1c选择起始治疗方案,目前尚无定论。推荐当HbA1c≤8．5％时主要选择基础胰岛素,HbA1c〉8．5％时选择预混胰岛素或基础—餐时或持续皮下胰岛素输注（CSII）作为起始胰岛素治疗方案。     

A comparative study of the clinical profile of fibrocalculous pancreatic diabetes and type 2 diabetes mellitus

AimsThe present study aimed to compare the clinical characteristics of patients with fibrocalculous pancreatic diabetes (FCPD) and those with type 2 diabetes mellitus (T2DM) to identify the characteristics distinctive of FCPD.MethodsA total of 133 patients with FCPD were compared with 665 patients with T2DM matched for duration of diabetes. Biochemical parameters and microvascular and macrovascular complications were assessed in all patients. Multivariate regression analyses were performed to study the determinants of microvascular and macrovascular complications in both groups.ResultsThe mean duration of diabetes was 4.42 ± 5.65 years in the FCPD group and 4.51 ± 3.88 years in the T2DM group. FCPD participants were significantly younger at diagnosis and leaner than patients with T2DM. The FCPD group had higher fasting and postprandial glucose and HbA1c levels than the T2DM group. The FCPD group had significantly lower triglyceride, total cholesterol, low-density lipoprotein cholesterol, serum total calcium, hemoglobin, and serum creatinine values than the T2DM group. The prevalence of coronary artery disease, stroke, and retinopathy was significantly higher in the T2DM patients while the prevalence of distal symmetric polyneuropathy was significantly lower. On multivariate logistic regression analysis, duration of diabetes and HbA1c (OR = 1.17, P = 0 0.04) in FCPD patients and age (OR = 1.04, P < 0 0.001), duration of diabetes (OR = 1.17, P < 0 0.001) and HbA1c (OR = 1.28, P < 0.001) in T2DM patients were associated with microvascular complications.ConclusionsThere are several differences in the phenotype, biochemical parameters, and prevalence of diabetic complications between patients with FCPD and T2DM. Timely diagnosis may have implications in the follow-up and management of patients.     

Toll样受体4与2型糖尿病及其并发症

介导先天免疫和炎性反应的Toll样受体(TLR)4参与了炎性反应性疾病的发病.炎性反应在2型糖尿病(T2DM)及其并发症的发生、发展中具有重要作用.TLR4信号通路的激活与胰岛素抵抗(IR)有关,而IR是T2DM及其大血管病变的重要病理生理基础,TLR4信号通路激活后炎性反应因子释放增加,与糖尿病微血管病变及神经病变密切相关.抑制TLR4信号通路的激活可能会防治T2DM及其并发症的发生、发展.