Impairment of α1‐adrenoceptor‐mediated contractile activity in caudal arterial smooth muscle from Type 2 diabetic Goto‐Kakizaki rats

1. In the present study, we compared the responsiveness of de‐endothelialized caudal artery smooth muscle strips, isolated from Type 2 diabetic Goto‐Kakizaki (GK) and normal Wistar rats, to α₁‐adrenoceptor stimulation (cirazoline) and membrane depolarization (K⁺). 2. The contractile and myosin 20 kDa light chain (LC₂₀) phosphorylation responses to 0.3 μmol/L cirazoline of caudal artery strips isolated from 12‐week‐old GK rats were significantly reduced compared with those of age‐matched Wistar rats, whereas the contractile and LC₂₀ phosphorylation responses to 60 mmol/L K⁺ were unaltered. 3. Stimulation of fura 2‐AM‐loaded strips from GK rats with 0.3 μmol/L cirazoline induced a significantly smaller rise in [Ca²⁺]_i (by ～20%) compared with that in strips from Wistar rats, whereas comparable Ca²⁺ transients were evoked by K⁺ in both. 4. Using quantitative polymerase chain reaction, no significant differences were detected in the mRNA expression of α_1A‐, α_1B‐ and α_1D‐adrenoceptor subtypes between GK and Wistar rats. 5. Cirazoline (1 μmol/L)‐ and caffeine (20 mmol/L)‐induced contractions in the absence of extracellular Ca²⁺ were unaltered in GK rats, suggesting that the release of Ca²⁺ from the sarcoplasmic reticulum in response to cirazoline does not differ between GK and Wistar rats. 6. The results of the present study suggest that Ca²⁺ entry from the extracellular space via α₁‐adrenoceptor‐activated, Ca²⁺‐permeable channels, but not via membrane depolarization and voltage‐gated L‐type Ca²⁺ channels, is impaired in caudal artery smooth muscle of GK rats.     

Mechanism-based disease progression modeling of type 2 diabetes in Goto-Kakizaki rats

The dynamics of aging and type 2 diabetes (T2D) disease progression were investigated in normal [Wistar-Kyoto (WKY)] and diabetic [Goto-Kakizaki (GK)] rats and a mechanistic disease progression model was developed for glucose, insulin, and glycosylated hemoglobin (HbA1c) changes over time. The study included 30 WKY and 30 GK rats. Plasma glucose and insulin, blood glucose and HbA1c concentrations and hematological measurements were taken at ages 4, 8, 12, 16 and 20 weeks. A mathematical model described the development of insulin resistance (IR) and β-cell function with age/growth and diabetes progression. The model utilized transit compartments and an indirect response model to quantitate biomarker changes over time. Glucose, insulin and HbA1c concentrations in WKY rats increased to a steady-state at 8 weeks due to developmental changes. Glucose concentrations at 4 weeks in GK rats were almost twice those of controls, and increased to a steady-state after 8 weeks. Insulin concentrations at 4 weeks in GK rats were similar to controls, and then hyperinsulinemia occurred until 12–16 weeks of age indicating IR. Subsequently, insulin concentrations in GK rats declined to slightly below WKY controls due to β-cell failure. HbA1c showed a delayed increase relative to glucose. Modeling of HbA1c was complicated by age-related changes in hematology in rats. The diabetes model quantitatively described the glucose/insulin inter-regulation and HbA1c production and reflected the underlying pathogenic factors of T2D—IR and β-cell dysfunction. The model could be extended to incorporate other biomarkers and effects of various anti-diabetic drugs.     

替格列汀在2型糖尿病特殊人群中用药优势的研究进展

第3代二肽基肽酶-4（DPP-4）抑制剂替格列汀是治疗2型糖尿病的有效药物之一,能够抑制DPP-4酶活性,减少胰高血糖素样肽-1（GLP-1）和葡萄糖依赖性促胰岛素分泌多肽（GIP）的降解,改善高血糖,修复β细胞功能。替格列汀具有独特的化学结构和药动学特征。归纳了替格列汀在2型糖尿病特殊人群中的应用,如肾功能不全者、肝功能不全者以及不同年龄、性别、种族患者,希望为患2型糖尿病特殊人群提供一种有效、安全、长效的降糖药物新选择。     

新疆布尔津县哈萨克族糖尿病和高血压流行病学调查研究

目的：调查新疆布尔津县哈萨克族2型糖尿病（T2DM）和高血压（HP）的患病率,为T2DM和HP的预防提供依据。方法：采用随机抽样的调查方法对新疆布尔津县1766例哈萨克族居TT2DM和HP的患病情况进行分析。结果：1766例中T2DM检出率为1．81％,糖耐量异常（IGT）检出率为1．42％,空腹血糖受损（IFG）检出率为0．91％;三组的年龄、收缩压（SBP）、舒张压（DBP）、体重指数（BMI）、腰围,身高比值（WHtR）、总胆固醇（TC）、胰岛素抵抗指数（HOMA—IR）均高于正常糖耐量组（NGT）,差异均有显著性。HP检出率为38．05％,高血压人群的年龄、BMI、WHtR、空腹血糖、TC、TG、HDL、LDL、HOMA—IR均高于血压正常人群,差异有显著性。结论：应对当地居民加强健康教育,提倡合理的饮食结构,控制血糖和血压。关注身体健康。     

Mechanism-based population pharmacokinetic modelling in diabetes: vildagliptin as a tight binding inhibitor and substrate of dipeptidyl peptidase IV

AIMS

To assess the pharmacokinetics of vildagliptin at different doses and build a mechanism-based population model that simultaneously describes vildagliptin pharmacokinetics and its effects on DPP-4 activity based on underlying physiology and biology.

METHODS

Vildagliptin concentrations and DPP-4 activity vs. time from 13 type 2 diabetic patients after oral vildagliptin 10, 25 or 100 mg and placebo twice daily for 28 days were co-modelled. NONMEM VI and S-ADAPT were utilized for population modelling.

RESULTS

A target-mediated drug disposition (TMDD) model accounting for capacity-limited high affinity binding of vildagliptin to DPP-4 in plasma and tissues had good predictive performance. Modelling the full time course of the vildagliptin-DPP-4 interaction suggested parallel vildagliptin dissociation from DPP-4 by a slow first-order process and hydrolysis by DPP-4 to an inactive metabolite as a disposition mechanism. Due to limited amounts of DPP-4, vildagliptin concentrations increased slightly more than dose proportionally. This newly proposed model and the parameter estimates are supported by published in vitro studies. Mean parameter estimates (inter-individual coefficient of variation) were: non-saturable clearance 36 l h⁻¹ (25%), central volume of distribution 22 l (37%), half-life of dissociation from DPP-4 1.1 h (94%) and half-life of hydrolysis 6.3 h (81%).

CONCLUSIONS

Vildagliptin is both an inhibitor and substrate for DPP-4. By utilizing the TMDD approach, slow dissociation of vildagliptin from DPP-4 was found in patients and the half-life of hydrolysis by DPP-4 estimated. This model can be used to predict DPP-4 inhibition effects of other dosage regimens and be modified for other DPP-4 inhibitors to differentiate their properties.     

链脲菌素制备2型糖尿病大鼠模型的研究

目的优化建立操作简便、条件稳定、成模率高、造模周期短、具有胰岛素抵抗的2型糖尿病模型。方法 6周龄大鼠以高糖高脂饲料喂养4周后,禁水禁食18 h,一次性腹腔注射1%链脲菌素(STZ)溶液35mg·kg-1,注射后继续禁水禁食1 h;对照组腹腔注射相同剂量柠檬酸-柠檬酸钠缓冲液。结果 STZ注射后14 d空腹血糖值稳定,口服葡萄糖耐量实验符合糖尿病标准,空腹胰岛素水平接近对照组,成模率93%,模型死亡率0%。结论成功制备了2型糖尿病模型,优化了2型糖尿病造模过程及提高了成模率。     

2型糖尿病大血管病变的独立危险因素调查

目的探讨2型糖尿病（T2DM）合并大血管病变（MA）的独立危险因素。方法将107例T2DM患者临床数据进行大血管病变的单因素Logistic回归分析,对有统计学意义的危险因素再进行多因素非条件的Logistic回归分析。结果年龄（age）、病程、体重指数（BMI）、糖化血红白蛋白（GHbA1c）、高血压（HT）及微血管并发症（MI）在单因素Logistic回归分析中为大血管病变的危险因素（P〈0.05）;多因素非条件的Logistic回归分析结果显示HT是T2DM合并MA的独立危险因素（P〈0.01）;合并HT的T2DM患MA的几率为非HT的T2DM的11.038倍。结论HT是T2DM合并MA的独立危险因素,积极控制血压对糖尿病病人预防MA有重要意义。     

脂联素与2型糖尿病和心血管疾病

脂肪组织的内分泌功能的发现是近几年内分泌学科领域的突破性进展之一，研究表明，脂肪组织不仅是能量储存器官，而且是控制能量平衡的内分泌器官，在代谢状态改变及受外来刺激时脂肪组织可分泌多种具有生理活性的蛋白质，分泌的这些蛋白质共同命名为脂肪细胞因子，包括瘦素、肿瘤坏死因子（TNF）-α、纤溶酶原激活抑制剂-1、抵抗素、白细胞介素6（interleukin-6，IL-6）和脂联素等。脂联素（adiponectin）由于近年来的研究发现其在糖尿病及心血管疾病中具有积极作用而备受关注。本文就脂联素与2型糖尿病和心血管疾病的关系进行综述。     

交泰丸及其单味药对大鼠2型糖尿病的治疗作用

目的:探讨交泰丸及其单味药对大鼠2型糖尿病(T2DM)的治疗作用。方法:采用尾静脉注射小剂量链脲佐菌素(STZ)加高脂高热卡喂养的方法建立大鼠T2DM模型,将大鼠随机分为模型组、交泰丸组、黄连组、肉桂组、二甲双胍组,各治疗组分别给与相应药物灌胃治疗,另设正常对照组。干预治疗8周后观察各组大鼠体重、口服葡萄糖耐量试验(OGTT)、血脂(TC、TG、HDL-C、LDL-C)、血清脂联素、游离脂肪酸(FFA)的差异。结果:与正常组比较,模型组大鼠体重增加,空腹血糖(FPG)、餐后1h(PG-1h)和餐后2h(PG-2h)升高,TC、TG、LDL-C、FFA均升高,HDL-C和脂联素水平均下降(P<0.01);与模型组比较,各治疗组OGTT改善,TC、TG、LDL-C、FFA均下降,HDL-C和脂联素水平均升高(P<0.05或P<0.01);与二甲双胍组比较,交泰丸组HDL-C升高明显(P<0.05),其余指标差异无显著性;各中药组比较,交泰丸组升高HDL-C功效为最佳(P<0.05)。结论:交泰丸及其单味药对大鼠T2DM有一定治疗作用,而以交泰丸疗效最佳。     

Fructose-fed streptozotocin-injected rat: an alternative model for type 2 diabetes

The main objective of the study was to develop an alternative non-genetic rat model for type 2 diabetes (T2D). Six-week-old male Sprague-Dawley rats (190.56 ± 23.60 g) were randomly divided into six groups, namely: Normal Control (NC), Diabetic Control (DBC), Fructose-10 (FR10), Fructose-20 (FR20), Fructose-30 (FR30) and Fructose-40 (FR40) and were fed a normal rat pellet diet ad libitum for 2 weeks. During this period, the two control groups received normal drinking water whilst the fructose groups received 10, 20, 30 and 40% fructose in drinking water ad libitum, respectively. After two weeks of dietary manipulation, all groups except the NC group received a single injection (i.p.) of streptozotocin (STZ) (40 mg/kg b.w.) dissolved in citrate buffer (pH 4.4). The NC group received only a vehicle buffer injection (i.p.). One week after the STZ injection, animals with non-fasting blood glucose levels > 300 mg/dl were considered as diabetic. Three weeks after the STZ injection, the animals in FR20, FR30 and FR40 groups were eliminated from the study due to the severity of diabetes and the FR10 group was selected for the remainder of the 11 weeks experimental period. The significantly (p < 0.05) higher fluid intake, blood glucose, serum lipids, liver glycogen, liver function enzymes and insulin resistance (HOMA-IR) and significantly (p < 0.05) lower body weight, oral glucose tolerance, number of pancreatic β-cells and pancreatic β-cell functions (HOMA-β) of FR10 group demonstrate that the 10% fructose-fed followed by 40 mg/kg of BWSTZ injected rat can be a new and alternative model for T2D.     

缬沙坦对2型糖尿病大鼠心肌病变的防治作用

目的　观察 2型糖尿病大鼠心肌病变时一氧化氮(NO)、一氧化氮合酶 (NOS)基因表达的变化及缬沙坦对心肌病变的防治作用。方法　采用高能量饮食加小剂量腹腔注射链脲佐菌素 (STZ)的方法 ,建立 2型糖尿病大鼠模型。缬沙坦连续灌胃 8wk。观察注射STZ 12wk和 2 0wk后大鼠的心功能、心脏重量指数、心肌和血浆中NO含量、心肌中eNOSmRNA和iNOSmRNA表达情况。结果　从注射STZ后的 12wk到 2 0wk ,2型糖尿病组大鼠左心室收缩和舒张功能进行性减退 ,心脏重量指数增加 ;心肌和血浆中NO水平于注射STZ 12wk时上升 ,2 0wk时下降 ;心肌iNOSmR NA的表达在 12wk和 2 0wk时均明显增加 ,eNOSmRNA的表达在 12wk时无明显改变 ,在 2 0wk时则明显减少 ;缬沙坦能使上述异常显著减轻。结论　NO及NOSmRNA基因表达的异常改变可能参与了 2型糖尿病心肌病变发生发展的过程 ;缬沙坦对 2型糖尿病心肌病具有一定防治作用。     

Using DPP-4 inhibitors to modulate beta cell function in type 1 diabetes and in the treatment of diabetic kidney disease

Introduction: DPP-4 inhibitors have pleomorphic effects that extend beyond the anti-hyperglycemic labeled use of the drug. DPP-4 inhibitors have demonstrated promising renal protective effects in T2DM and T1DM and protective effects against immune destruction of pancreatic beta-cells in T1DM.

Areas covered: The efficacy of DPP-4 inhibitors in the treatment of diabetic kidney disease and possible adjunct with insulin in the treatment of T1DM to preserve beta-cell function. Pertinent literature was identified through Medline, PubMed and ClinicalTrials.gov (1997-November 2018) using the search terms T1DM, sitagliptin, vildagliptin, linagliptin, beta-cell function, diabetic nephropathy. Only articles are written in the English language, and clinical trials evaluating human subjects were used.

Expert opinion: DPP-4 inhibitors can be used safely in patients with diabetic kidney disease and do not appear to exacerbate existing diabetic nephropathy. Linagliptin reduces albuminuria and protects renal endothelium from the deleterious effects of hyperglycemia. The effects of DPP-4 inhibitors on preserving beta-cell function in certain subtypes of T1DM [e.g. Latent Autoimmune Diabetes in Adult (LADA) and Slowly Progressive Type 1 Diabetes (SPIDDM)] are encouraging and show promise.     

Thoughts on the progression of type 2 diabetes drug discovery

Introduction: Type 2 diabetes is a growing epidemic in need of effective treatments. There has been research in recent years involving numerous drug therapies and targets. This article is a review of the progress thus far in type 2 diabetes drug discovery.

Areas covered: This editorial reviews type 2 diabetes drug discovery mainly over the past decade through a literature search of PubMed. Furthermore, the author reviews several avenues of research, including the expansion of knowledge for possible drug therapies involving the β-cell, such as targeting its proliferation, function and apoptosis. This knowledge has led to possible drug therapies in clinical trials, particularly insulin secretagogues that are glucose-dependent. Other areas of research in type 2 diabetes drug discovery discussed by the author relate to the new frontier of genome-wide association studies (GWAS), the challenges of oral insulin development and drug targets of inflammation. The author also reviews sirtuin activators and resveratrol, especially its relationship to insulin resistance.

Expert opinion: The progression of type 2 diabetes drug discovery holds much promise, but many agents are in the nascent stages of investigation and human trials proving efficacy are needed. Furthermore, basic science research into some of these agents may need to be further elucidated before clinical trials can be initiated.     

2型糖尿病伴非酒精性脂肪肝的危险因素分析

目的 探讨2型糖尿病（T2DM）伴非酒精性脂肪肝（NAFLD）患者的相关危险因素.方法 选取T2DM患者122例,根据肝脏彩超检查分为T2DM伴NAFLD组和T2DM不伴NAFLD组.对其腰围、腰臀比（WHR）、BMI、肝功能、血脂、胰岛素抵抗指数（HOMA-IR）进行比较分析.结果 与单纯T2DM组相比,T2DM伴NAFLD组的腰围、WHR、BMI、TC、TG、LDL-C、ALT、HOMA-IR升高（P＜0.05）.多元逐步回归分析显示,TG、腰围、BMI、HOMAIR是NAFLD的独立危险因素.结论 T2DM伴NAFLD患者存在多种代谢异常,其中肥胖、TG、胰岛素抵抗对其影响最大.     

Initial therapy,persistence and regimen change in a cohort of newly treated type 2 diabetes patients

Aims

The aim was to describe the utilization of antidiabetic agents, in terms of persistence and regimen change, in the management of a cohort of newly treated type 2 diabetes patients and to investigate associated socio-demographic and treatment factors.

Methods

A population-based retrospective cohort study was conducted using the national pharmacy claims database in Ireland. Subjects were analyzed for persistence and regimen change. Cox proportional hazards regression examined associations of socio-demographic and treatment factors on treatment patterns. Hazard ratios (HR) and 95% CIs are presented.

Results

A total of 20947 subjects were identified in the study over a 2 year period. Most were initiated on metformin (76%) or sulphonylureas (22%) and 77% were persistent with therapy 12 months after initiation. The likelihood of non-persistence was significantly lower in the youngest (40–49 years) age groups (reference 60–69 years) (HR 1.62, 95% CI 1.42, 1.84) and those on sulphonylureas (HR 1.49, 95% CI 1.36, 1.64). The likelihood of receiving a regimen change was significantly lower in the older (80+ years) age groups (HR 0.63, 95% CI 0.56, 0.71), females (HR 0.91, 95% CI 0.86, 0.95), and those with pre-existing CVD (1 vs. 0 CVD medicines) (HR 0.82, 95% CI 0.74, 0.90), and higher in those on sulphonylureas (HR 1.83, 95% CI 1.73, 1.94).

Conclusions

Type of treatment, pre-existing CVD and demographic factors are shown to be associated with the observed treatment patterns. Guideline recommended agents were widely used on treatment initiation though a substantial minority were not initiated on the recommended first line agent. Use of guideline recommended agents was not as evident during treatment progression. Further optimization of initial and subsequent antidiabetic agent prescribing may be possible.     

甲壳低聚糖硒对2型糖尿病大鼠胰岛素指标及胰腺组织的影响

目的观察甲壳低聚糖硒(COS-Se)对2型糖尿病大鼠的胰岛素含量、胰岛素敏感性及胰腺组织的影响。方法制备2型糖尿病大鼠模型,分别给予COS-Se、Se、甲壳低聚糖(COS)对其进行干预,观察20周,期间检测血糖、胰岛素的含量、胰岛素敏感指数及胰腺组织HE染色观察。结果 COS-Se、Se、COS对糖尿病模型的高胰岛素血症都有一定改善作用,随着时间的延长,COS-Se的改善作用更明显。结论 COS-Se可保护胰岛细胞,改善2型糖尿病大鼠的胰岛素敏感性。     

糖尿病患者胰岛细胞抗体检测123例结果分析

目的：比较1型糖尿病（1－DM）和2型糖尿病（2－DM）患者胰岛细胞抗体（ICA）阳性率。方法：分为1－DM组、2－DM组、正常对照组,均取清晨空腹静脉血采用免疫组织化学法检测ICA。结果：三组间CA性率差异非常显著（P＜0．01）;1－DM组与2－DM组比较,ICA阳性率差异亦非常显著（P＜0．01）;2－DM组与对照比较,胰岛素抗体（ICA）阳性率差异无显著性（P＞0．05）。结论：1－DM组ICA阳性率明显高于2－DM组。ICA的检测,为糖尿病的分型诊断提供了重要的实验室依据。     

糖尿病合并血管病变的血小板参数变化

目的 探讨Ⅱ型糖尿病患者血小板聚集功能（PagT）与血小板计数（PLT）,血小板平均体积（MPV）变化与血管病变的关系。方法 同时测定52例Ⅱ型糖尿病患者和12例正常人血小板聚集功能与血小板计数（PLT）、血小板平均体积（MPV）、血小板分布宽度（PCT）。结果 糖尿病合并血管病变患者血小板聚集率明显增高、血小板平均体积、血小板分布宽度明显增大,与健康人比较有明显差异（P〈0．05）。结论 糖尿病患者血小板功能亢进表现为血小板聚集增高,平均体积变大。这些指标可作为糖尿病患者并发血栓性疾病的检测指标。     

Effects of active and passive smoking on the development of cardiovascular disease as assessed by a carotid intima‐media thickness examination in patients with type 2 diabetes mellitus

Carotid intima‐media thickness has been widely used as a surrogate end‐point for cardiovascular disease, myocardial infarction, and stroke. This study aimed to assess the effects of active and passive smoking exposure on the development of cardiovascular disease in patients with type 2 diabetes mellitus. Seven hundred twenty‐two patients with type 2 diabetes mellitus were recruited for the study. A standardized questionnaire on smoking status, pack‐years of smoking, and the number of years of smoking cessation was provided to the patients, and their responses were collected for analysis. The carotid intima‐media thickness, carotid plaque, and the internal diameter of the common carotid artery were determined by high‐resolution B‐mode ultrasonography. Compared to non‐smokers, passive female smokers had a higher risk of cardiovascular disease (odds ratio = 3.50, 95% confidence interval: 1.29–9.49, P = 0.009); they also had a significantly larger common carotid artery (P = 0.041) and risk of carotid plaque (odds ratio = 2.20, 95% confidence interval: 1.1980–4.0505, P = 0.01). Both active and passive male smokers had a significantly greater carotid intima‐media thickness than non‐smokers (P = 0.003 and P = 0.005, respectively). Male active smokers had a significantly higher risk of carotid plaque (odds ratio = 2.88, 95% confidence interval: 1.4788–5.6094, P = 0.001). In conclusion, cumulative active and passive smoking exposures are significant risk factors for carotid atherosclerosis in patients with type 2 diabetes mellitus. Our results highlight the importance of endorsing a smoke‐free environment for patients with type 2 diabetes mellitus.