Postmarketing study of nateglinide in Japan: treatment of medication-naïve patients with type 2 diabetes

Nateglinide is an oral antidiabetic medication (OAD) that acts through rapid, short-term stimulation of insulin production. This study was conducted to identify the nature of any adverse effects associated with nateglinide and to evaluate its clinical efficacy in patients with type 2 diabetes, with particular attention to hypoglycemia. Patients with type 2 diabetes who were OAD naïve (n=547), whose fasting blood glucose levels were 150 mg/dL or lower, and who had started to take nateglinide alone were recruited from 139 centers in Japan with a 12-week observation period. The incidence of adverse reactions was 7.62%. Hypoglycemia accompanied by hypoglycemic symptoms was the most prevalent adverse event (2.10%; 11/525). Nine of 11 episodes required no therapeutic intervention. Severe hypoglycemia was recognized in only 1 case of diabetes complicated by serious renal dysfunction, for which nateglinide has been contraindicated in Japan. No subject experienced symptoms of nocturnal or prolonged hypoglycemia. After 12 weeks of nateglinide treatment, decreases were noted in hemoglobin A_1c (0.82%), postprandial glucose (reduced by 59.4 mg/dL to 158.0 mg/dL), and fasting glucose (reduced by 11.7 mg/dL to 122.4 mg/dL). Nateglinide, which demonstrates limited risk of hypoglycemia and effectively controls blood glucose level, is regarded as a useful drug for the treatment of patients with type 2 diabetes.     

Decreased insulin secretory capacity and normal pancreatic B-cell glucose sensitivity in non-obese patients with NIDDM

We investigated the dose-response characteristics of glucose-induced insulin release and the influence of hyperglycaemia on arginine-induced insulin secretion in eight non-obese subjects with NIDDM and in eight non-diabetic volunteers. Plasma C-peptide levels, achieved during 60 min hyperglycaemic clamps with and without the infusion of a primed continuous infusion of arginine (infusion rate 15 mg kg-1 min-1) during the last 30 min, were analysed with a modified Michaelis-Menten equation. The insulin secretory capacity (Vmax) for glucose-stimulated insulin release showed a trend towards a negative correlation with the fasting blood glucose in the NIDDM subjects (r = 0.68, P = 0.6); it was lower than the Vmax of non-diabetic controls (2.2 +/- 0.2 vs 4.2 +/- 0.4 nmol l-1 respectively; P less than 0.001). The ED50 (half maximal stimulating blood glucose concentration) of the second-phase glucose-stimulated insulin release (determined from the plasma C-peptide levels at 60 min) was not significantly different from the ED50 of the controls (11.9 +/- 0.8 vs 13.3 +/- 1.9 mmol l-1 respectively; P greater than 0.2). Combined glucose-arginine stimulation significantly increased insulin release. The Vmax for both phases were significantly lower in NIDDM patients than in controls (2.3 +/- 0.2 vs 5.0 +/- 0.9 and 3.8 +/- 0.5 vs 8.5 +/- 0.9 nmol l-1 respectively; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

NIDDM合并视网膜病变患者红细胞聚集性变化及其影响因素

本文测定了 ＮＩＤＤＭ合并视网膜病变患者２１例、无视网胰病变患 者１９例及正常对照２０例的红细胞聚集性有关参数。的果显示，ＮＩＤＤＭ视网膜病 变组的低切全血粘度、红细胞聚集指数均显著高于无视网膜病变组及对照组（Ｐ＜ ０．０１）。ＮＩＤＤＭ组和合并视网膜病变组的血沉及血沉方程Ｋ值均显著高于对照组 （Ｐ＜０．０１）。ＮＩＤＤＭ视网膜病变组的血浆纤维蛋白原水平及糖化血清蛋白指数 均显著高于无视网膜病变组和对照组（Ｐ＜０．０５，Ｐ＜０．０１）。ＮＩＤＤＭ视网膜病变 组血清白蛋白及超氧化物歧化酶（ＳＯＤ）均显著低于无视网膜病变组和对照组（Ｐ ＜０．０５，Ｐ＜０．０１）．ＮＩＤＤＭ视网膜病变组红细胞聚集指数与血浆纤维蛋白原、 糖化血清蛋白指数呈显著正相关（ｒ值 ０．４５２、０．４４６，Ｐ＜０．０５）．与血清ＳＯＤ、白蛋 白呈显著负相关（ｒ－０．４６２、－０．４３９，Ｐ＜０．０５）．结果提示，ＮＩＤＤＭ合并视网膜 病变患者上细胞聚集性增高，这种增高与血中纤维蛋白原水平增高，蛋白质非酶糖 基化增加、ＳＯＤ及白蛋白水平降低有关．     

NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X

Summary Non-insulin-dependent diabetes mellitus (NIDDM) is commonly associated with hypertriglyceridaemia, low serum HDL-cholesterol concentrations, hypertension, obesity and accelerated atherosclerosis (metabolic syndrome X). Since a similar dyslipidaemia occurs with the acute-phase response, we investigated whether elevated acute-phase/stress reactants (the innate immune system's response to environmental stress) and their major cytokine mediator (interleukin-6, IL-6) are associated with NIDDM and syndrome X, and may thus provide a unifying pathophysiological mechanism for these conditions. Two groups of Caucasian subjects with NIDDM were studied. Those with any 4 or 5 features of syndrome X (n = 19) were compared with a group with 0 or 1 feature of syndrome X (n = 25) but similar age, sex distribution, diabetes duration, glycaemic control and diabetes treatment. Healthy non-diabetic subjects of comparable age and sex acted as controls. Overnight urinary albumin excretion rate, a risk factor for cardiovascular disease, was also assayed in subjects to assess its relationship to the acute-phase response. Serum sialic acid was confirmed as a marker of the acute-phase response since serum concentrations were significantly related to established acute-phase proteins such as α-1 acid glycoprotein (r = 0.82, p < 0.0001). There was a significant graded increase of serum sialic acid, α-1 acid glycoprotein, IL-6 and urinary albumin excretion rate amongst the three groups, with the lowest levels in non-diabetic subjects, intermediate levels in NIDDM patients without syndrome X and highest levels in NIDDM patients with syndrome X. C-reactive protein and cortisol levels were also higher in syndrome X-positive compared to -negative patients and serum amyloid A was higher in both diabetic groups than in the control group. We conclude that NIDDM is associated with an elevated acute-phase response, particularly in those with features of syndrome X. Abnormalities of the innate immune system may be a contributor to the hypertriglyceridaemia, low HDL cholesterol, hypertension, glucose intolerance, insulin resistance and accelerated atherosclerosis of NIDDM. Microalbuminuria may be a component of the acute-phase response. [Diabetologia (1997) 40: 1286–1292] Received: 17 April 1997 and in revised form: 6 June 1997     

盐酸罗格列酮治疗75例NIDDM的疗效观察

目的研究盐酸罗格列酮治疗NIDDM中的增效作用。方法75例NIDDM患者中在原治疗基础上加服盐酸罗格列酮（文迪雅）2～8mg/d,共12周观察血糖、血脂LDL、HDL各项指标的变化,并将各项指标进行比较。结果治疗12周后,空腹和餐后2h血糖及糖化血红蛋白均明显降低,三酰甘油明显降低;胆固醇、高密度脂蛋白升高。结论罗格列酮在降低血糖的同时能改善血脂代谢,对NIDDM及其并发症有良好的防治功能。     

Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration

Mitochondrial impairment is increasingly implicated in the etiology of toxicity caused by some thiazolidinediones, fibrates, and statins. We examined the effects of members of these drug classes on respiration of isolated rat liver mitochondria using a phosphorescent oxygen sensitive probe and on the activity of individual oxidative phosphorylation (OXPHOS) complexes using a recently developed immunocapture technique. Of the six thiazolidinediones examined, ciglitazone, troglitazone, and darglitazone potently disrupted mitochondrial respiration. In accord with these data, ciglitazone and troglitazone were also potent inhibitors of Complexes II+III, IV, and V, while darglitazone predominantly inhibited Complex IV. Of the six statins evaluated, lovastatin, simvastatin, and cerivastatin impaired mitochondrial respiration the most, with simvastatin and lovastatin impairing multiple OXPHOS Complexes. Within the class of fibrates, gemfibrozil more potently impaired respiration than fenofibrate, clofibrate, or ciprofibrate. Gemfibrozil only modestly inhibited Complex I, fenofibrate inhibited Complexes I, II+III, and V, and clofibrate inhibited Complex V. Our findings with the two complementary methods indicate that (1) some members of each class impair mitochondrial respiration, whereas others have little or no effect, and (2) the rank order of mitochondrial impairment accords with clinical adverse events observed with these drugs. Since the statins are frequently co-prescribed with the fibrates or thiazolidinediones, various combinations of these three drug classes were also analyzed for their mitochondrial effects. In several cases, the combination additively uncoupled or inhibited respiration, suggesting that some combinations are more likely to yield clinically relevant drug-induced mitochondrial side effects than others.     

糖适平治疗Ⅱ型糖尿病临床疗效观察

本文总结了糖适平治疗Ⅱ型糖尿病29例的疗效观察,肯定了糖适平的降糖效果。空腹血糖平均下降幅度达55.2mg/dl;餐后2小时血糖平均下降100.6mg/dl。没有发现明显的副作用,证明本药安全有效,尤其适用于老年Ⅱ型糖尿病人。     

216例糖尿病患者血清微量元素的含量及与胰岛素和血糖的关系

目的 :探讨非胰岛素依赖性糖尿病 (NIDDM )患者血清锌、铬、铜、铁的变化及与胰岛素和血糖的关系。方法 :对 2 16例NIDDM患者血清微量元素、胰岛素、血糖水平进行了观察 ,并与正常对照组做比较 ,各指标间做相关分析。结果 :糖尿病组血清Zn、Cr显著下降 ,Cu显著升高 ,Fe无明显改变。结论 :血清微量元素含量变化与糖尿病关系密切 ,动态检测Zn、Cr、Cu、Fe对防治糖尿病并发症的发生及判断预后有着特殊的诊断价值。     

Cholesterol Rich apo B Containing Lipoproteins and Smoking are Independently Associated with Macrovascular Disease in Normotensive NIDDM Patients

A cross-sectional study of macrovascular disease (MVD) and associated metabolic and other risk factors was conducted in 87 normotensive NIDDM patients. MVD was assessed by Rose questionnaire, 12 lead resting ECG, duplex scanning of carotid and peripheral vessels, and ankle:brachial systolic blood pressure ratio. Fasting serum total cholesterol, total triglycerides, LDL cholesterol, HDL cholesterol, apolipoproteins AI and B, lipoprotein (a), HbA₁, plasma glucose, insulin, and C-peptide responses to a carbohydrate rich meal, body mass index (BMI), waist-hip ratio, urinary albumin excretion rate, blood pressure, smoking and family history were assessed as possible ‘risk factors’. Apolipoprotein:lipid ratios were calculated to estimate lipoprotein composition. Thirty-six patients had demonstrable MVD. The presence of MVD was associated with higher total triglycerides (p < 0.05), BMI (p < 0.05), systolic blood pressure (p < 0.01), a lower apo B:non HDL cholesterol ratio (p < 0.001), and smoking (p < 0.005) but no other measures. Multiple regression analysis revealed smoking and a low apo B:non HDL cholesterol to be independently associated with MVD. The low apo B:non HDL cholesterol suggests a high cholesterol content of apo B containing lipoproteins. This lipoprotein abnormality is not a feature of NIDDM, but when present in these patients may be particularly atherogenic.     

486例中老年人餐后血糖调查及分析

作者对４８６例住院病人做了空腹血糖、早餐后２ｈ血糖及尿糖的调查，结果发现非胰岛素依赖型糖尿病（ＮＩＤＤＭ）４３例，ＩＧＴ２６例，６９例均发生于中老年人。新检出的ＤＭ及ＩＧＴ空腹血糖异常例数分别为１１，１；尿糖阳性分别为５，０；早餐后２ｈ血糖均为异常，各组差异有显著性。提示餐后血糖较空腹血糖、尿糖ＤＭ检出率高，尤其对中老年人ＤＭ具明显的临床价值。