2型糖尿病患者胰岛素抵抗、血管内皮细胞功能与微量白蛋白尿

目的观察伴或不伴微量白蛋白尿的2型糖尿病(DM)患者胰岛素抵抗(IR)状态及内皮细胞功能,探讨2型DM大血管病变危险性增加的发病机制.方法伴微量白蛋白尿的2型DM组(DM-MA)、尿白蛋白正常的2型DM组(DM-NA)及正常对照组(NC)各12例.3组研究对象均采用正常血糖高胰岛素钳夹试验评价其外周组织葡萄糖利用率(GDR),采用彩色多普勒超声技术测定其内皮细胞依赖性血管舒张功能(EDV)以及非内皮细胞性血管舒张功能(EIV).结果 DM组GDR明显低于正常对照组,且DM-MA组GDR较DM-NA组更低[对照组(13.06±1.98)mg·kg-1·min-1,DM-MA和DM-NA组分别为(7.90±1.79)、(9.46±1.52) mg·kg-1·min-1,P＜0.05或P＜0.01].两组DM患者的EDV较正常对照组降低(均P＜0.05),且DM-MA组EDV受损程度重于DM-NA组(P＜0.05).3组间的EIV差异无显著性.DM组的血游离脂肪酸(FFA)水平明显高于正常对照组(P＜0.05),其中DM-MA组FFA水平最高.偏相关分析显示GDR与EDV呈显著正相关(r=0.47,P＜0.01,n=36).结论与尿白蛋白正常的2型DM患者相比,伴有微量白蛋白尿的2型DM患者具有更严重的IR,EDV明显受损和较高的血FFA水平.提示伴微量白蛋白尿的2型DM患者大血管病变危险性增高的机制可能与IR以及伴随的内皮细胞功能障碍有关.     

Preventing microalbuminuria in patients with type 2 diabetes

The public health burden of type 2 diabetes mellitus has been dramatically increasing world-wide. The chronic complications of type 2 diabetes play an important role in decreasing life expectancy and adversely affecting quality of life. Diabetic nephropathy, which is originally microvascular in nature, is widely considered an important complication of diabetes. In prospective clinical investigations, increased urinary albumin excretion proved to be associated not only with subsequent renal outcomes but also with cardiovascular morbidity/mortality independently of other risk factors. Therefore, microalbuminuria as an early sign of increased urinary albumin excretion should be considered important for both treatment and even for prevention. Preventing microalbuminuria might diminish progression to overt nephropathy and, hopefully, might limit cardiovascular events. Regarding primary prevention of diabetic nephropathy, therapeutic intervention should optimally be initiated at the stage of normoalbuminuria. Although additional factors such as smoking cessation, reduction of protein intake, and treatment of lipid abnormalities are important, providing optimal diabetic control as well as targeting optimal blood pressure are the key elements of a prevention strategy in diabetic patients. Recently, the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) documented that a significant decrease of the development of persistent microalbuminuria could be achieved by using an ACE-inhibitor, trandolapril alone or in combination with verapamil SR, a non-dihydropyridine calcium-channel blocker in hypertensive type 2 diabetic patients with normoalbuminuria. The results of this primary-prevention strategy should be corroborated by further investigations to determine whether these beneficial changes could later result in improvement of renal clinical outcomes, macrovascular complications, or both.     

Insulin resistance,hypertension and microalbuminuria in patients with Type 2 (non-insulin-dependent) diabetes mellitus

Summary We examined the impact of hypertension and microalbuminuria on insulin sensitivity in patients with Type 2 (non-insulin-dependent) diabetes mellitus using the euglycaemic insulin clamp technique in 52 Type 2 diabetic patients and in 19 healthy control subjects. Twenty-five diabetic patients had hypertension and 19 had microalbuminuria. Hypertension per se was associated with a 27% reduction in the rate of total glucose metabolism and a 40% reduction in the rate of non-oxidative glucose metabolism compared with normotensive Type 2 diabetic patients (both p<0.001). Glucose metabolism was also impaired in normotensive microalbuminuric patients compared with normotensive normoalbuminuric patients (29.4±2.2 vs 40.5±2.8 mol · kg lean body mass^–1 · min^–1; p=0.012), primarily due to a reduction in non-oxidative glucose metabolism (12.7±2.9 vs 21.1±2.6 mol · kg lean body mass^–1 ·min^–1; p=0.06). In a factorial ANOVA design, however, only hypertension (p=0.008) and the combination of hypertension and microalbuminuria (p=0.030) were significantly associated with the rate of glucose metabolism. The highest triglyceride and lowest HDL cholesterol concentrations were observed in Type 2 diabetic patients with both hypertension and microalbuminuria. Of note, glucose metabolism was indistinguishable from that in control subjects in Type 2 diabetic patients without hypertension and microalbuminuria (40.5±2.8 vs 44.4±2.8 mol · kg lean body mass^–1 · min^–1). We conclude that insulin resistance in Type 2 diabetes is predominantly associated with either hypertension or microalbuminuria or with both.     

Insulin resistance and endothelial dysfunction

Insulin has multiple metabolic actions, including effects on blood vessels. Insulin normally increases blood flow by a mechanism which involves generation of nitric oxide (NO) via the arginine-NO pathway. Although insulin itself is a weak and physiologically unimportant vasodilatator, it appears to markedly potentiate endothelium-dependent vasodilatation. Therefore, anything that impairs insulin action in endothelial cells can be expected to be associated with endothelial dysfunction, i.e. loss of NO bioactivity in the vessel wall. Consistent with the idea that insulin resistance and endothelial dysfunction frequently coexist, all insulin-resistant conditions examined to date have been associated with endothelial dysfunction. However, the latter can also be caused by factors other than insulin resistance-such as a high concentration of low-density lipoprotein (LDL) cholesterol. Therapies which reverse insulin resistance-such as exercise, insulin and inhibitors of the renin-angiotensin-aldosterone (RAA) axis-also reverse endothelial dysfunction, which may thus be an inherent feature of insulin resistance.     

Carotid stiffness and microalbuminuria in patients with type 2 diabetes

Microalbuminuria is associated with higher cardiovascular mortality, especially in diabetics. But the direct association between microalbuminuria and vascular wall properties is still not clear. We investigated quantitative carotid stiffness (QCS) index in relation to microalbuminuria in 260 Chinese diabetic patients. In categorical analyses, patients with elevated urinary albumin-to-creatinine ratio (uACR) had higher QCS than those with normal uACR (P < 0.001). The corresponding values for QCS values were 4.4 and 5.9, respectively. In multiple stepwise regression analyses, QCS was significantly associated with age, uACR, plasma glycosylated hemoglobin A_1C (HbA_1C), and current smoking (P < 0.05 for all). In conclusion, carotid stiffness as measured by QCS, a local functional measurement of the arterial wall, is increased in type 2 diabetes with microalbuminuria. Wei-Wei Zhan and Yu-Hong Chen have contributed equally to this article.     

老年2型糖尿病患者微量白蛋白尿与胰岛素抵抗的关系

目的了解老年２型糖尿病患者的微量白蛋白尿（ＭＡＵ）与胰岛素抵抗的关系。方法对血压正常的３０例老年２型糖尿病合并ＭＡＵ患者与２６例未合并ＭＡＵ患者的空腹血糖、胰岛素、胰岛素敏感性指数（ＩＳＩ）和血脂等进行比较分析,并对所有患者的尿白蛋白排泄率（ＵＡＥＲ）与有关因素进行多元回归分析。结果２型糖尿病合并ＭＡＵ组ＩＳＩ（－４．９９±０．４８）显著低于未合并ＭＡＵ组（－４．７６±０．４８,Ｐ＜０．０５）,而且ＩＳＩ与ＵＡＥＲ呈独立相关〔标准偏回归系数（β）＝－０．３９７,Ｐ＜０．０１〕。结论在血压正常的老年２型糖尿病患者中,胰岛素抵抗是ＭＡＵ的独立危险因素。     

胰岛素抵抗与血管内皮功能障碍

胰岛素抵抗和血管内皮功能障碍之间有重要联系,两者相辅相成,共同在代谢综合征和心血管疾病的发生发展中起重要作用.高血糖导致的葡萄糖中毒、血中游离脂肪酸水平升高和血脂异常导致的脂质毒性增加、与代谢和心血管疾病有关的炎性状态是引起胰岛素抵抗和血管内皮功能障碍的共同机制.采用多种措施改善胰岛素抵抗和血管内皮功能障碍对预防和治疗代谢性疾病和心血管疾病具有重要意义.     

Insulin resistance and NAFLD may influence memory performance in obese patients with prediabetes or newly-diagnosed type 2 diabetes

Background and aimsDiabetes has consistently been shown to increase risk for cognitive decline. Cognitive deficits may occur at the very earliest stages of diabetes.We sought to estimate the determinants of memory function in a group of middle-aged obese subjects with prediabetes or newly-diagnosed type 2 diabetes mellitus.Methods and resultsSixty-two obese patients in treatment with metformin-with prediabetes (n = 41) or newly diagnosed T2DM (n = 21), were studied. Short- and long-term memory function was assessed through a neuropsychological assessment consisting of two tests and a composite domain z score was calculated. Cardiometabolic variables, such as abdominal MRI quantification of subcutaneous (SAT) and visceral (VAT) adipose tissue content, and of intra-hepatocellular lipid content, as well as insulin sensitivity (Matsuda Index, HOMA-IR) and beta cell performance (Beta Index), by multiple sampling, 8-point oral glucose tolerance test, were also evaluated.Age, non-alcoholic fatty liver disease (NAFLD), and lnHOMA-IR together explained 18% (R square) of the variance in memory domain. Including NAFLD increased the explained variance by 8% and including lnHOMA-IR by 9.1%, whereas the contribution of age and other factors was negligible.ConclusionPreventing and managing insulin resistance in precocious and possibly earlier stages of diabetes might provide benefit in slowering down future cognitive decline.     

Acute-phase proteins and microalbuminuria among patients with type 2 diabetes

OBJECTIVE: to determine the relationship between acute-phase proteins and microalbuminuria in type 2 diabetic patients without clinical evidence of macrovascular disease. RESEARCH DESIGN AND METHODS: We studied cross-sectionally 64 non-smoking outpatients with type 2 diabetes mellitus without clinical evidence of cardiovascular disease attended at Brazilian University General Hospital aged 59.5 +/- 8.1 years and with a known duration of diabetes of 11.5 +/- 8 years. Urinary albumin excretion rate (AER) was determined in timed overnight urine samples. Serum alpha(1)-acid glycoprotein (AGP) and plasma fibrinogen were determined by immunoturbidimetry assay and serum C-reactive protein (CRP) was measured by a high-sensitive immunonephelometry assay. RESULTS: A higher levels of AGP (P = 0.0000), CRP (P= 0.003) and fibrinogen ( P = 0.0001) were found in microalbuminuric (n = 26) than in normoalbuminuric patients ( n = 38). All the acute-phase proteins were correlated with each other and with AER, respectively (r = 0.67 for AGP; 0.35 for fibrinogen, and 0.41 for CRP, P < 0.01 for all). Stepwise multiple regression analysis showed that AGP was independently associated with AER along with systolic blood pressure (r2 = 0.49, P = 0.000). Logistic regression analysis showed that AGP was independently related to microalbuminuria with an odds ratio (95% CI) of 1.16 ((1.08-1.24), P = 0.000). CONCLUSIONS: According to our results acute-phase proteins a known markers of chronic inflammation were associated with microalbuminuria independently of clinical cardiovascular disease. The influence of AGP on AER and microalbuminuria needs to be confirmed in prospective studies. Intervention studies are necessary to assess whether anti-inflammatory treatment would have a beneficial effect on this chronic complication of diabetes.     

Insulin secretory dysfunction and insulin resistance in the pathogenesis of korean type 2 diabetes mellitus

Although insulin resistance has been shown to be a primary defect causing type 2 (non insulin-dependent) diabetes mellitus in Pima Indians and Caucasians, insulin secretory defect has also been known to be an important factor in the development of type 2 diabetes. We undertook a study to investigate the initial abnormality of glucose intolerance in Koreans. A total of 370 Korean subjects were classified into 5 groups according to their degree of glucose intolerance (normal fasting glucose [NFG]/normal glucose tolerance [NGT], n = 95; impaired fasting glucose [IFG]/NGT, n = 29; NFG/impaired glucose tolerance [IGT], n = 60; IFG/IGT, n = 68; diabetes, n = 118). Insulinogenic index was used as an index of early-phase insulin secretion. Insulin resistance was assessed by the R value of the homeostasis model assessment [HOMA(R)]. Insulinogenic index significantly decreased in subjects with IFG/NGT and NFG/IGT compared with those with NFG/NGT. However, there was no significant difference in HOMA(R) between subjects with NFG/NGT and those with IFG/NGT or NFG/IGT. Insulinogenic index decreased significantly with the increase of plasma glucose 120-minute value at the earlier stage of glucose intolerance compared with HOMA(R). These results suggest that early-phase insulin secretory defect may be the initial abnormality in the development of type 2 diabetes in Korean subjects.     

血管内皮功能异常与2型糖尿病血管并发症

2型糖尿病血管并发症是糖尿病患者的主要并发症,是2型糖尿病患者致死致残的主要原因.据统计,80%的2型糖尿病患者死于心血管疾病.50%新诊断的2型糖尿病患者已存在大血管病变.     

Neither proteinuria nor albuminuria is associated with endothelial dysfunction in HIV-infected patients without diabetes or hypertension

It is unknown whether systemic endothelial dysfunction underlies the association between nephropathy and cardiovascular disease (CVD) in persons infected with human immunodeficiency virus (HIV). Spot urine protein to creatinine ratio, spot urine albumin to creatinine ratio, creatinine clearance, estimated glomerular filtration rate, and flow-mediated dilation (FMD) of the brachial artery were evaluated in 123 study participants infected with HIV (58 receiving antiretroviral therapy [ART] and 65 not receiving ART) with no history of diabetes or hypertension. None of the renal markers, modeled as either continuous or categorical variables, correlated with FMD. Contrary to expectations, endothelial dysfunction may not be the link between nephropathy and CVD in HIV.     

2型糖尿病患者微量白蛋白尿与大血管病变的关系

近年来,尿白蛋白与糖尿病患者大血管病变的关系受到重视。我们检测了对115例2型糖尿病患者的尿白蛋白排泄率(UAER),探讨其与糖尿病大血管病变的关系。　　对象与方法1.对象:115例2型糖尿病患者,均符合WHO糖尿病诊断标准。按尿白蛋白水平分为三组。(1)DM1组38例,UAER<20μg/min,     

Insulin therapy improves endothelial function in type 2 diabetes

A total of 75 in vivo endothelial function tests (intrabrachial artery infusions of endothelium-dependent [acetylcholine] and -independent [sodium nitroprusside] vasoactive agents) were performed in 18 type 2 diabetic patients (aged 58+/-2 years, body mass index 28.5+/-0.6 kg/m(2), and fasting plasma glucose 229+/-11 mg/dL) and 27 matched normal subjects. These tests were performed before and 6 months after combination therapy with insulin and metformin and before and 6 months after metformin therapy only. Before insulin therapy, blood flow responses to acetylcholine (15 microg/min) were significantly blunted in type 2 diabetic patients (7.5+/-0.7 mL x dL(-1) x min(-1)) compared with normal subjects (11.6+/-0.9 mL x dL(-1) x min(-1), P<0.01). During insulin therapy, the acetylcholine response increased by 44% to 10.8+/-1.6 mL x dL(-1) x min(-1) (P<0.05). Insulin therapy also significantly increased the blood flow responses to both low and high doses of sodium nitroprusside. We conclude that insulin therapy improves endothelium-dependent and -independent vasodilatation. These data support the idea that insulin therapy has beneficial rather than harmful effects on vascular function.     

Rosiglitazone reduces microalbuminuria and blood pressure independently of glycemia in type 2 diabetes patients with microalbuminuria

OBJECTIVE: To test the hypothesis that rosiglitazone combined with metformin provides a greater reduction in microalbuminuria and blood pressure than metformin and glyburide at comparable levels of glycemic control. METHODS: In a double-blind, parallel-group design 389 participants with type 2 diabetes were followed for 32 weeks. RESULTS: Urinary albumin: creatinine ratio was significantly reduced at 32 weeks compared with baseline in the rosiglitazone plus metformin group (-22.7%; P < 0.01) but not in the glyburide plus metformin comparator group (-7.1%; P = 0.32). Patients who completed the study (81.5%) demonstrated a treatment difference of -19.5% (P = 0.03), favoring the rosiglitazone group. Rosiglitazone plus metformin reduced both mean 24-h systolic (-3.4 mmHg; P = 0.01) and diastolic (-2.5 mmHg; P < 0.01) ambulatory blood pressure compared with glyburide plus metformin. Addition of rosiglitazone to metformin also reduced levels of plasminogen activator inhibitor-1 antigen and activity, C-reactive protein, von Willebrand factor and fibrinogen compared with addition of glyburide. CONCLUSIONS: Rosiglitazone added to background therapy with metformin provides greater reductions in microalbuminuria and blood pressure as compared with glyburide. These additional improvements in microalbuminuria, blood pressure and cardiovascular biomarkers were observed despite comparable improvements in glycemic control in both groups and may be related to the anti-inflammatory properties of rosiglitazone.