Association of polymorphisms in monocyte chemoattractant protein-1 promoter with diabetic kidney failure in Korean patients with type 2 diabetes mellitus

Monocyte chemoattractant protein-1 (MCP-1) is suggested to be involved in the progression of diabetic nephropathy. We investigated the association of the -2518 A/G polymorphism in the MCP-1 gene with progressive kidney failure in Korean patients with type 2 diabetes mellitus (DM). We investigated -2518 A/G polymorphism of the MCP-1 gene in type 2 DM patients with progressive kidney failure (n=112) compared with matched type 2 DM patients without nephropathy (diabetic control, n=112) and healthy controls (n=230). The overall genotypic distribution of -2518 A/G in the MCP-1 gene was not different in patients with type 2 DM compared to healthy controls. Although the genotype was not significantly different between the patients with kidney failure and the diabetic control (p=0.07), the A allele was more frequent in patients with kidney failure than in DM controls (42.0 vs. 32.1%, p=0.03). The carriage of A allele was significantly associated with kidney failure (68.8 vs. 54.5%, OR 1.84, 95% CI 1.07-3.18). In logistic regression analysis, carriage of A allele retained a significant association with diabetic kidney failure. Our result shows that the -2518 A allele of the MCP-1 gene is associated with kidney failure in Korean patients with type 2 DM.     

Cystatin C as an early biomarker of nephropathy in patients with type 2 diabetes

This study was done to evaluate clinical usefulness of cystatin C levels of serum and urine in predicting renal impairment in normoalbuminuric patients with type 2 diabetes and to evaluate the association between albuminuria and serum/urine cystatin C. Type 2 diabetic patients (n = 332) with normoalbuminuria (n = 210), microalbuminuria (n = 83) and macroalbuminuria (n = 42) were enrolled. Creatinine, urinary albumin levels, serum/urine cystatin C and estimated glomerular filtration rate (eGFR by MDRD [Modification of Diet in Renal Disease] and CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration] equations) were determined. The cystatin C levels of serum and urine increased with increasing degree of albuminuria, reaching higher levels in macroalbuminuric patients (P < 0.001). In multiple regression analysis, serum cystatin C was affected by C-reactive protein (CRP), sex, albumin-creatinine ratio (ACR) and eGFR. Urine cystatin C was affected by triglyceride, age, eGFR and ACR. In multivariate logistic analysis, cystatin C levels of serum and urine were identified as independent factors associated with eGFR < 60 mL/min/1.73 m(2) estimated by MDRD equation in patients with normoalbuminuria. On the other hand, eGFR < 60 mL/min/1.73 m(2) estimated by CKD-EPI equation was independently associated with low level of high-density lipoprotein in normoalbuminuric patients. The cystatin C levels of serum and urine could be useful markers for renal dysfunction in type 2 diabetic patients with normoalbuminuria.     

2型糖尿病鼠脑梗死模型的建立及相关指标分析

目的：在具有胰岛素抵抗特征近似人类2型糖尿病（T2DM）的大鼠身上建立脑梗死模型。方法：SD雄性大鼠120只,其中90只用高脂高糖和链脲佐菌素（STZ）制成T2DM模型,另30只为对照组。对照组和T2DM成模大鼠随机分为假手术组（A1组、B1组）和手术组（A2组、B2组）。采用神经功能缺损量表（NSS）评分、TTC染色与HE染色观察神经功能缺损征、脑梗死体积及病理改变。结果：T2DM成模率为72％,血脂指标与对照组相比差异有统计学意义（P〈0．01）,且血脂异常表现与临床T2DM患者近似。A2组NSS评分3—4级者占75％,脑梗死体积为（55．23±9．59）mm^3,脑梗死成模率为75％;B2组NSS评分3—4级者占60％,脑梗死体积为（54．33±6．39）mm^3,脑梗死成模率为53％。结论：高脂膳食结合STZ注射能复制出接近人类T2DM的动物模型,在此基础上制成的脑梗死模型稳定性和重复性好,是研究人类糖尿病脑梗死病理过程较为理想的动物模型。     

Metabolic effects of an entero-omentectomy in mildly obese type 2 diabetes mellitus patients after three years

BACKGROUND:

Various digestive tract procedures effectively improve metabolic syndrome, especially the control of type 2 diabetes mellitus. Very good metabolic results have been shown with vertical gastrectomy and entero-omentectomy; however, the metabolic effects of an isolated entero-omentectomy have not been previously studied.

METHODS

: Nine patients with type 2 diabetes mellitus and a body mass index ranging from 29 to 34.8 kg/m² underwent an entero-omentectomy procedure that consisted of an enterectomy of the middle jejunum and exeresis of the major part of the omentum performed through a mini-laparotomy. Glucagon-like peptide-1 and peptide YY were measured preoperatively and three months following the operation. Fasting and postprandial variations in glycemia, insulinemia, triglyceridemia, hemoglobin A1c, and body mass index were determined in the preoperative period and 3, 18 and, 36 months after the operation.

RESULTS

: All patients significantly improved the control of their type 2 diabetes mellitus. Postprandial secretion of peptide YY and Glucagon-like peptide-1 were enhanced, whereas hemoglobin A1c, fasting and postprandial glucose, insulin, and triglyceride levels were significantly reduced. Mean body mass index was reduced from 31.1 to 27.3 kg/m². No major surgical or nutritional complications occurred.

CONCLUSIONS

: Entero-omentectomy is easy and safe to perform. A simple reduction in jejunal extension and visceral fat causes important improvements in the metabolic profile.     

小檗碱对2型糖尿病大鼠肾脏GLUT1表达的影响

目的 探讨小檗碱(Berberine,BBR)对2型糖尿病(type 2 diabetes mellitus,T2DM)大鼠肾脏葡萄糖转运蛋白1(glucose transporter protein 1,GLUT1)表达的影响及其对肾保护作用的机制,为临床用其防治糖尿病肾病打下理论基础.方法 45只健康雄性SD大鼠适...     

Retinol binding protein 4 correlates with and is an early predictor of carotid atherosclerosis in type 2 diabetes mellitus patients

The association of retinol binding protein 4 (RBP4) with atherosclerosis of the carotid artery in type 2 diabetes mellitus (T2DM) remains undefined. We aimed to investigate the correlation of RBP4 expression with atherosclerosis of the carotid artery in T2DM. A total of 1,076 subjects were investigated for intima-media thickness of the bilateral common carotid arteries, and they were divided into three groups: in group I, patients had normal neck vascular ultrasound, in group II, intimal carotid artery media thickness was equal to or more than 1 mm, and in group III, carotid artery plaque was present. Height, weight, blood pressure (BP), fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-1 (apoA-1), apolipoprotein B (apoB) and lipoprotein (a) [Lp(a)] were determined by routine laboratory methods. RBP4 and high sensitivity C reactive protein (HsCRP) were measured by an enzyme-linked immuno-sorbent assay, and insulin concentration was measured by an electrochemiluminescence sandwich immunoassay. Duration of diabetes, waist and BP, FPG, HbA1c, TG, TC, LDL-C, APOB, Lp(a), HsCRP, RBP4 and homeostasis model assessment insulin resistance index (HOMA-IR) were significantly lower in group I than in the other two groups (P<0.01, P<0.01). Plasma levels of HbA1c, RBP4, LDL-C, TC, HOMA-IR, HsCRP and Lp(a), waist and BP were significantly increased in group III than in group II (P<0.01). Multivariate logistic regression analysis showed that there were seven factors associated with the occurrence of carotid artery atherosclerosis and its risks in descending order were: high LDL-C, high waist, high HsCRP, duration of diabetes, high HOMA-IR, HbA1c and high RBP4. Our finding supported that RBP4 was positively correlated with carotid atherosclerosis in patients with T2DM and could be used as an early predictor of cardiovascular disease.     

A role for astrocyte‐derived amyloid β peptides in the degeneration of neurons in an animal model of temporal lobe epilepsy

Kainic acid, an analogue of the excitatory neurotransmitter glutamate, can trigger seizures and neurotoxicity in the hippocampus and other limbic structures in a manner that mirrors the neuropathology of human temporal lobe epilepsy (TLE). However, the underlying mechanisms associated with the neurotoxicity remain unclear. Since amyloid‐β (Aβ) peptides, which are critical in the development of Alzheimer's disease, can mediate toxicity by activating glutamatergic NMDA receptors, it is likely that the enhanced glutamatergic transmission that renders hippocampal neurons vulnerable to kainic acid treatment may involve Aβ peptides. Thus, we seek to establish what role Aβ plays in kainic acid‐induced toxicity using in vivo and in vitro paradigms. Our results show that systemic injection of kainic acid to adult rats triggers seizures, gliosis and loss of hippocampal neurons, along with increased levels/processing of amyloid precursor protein (APP), resulting in the enhanced production of Aβ‐related peptides. The changes in APP levels/processing were evident primarily in activated astrocytes, implying a role for astrocytic Aβ in kainic acid‐induced toxicity. Accordingly, we showed that treating rat primary cultured astrocytes with kainic acid can lead to increased Aβ production/secretion without any compromise in cell viability. Additionally, we revealed that kainic acid reduces neuronal viability more in neuronal/astrocyte co‐cultures than in pure neuronal culture, and this is attenuated by precluding Aβ production. Collectively, these results indicate that increased production/secretion of Aβ‐related peptides from activated astrocytes can contribute to neurotoxicity in kainic acid‐treated rats. Since kainic acid administration can lead to neuropathological changes resembling TLE, it is likely that APP/Aβ peptides derived from astrocytes may have a role in TLE pathogenesis.     

厄贝沙坦对高血压合并2型糖尿病大鼠胰岛素抵抗IRS-1/PI3K/GLUT4信号通路的影响

目的　探讨厄贝沙坦对高血压合并2型糖尿病（T2DM）大鼠胰岛素抵抗的影响及其作用。 方法　自发性高血压大鼠（SHR）采用高糖高脂饮食联合链脲佐菌素（STZ）建立T2DM模型,随机分为模型组、厄贝沙坦低、高剂量组。以正常大鼠作为对照组。厄贝沙坦低、高剂量组每日分别按30、60 mg/kg剂量灌服厄贝沙坦,对照组和模型组灌服等量生理盐水。测量大鼠收缩压（SBP）、空腹血糖（FBG）、胰岛素抵抗模型评估指数（HOMA-IR）、胰岛素受体底物-1（IRS-1）、磷脂酰肌醇（-3）激酶p85亚基（PI3Kp85）、蛋白激酶B（AKT）、磷酸化蛋白（p-AKT）及葡萄糖转运蛋白4（GLUT4）的表达。 结果　与对照组相比,模型组SBP、FBG、FINS和HOMA-IR升高（P<0.05）,IRS-1、PI3Kp85、p-AKT和GLUT4降低（P<0.05）;与模型组相比,厄贝沙坦低、高剂量上述指标均发生逆转（P<0.05）。 结论　厄贝沙坦可通过IRS-1/PI3K/GLUT4信号通路改善高血压合并T2DM大鼠胰岛素抵抗。     

Increased expression of toll‐like receptor 4 and inflammatory cytokines,interleukin‐6 in particular,in islets from a mouse model of obesity and type 2 diabetes

Toll‐like receptor 4 (TLR4) has received much attention in the recent years due to its role in development of insulin resistance in type 2 diabetes mellitus. Its expression is elevated in fat and muscle from insulin‐resistant mice. Several cells of the pancreatic islets, including β‐cells and resident macrophages, express TLR4. Our hypothesis is that expression of TLR4 and downstream signalling molecules in islets increases during progression of type 2 diabetes, thereby contributing to β‐cell damage. We investigated the hypothesis in the db/db mouse. Islets from male db/db (4, 8 and 15 weeks old) and control db/+ (4 and 15 weeks old) mice were examined for mRNA expression of TLR4 and selected cytokines using qPCR. In addition, cytokine secretion from islets was quantified. TLR4 is expressed in islets from lean and obese mice, displaying a 7.4‐fold higher level in 15 weeks old db/db relative to age‐matched control (p < 0.01). During progression of clinical type 2 diabetes manifested by hyperglycaemia, TLR4 expression increases 5.6‐fold in islets from 15 weeks compared with 4 weeks old db/db mice (p < 0.01). Furthermore, both protein and mRNA levels of all cytokines examined increased. In particular, expression of IL‐6 increased with 37 fold. Expression of TLR4 in db/db mouse islets increased in parallel with hyperglycaemia. A similar increase in expression and secretion of TNFα, IL‐1 and IL‐6 was observed. Our results demonstrate that, in addition to its contribution to insulin resistance, TLR4 might also play a role in β‐cell dysfunction in type 2 diabetes.