Level of skeletal muscle glucose transporter protein correlates with insulin-stimulated whole body glucose disposal in man

Summary The content of GLUT4 glucose transporter mRNA and protein were measured in samples of the vastus lateralis muscle of normal volunteers subjected to a 4-h hyperinsulinaemic, euglycaemic clamp. Plasma glucose concentration was clamped at 5.3±0.1 mmol/l, and serum insulin concentration was maintained at 740±5 pmol/l. Whole body glucose uptake averaged 38.3±2.2 mol · kg^–1 · min^–1, 62% of this being due to disposal via non-oxidative pathways. A significant correlation existed between basal levels of GLUT4 protein and the rate of whole body glucose disposal (r=0.77, p<0.02) and non-oxidative glucose disposal (r=0.80, p<0.02). There was no correlation between GLUT4 protein content and oxidative glucose disposal (r=0.08, NS). These observations are consistent with an important role for skeletal muscle GLUT4 protein in whole body glucose disposal.     

大样本中国人PCOS临床特点分析

目的 为多囊卵巢综合征(PCOS)的临床诊治提供依据.方法 回顾性分析1 040例PCOS患者的临床特征及内分泌、血糖、血脂、胰岛素等检查指标.结果 ①1 040例PCOS患者中,月经稀发占62.60%,闭经占19.71%,所有成年患者的月经紊乱史均可追溯到青春期初潮后;450例存在肥胖(259例为腹部型);158例存在黑棘皮症(肥胖型103例,非肥胖型55例).②PCOS患者中高甘油三酯血症占5.58%、高胆固醇血症占7.02%、HDL异常占0.10%、LDL异常占12.69%,其中肥胖患者胆固醇、低密度脂蛋白明显高于非肥胖患者,P＜0.05.173例符合糖尿病诊断标准,179例糖耐量减低(IGT),27例空腹葡萄糖异常(IFG),9例IFG IGT;平均空腹及口服葡萄糖耐量试验(OGTT)30、60、120和180 min血糖超过正常范围的人次分别为19、74、110、42和12,如果不取空腹血糖值有10例患者被漏诊,分别略去30、60、120和180 min的血糖值,依次有16、50、28和1例被漏诊,5次抽血及3次抽血(空腹 60 min 120 min)的血糖及胰岛素曲线下面积有显著差异;体质量指数(BMI)和腰臀比(WHR)均与胰岛素抵抗指数(HOMA-IR)呈正相关(r=0.29987、P＜0.01,r=0.12441、P＜0.000 1).结论 PCOS患者肥胖发生率较高,肥胖型PCOS患者较非肥胖型存在更严重的内分泌及代谢紊乱;阻断肥胖、IR,打破内分泌代谢间的恶性循环,不但对阻断PCOS的进程具有重要意义,更是预防2型糖尿病、心血管疾病等远期并发症的关键.     

胰岛素促进在体犬心肌GLUT1移位及其意义

目的 :观察胰岛素能否刺激心肌葡萄糖转运子 1（GL UT1）移位和葡萄糖摄取。方法 :利用自动分析仪测定生理代谢参数 ,应用免疫印迹和免疫荧光法检测 GL UT1。结果 :胰岛素使心肌细胞质膜 GL UT1增加 [从 （42± 5 ） %至 （6 3± 8） % ,P<0 .0 5 ]。细胞器膜 GL U T1则相应减少 ,同时伴随葡萄糖摄取量增加 （P<0 .0 1）。结论 :胰岛素刺激引起 GL UT1移位 ,使心肌葡萄糖摄取增加。应用胰岛素有助于增加心肌葡萄糖的摄取和利用。     

Long-term insulin treatment of 3T3-L1 adipocytes results in mis-targeting of GLUT4: implications for insulin-stimulated glucose transport

Aims/hypothesis. Insulin stimulates glucose transport in adipose and muscle tissue by the translocation of a specialised pool of intracellular GLUT4-containing vesicles to the cell surface. It is well established that defective insulin-stimulated GLUT4 translocation is associated with insulin resistance. Long-term insulin treatment (500 nmol/l for 24 h) of 3T3-L1 adipocytes has previously been shown to decrease cellular GLUT4 content and reduce insulin-stimulated GLUT4 translocation. Here, we test the hypothesis that the insulin resistance observed after long-term insulin treatment arises by the selective loss of GLUT4 from a specific intracellular compartment.¶Methods. Using iodixanol gradient centrifugation we have separated intracellular GLUT4 containing membranes into two distinct populations corresponding to recycling endosomes and a distinct intracellular compartment which probably represents GLUT4 storage vesicles (GSVs).¶Results. A short-term insulin stimulation reduced the content of GLUT4 in the GSV fraction (51 ± 3.5 %) with only a modest decrease from the endosomal fraction (23 ± 2.6 %). Long-term insulin treatment decreased cellular GLUT4 content by about 40 % and diminished the ability of a short-term insulin challenge to promote GLUT4 translocation. We further show that this depletion of cellular GLUT4 is selectively from the GSV fraction (68 ± 7 % decrease compared to untreated cells).¶Conclusions/interpretation. Such data argue that long-term insulin treatment results in the mis-targeting of GLUT4 such that it no longer accesses the GSV compartment. These data imply that defective targeting of GLUT4 away from the GSV compartment plays an important role in the aetiology of insulin resistance. [Diabetologia (2000) 43: 1273–1281]     

胰岛素对缺血心肌细胞葡萄转运子1移位的增强作用

目的：观察胰岛素对缺血心肌葡萄糖转运子1（GLUT1）移位的增强作用。方法：用自动分析仪测定生理代谢参数,用免疫抑迹和免疫荧光法检测GLUT1。结果：胰岛素使犬在体缺血心肌细胞质膜GLUT1增加1．5倍,同时伴随葡萄糖摄取增多,缺血区心肌葡萄糖摄增加4倍。结论：胰岛素对缺血心肌细胞GLUT1移位有增强作用,并促使心肌摄取更多的葡萄糖,心肌缺血时,应用胰岛素有助于增加心肌葡萄糖的摄取和利用。     

Inhibition of the high-affinity glucose transporter GLUT 1 affects the sensitivity to glucose in a hamster-derived pancreatic beta cell line (HIT)

Summary HIT is a hamster-derived beta-cell line which in contrast to normal beta cells that only express the high K_m GLUT-2 glucose transporter, also expresses the low K_m glucose transporter GLUT 1. In HIT cells the abnormal glucose transport mechanism is associated with a marked shift to the left of the glucose-induced insulin release dose-response curve. We have used this cell model to investigate whether changes in glucose transport affect the glucose-induced insulin release. HIT cells were first incubated with a concentration of cytochalasin B (0.4 mol/l) that selectively inhibits the GLUT-1 but not the GLUT-2 transporter. The consequences of blocking glucose phosphorylation and insulin release were studied. Exposure to 0.4 mol/l cytochalasin B for 1 h caused a selective loss of the low K_m transport: the calculated V_max of GLUT 1 was reduced from 1726±98 to 184±14 pmol · mg protein^–1 5 min^–1 (mean±SEM, n=6, p<0.005), while no major difference in the high K_m (GLUT-2) transport was observed. In cytochalasin B exposed HIT cells the glucose phosphorylating activity (due to hexokinase and glucokinase) was unaffected. In these cells, however, the dose-response curve of glucose-induced insulin release was significantly shifted to the right: the 50% of maximal response (increment over baseline) was reached at an average glucose concentration of 2.9±0.2 mmol/l (vs 0.6±0.01 mmol/l in control HIT cells mean±SE, n=5, p<0.05) and the maximal effect was reached at 11.0 mmol/l glucose (vs 2.8 mmol/l in control HIT cells p<0.005). These results are consistent with the hypothesis that the affinity of the glucose transport system may contribute to determination of the glucose threshold concentration that triggers insulin secretion.     

Sodium‐glucose co‐transporter (SGLT) and glucose transporter (GLUT) expression in the kidney of type 2 diabetic subjects

The sodium‐glucose co‐transporters (SGLTs) are responsible for the tubular reabsorption of filtered glucose from the kidney into the bloodstream. The inhibition of SGLT2‐mediated glucose reabsorption is a novel and highly effective strategy to alleviate hyperglycaemia in patients with type 2 diabetes mellitus (T2DM). However, the effectiveness of SGLT2 inhibitor therapy is diminished due, in part, to a compensatory increase in the maximum reabsorptive capacity (Tm) for glucose in patients with T2DM. We hypothesized that this increase in Tm could be explained by an increase in the tubular expression of SGLT and glucose transporters (GLUT) in these patients. To examine this, we obtained human kidney biopsy specimens from patients with or without T2DM and examined the mRNA expression of SGLTs and GLUTs. The expression of SGLT1 is markedly increased in the kidney of patients with T2DM, and SGLT1 mRNA is highly and significantly correlated with fasting and postprandial plasma glucose and HbA1c. In contrast, our data demonstrate that the levels of SGLT2 and GLUT2 mRNA are downregulated in diabetic patients, but not to a statistically significant level. These important findings are clinically significant and may have implications for the treatment of T2DM using strategies that target SGLT transporters in the kidney.     

Prediction of incident hypertension and arterial stiffness using the non–insulin‐based metabolic score for insulin resistance (METS‐IR) index

Hypertension is associated with insulin resistance (IR), metabolic syndrome (MS), and arterial stiffness. Non–insulin‐based IR indexes were developed as tools for metabolic screening. Here, we aimed to evaluate the novel non–insulin‐based Metabolic Score for IR (METS‐IR) index for the prediction of incident hypertension and arterial stiffness evaluated using pulse wave velocity (PWV) analysis, compared with other non–insulin‐based IR indexes. We evaluated two populations, a cross‐sectional evaluation of high‐risk individuals (n = 305) with a wide range of metabolic comorbidities and dyslipidemia in whom PWV measurement was performed and a 3‐year prospective cohort of normotensive individuals (N = 6850). We observed a positive correlation between METS‐IR and PWV in the cross‐sectional cohort, which was higher compared with other non–insulin‐based fasting IR indexes; furthermore, PWV values >75th percentile were associated with the upper tercile of METS‐IR values. In the prospective cohort, we observed an increased risk for incident hypertension for the upper METS‐IR tercile (METS‐IR ≥ 46.42; HR: 1.81, 95% CI: 1.41‐2.34), adjusted for known cardiovascular risk factors, and observed that METS‐IR had greater increases in the predictive capacity for hypertension along with SBP and the Framingham Hypertension Risk Prediction Model compared with other non–insulin‐based IR indexes. Therefore, METS‐IR is a novel non–insulin‐based IR index which correlates with arterial stiffness and is a predictor of incident hypertension, complementary to previously validated risk prediction models.