短期和长期热量限制对大鼠胰岛素抗性的影响

研究短期和长期热量限制（caloric restriction,CR）对大鼠胰岛素抗性的影响。结果显示:短期和长期CR鼠显著减轻其肝重、体重;血糖、胰岛素浓度显著低于自由进食（ad libitum,AL）鼠;胰岛素抵抗指数和敏感指数分别显著低于和高于对应的AL鼠。提示短期和长期CR鼠均能适应低浓度的葡萄糖与胰岛素环境,并有效地利用葡萄糖;胰岛素抗性随鼠龄增加而增高,此现象可通过CR而延缓;CR鼠可能由于体脂的减少、运动的增加而增加胰岛素敏感性、降低胰岛素抗性。CR可减轻大鼠的体重,降低血糖、胰岛素浓度,也增强胰岛素敏感性和降低胰岛素抗性。     

限制热量对NIT-1细胞胰岛素／胰岛素样生长因子通路及胰岛素分泌功能的影响

目的 研究限制热量(CR)对胰岛素β瘤细胞(NIT-1)细胞胰岛素/胰岛素样生长因子(IGF-1)信号通路及胰岛素分泌功能的影响,为2型糖尿病(T2DM)的发病机制及防治提供实验依据和理论基础.方法 NIT-1细胞培养至指数生长期,分别用PI3-K的阻断剂LY294002(LY)进行干扰,实验分成4组:对照组;CR组;LY+CR组;LY组.用RT-PCR、免疫细胞化学等方法检测Foxo1及其下游基因的转录及表达,用放射免疫及免疫细胞化学法检测胰岛素的分泌及表达,用细胞计数法检测细胞倍增周期.结果 ①CR可使NIT-1细胞倍增周期延长;②Foxo1主要定位于胞浆,阻断PI3-K后Foxo1从胞浆移入胞核,mRNA转录减少;③CR在正常状态及PI3-K通路障碍的细胞均可使Foxo1mRNA转录增加,并影响其下游基因p27、Bim的转录;④PI3-K通路障碍可使NIT-1细胞胰岛素分泌增加,CR则可使PI3-K通路障碍的NIT-1细胞胰岛素分泌减少.结论 CR不需通过上游PI3-K/Akt,可直接或间接作用于Foxo1参与对胰岛素/IGF-1信号通路的调控,延长细胞寿命,增强NIT-1细胞的糖耐量,改善胰岛素信号的传导及NIT-1的胰岛素分泌功能;可能参与了T2DM的发生发展.     

限制能量摄入对大鼠胰岛细胞衰老及胰岛素表达的影响

目的 探讨限制能量摄人对大鼠胰岛细胞衰老及胰岛素表达的影响.方法 18月龄SD大鼠经过限制能量摄入(给予正常饮食量的60%)6个月,建立限制能量摄入动物模型.取限制能量摄人组(实验组)及对照组胰腺,行β-半乳糖苷酶(SA-β-Gal)染色并检测胰岛内p16的表达,以了解胰岛细胞衰老状态;同时检测胰岛B细胞胰岛素的表达.结果 实验组与对照组比较,胰岛内p16表达减少,分别为(0.19130±0.02852)个和(0.24526±0.03191)/p,差异有统计学意义(P＜0.01);胰岛内β-Gal染色阳性率分别为84%和100%(P＜0.01)、着色面积1.672和2.118(P＜0.05)、着色程度1.725和2.412(P＜0.05);胰岛素表达增加(201.7±35.3和187.8±26.0),差异有统计学意义(P＜0.05)结论限制能量摄入可延缓胰岛B细胞衰老,改善胰岛的分泌功能.     

热量限制改善2型糖尿病患者胰岛素抵抗及胰岛功能的分子机制

2型糖尿病发生、发展的两大基本原因是胰岛素抵抗和胰岛β细胞功能紊乱.由于口服药物及胰岛素注射治疗所带来的不良反应及生活不便,2型糖尿病在临床上需要更方便而又安全的治疗方式.热量限制作为自然疗法中的一种,可以通过影响AMP活化蛋白激酶、自噬等改善2型糖尿病患者的胰岛素抵抗水平及胰岛功能.深入了解热量限制,改善2型糖尿病的分子机制,有助于转化到临床制定相应的治疗策略,延缓甚至阻止2型糖尿病的发生和发展.     

热量限制延长寿命机制的探讨—对糖代谢的影响

研究热量限制对雄性Ｆｉｓｈｅｒ－３４４大鼠一些糖代谢参数的影响。结果显示：热量限制鼠的血浆葡萄糖、血清胰岛素浓度较自由进食鼠显著降低；前者的肝重、体重、肝重与体重的比率显著小于后者；前者较后者有重大的肝糖原波动幅度；血清胰高血糖素浓度两组间差异无显著性（Ｐ＞０．０５）。上述结果表明：热量限制鼠能适应低浓度的葡萄糖与胰岛素环境，并在此情况下有效地利用葡萄糖；热量限制鼠有较强的肝糖原合成、储存、代谢能力。本研究提示：葡萄糖与胰岛素浓度的降低可能是热量限制可延长寿命的重要因素。     

热量限制对大鼠非酶糖化蛋白产物的影响

热量限制对大鼠非酶糖化蛋白产物的影响陈澍蔡如森余爱琴麦坤仪庄万江一、对象与方法７２只雌性Ｆｉｓｈｅｒ－３４４大鼠断奶后进入研究，其喂养方法参考文献〔１〕。在大鼠１４周龄，随机分成热量限制组（ｃａｌｏｒｉｃｒｅｓｔｒｉｃｔｉｏｎ，ＣＲ）与自由进食组（ａ...     

脂质诱导的胰岛素抵抗对大鼠糖代谢的影响

用正糖高胰岛素钳夹术估计脂质灌注大鼠胰岛素介导的外周组织和肝糖代谢。脂质组血浆游离脂肪酸明显升高 ,葡萄糖输注率明显降低 ,胰岛素对肝糖生成的抑制作用明显障碍 ,葡萄糖清除率轻度降低。脂质损害了胰岛素抗脂解和肝糖输出能力及其介导的外周葡萄糖利用     

不同浓度胰岛素输注对胰岛素钳夹大鼠糖代谢的影响

大鼠正糖钳夹技术(Euglycemic clamp technique)是近年来国外广泛应用胰岛素抵抗动物模型的实验研究。国内虽有个别报道,但其钳夹术是在麻醉及手术状态下,且未作糖代谢研究。我们设计了清醒大鼠胰岛素钳夹模型,用6,6-D_2葡萄糖作非放射性示踪剂,给予三种浓度胰岛素输注,观察了大鼠糖代谢及血浆游离脂肪酸(FFA)的改变。     

热量限制对肾缺血损伤后纤维化的影响及机制研究

目的：探讨热量限制(CR)在肾脏缺血再灌注损伤(IRI)后纤维化进展中的作用及机制。方法：构建小鼠单侧肾脏缺血再灌注纤维化模型。随机分为假手术组、假手术后CR组、IRI组、IRI-CR组。术后第3天,CR组小鼠限时喂食,每日饮食摄入量为正常水平的66%,对照组小鼠术后持续自由饮食,所有组均自由饮水。每天限食时观察并记录各组老鼠一般状态。再灌注第20天切除右肾,24 h后采血并留取肾组织。检测血清肌酐、尿素氮及相关实验分析。结果：CR组肾纤维化较重;CR增强了IRI后肾小管细胞自噬活性;抑制自噬可显著减轻CR对IRI后纤维化的影响。结论：CR可加重肾脏IRI后的肾纤维化进展,其机制可能是通过激活自噬实现的。     

瘦素对培养大鼠原代肝细胞葡萄糖吸收及肝细胞膜胰岛素受体磷酸化的影响

目的：观察瘦素对培养大鼠原代肝细胞葡萄糖吸收及肝细胞膜胰岛素受体磷酸化的影响,探讨瘦素参与胰岛素抵抗的分子生物学机制。方法：体外培养大鼠肝细胞,根据培养基中加入瘦素的浓度将实验分为空白对照组以及50、100、200、500／μg／L瘦素组,共5组,每组分别培养2h和24h,用全自动生化分析仪检测培养基中剩余的葡萄糖浓度,用ELISA方法测定肝细胞膜磷酸化胰岛素受体β亚基（pY 1158）含量。结果：①培养基剩余葡萄糖检测,瘦素抑制肝细胞对葡萄糖的吸收,且抑制效应随瘦素浓度增加和时间延长而增强（P〈0.01）;②肝细胞膜磷酸化胰岛素受体β亚基（pY1158）水平测定,50／μg／L瘦素组与对照组比较差异无统计学意义（P〉0．05）,100、200、500／2μg／L瘦素组与对照组比较差异有极显著性（P〈0．01）,并随瘦素剂量上升含量进一步下降。结论：瘦素与胰岛素抵抗相关,抑制细胞膜胰岛素受体β亚基（pY1158）磷酸化可能是其参与胰岛素抵抗的机制之一。     

Age-specific effects of short- and long-term caloric restriction on the expression of adiponectin and adiponectin receptors: influence of intensity of food restriction

Hormonal signals from adipose tissue regulate energy homeostasis and may be involved in anti-aging effects of caloric restriction (CR). The adipokine adiponectin is abundantly expressed in adipose tissue and directly sensitizes the body to insulin. The purpose of the current study was to investigate age-dependent effects of different levels of CR (16%, 2 months or 40%, 6 months) on adiponectin and on its receptors AdipoR1 and AdipoR2 in the left ventricle (LV). In young and senescent rats, 2 months of moderate CR reduced serum leptin. The same diet was sufficient to enhance serum adiponectin, adiponectin expression (visceral fat) and left ventricular AdipoR1 expression in young but not in senescent rats. The higher degree of CR, however, resulted in a mild induction of adiponectin expression in adipose tissue and release into plasma together with increased LV AdipoR1 also in old rats, while these effects were more pronounced in young rats. These changes in adiponectin activation were associated with reduced LV triglyceride content, suggesting an adiponectin-mediated reduced ectopic lipid deposition in nonadipose tissues. Thus, aging is associated with a loss of adiponectin inducibility by moderate CR. This reduction can only partially be overcome by increasing the degree and duration of CR.     

Calorie restriction (CR) and CR mimetics for the prevention and treatment of age-related eye disorders

The morbidity of ocular diseases, including macular degeneration, diabetic retinopathy, and dry eye disease, has been gradually increasing worldwide. Because these diseases develop from age-associated ocular dysfunctions, interventions against the aging process itself may be a promising strategy for their management. Among the several approaches to interrupt aging processes, calorie restriction (CR) has been shown to recover and/or slow age-related functional declines in various organs, including the eye. Here, we review interventions against the aging process as potential therapeutic approaches to age-related ocular diseases. The effects of CR and CR mimetics in animal models of age-related eye diseases are explored. Furthermore, we discuss the possibilities of expanding this research to prospective studies to elucidate the molecular mechanisms by which CR and/or CR mimetics preserve ocular functions.     

The effects of pitavastatin on glucose metabolism in patients with type 2 diabetes with hypercholesterolemia

BackgroundAlthough there have been several reports that statins cause insulin resistance that leads to the occurrence of type 2 diabetes in Caucasians, there has been no Japanese prospective studies investigating the effects of statins on the glucose metabolism system.Materials and methodsOur subjects were 86 Japanese patients with type 2 diabetes with hypercholesterolemia. Pitavastatin 2 mg/day was administered for 12 months and the lipid-related values, glucose metabolism values, and the presence/absence of side effects were investigated.ResultsNone of these factors was found to differ between before and after administration of pitavastatin in overall analysis of all subjects. In subgroup analysis, fasting blood glucose showed a decrease in the BMI ≥ 25 group and there was a significant difference between the BMI < 25 and BMI ≥ 25 groups (P-values: 0.021 and 0.0036). Although HbA1c showed an increase both in the group switched to pitavastatin and the BMI < 25 group (P-values: 0.035 and 0.033) and HOMA-β showed a decrease in the BMI < 25 group (P-values: 0.044), there were no significant differences in changes between each divided group and their counterparts.ConclusionIn the Japanese obese group with BMI ≥ 25, pitavastatin elicited a significant decrease in fasting blood glucose. It is not clear whether or not this is due to improved insulin resistance as a direct effect of pitavastatin, but in contrast to findings in Caucasians pitavastatin does not worsen insulin resistance in Japanese patients with type 2 diabetes complicated by hypercholesterolemia.     

The Effect of Intensive Insulin Therapy on the Insulin-regulatable Glucose Transporter (GLUT4) Expression in Skeletal Muscle in Type 1 Diabetes

Studies in normal man and rodents have demonstrated that the expression of the dominant glucose transporter in skeletal muscle, GLUT4, is regulated by insulin at supraphysiological circulating levels. The present study was designed to determine whether intensified insulin replacement therapy for 24 h given to patients with Type 1 diabetes in poor metabolic control was associated with an adaptive regulation of GLUT4 mRNA and protein levels in vastus lateralis muscle. Nine Type 1 diabetic patients with a mean HbA_1c of 10.3% were included in the protocol. After intensified treatment with soluble insulin for 24 h the fasting plasma glucose concentration decreased from 20.8 ± 2.3 (SD) to 8.7 ± 2.3 mmol 1^?1 whereas the fasting serum insulin level increased from 0.06 ± 0.02 to 0.17 ± 0.09 nmol 1^?1 However, despite a 2.8-fold increase in serum insulin levels and more than a halving of the plasma glucose concentration for at least 15 h no significant alterations occurred in the amount of GLUT4 protein (0.138 ± 0.056, poor control vs 0.113 ± 0.026 arb. units, improved control, p = 0.16) or GLUT4 mRNA (96432 ± 44985, poor control vs 81395 ± 25461 arb. units, improved control, p = 0.54). These results suggest, that in spite of evidence that high insulin levels affect GLUT4 expression in muscle, changes in serum insulin within the physiological range do not play a major role in the short-term regulation of GLUT4 expression in Type 1 diabetic patients.     

Acute Effect of Insulin on Autonomic Regulation of the Cardiovascular System: A Study by Heart Rate Spectral Analysis

Insulin is suggested to have direct effects on the cardiovascular system but these are not well described. We assessed the possible influence of insulin on autonomic control of heart function. A 2-h hyperinsulinaemic euglycaemic clamp was performed in 10 healthy women (mean age 21.7 ± 1.3 years), at two different insulin infusion rates: 80 mU m⁻² and 400 mU m⁻² min⁻¹, in 7 and 3 subjects, respectively. Saline alone was infused in 4 controls. Power spectral analysis (PSA) of heart rate was recorded before and after 90–120 min of insulin infusion, as were blood pressure and heart rate. Although there were no significant changes in heart rate or blood pressure, PSA showed marked reductions of high frequency (HF) bands after insulin (2.60 ± 0.12 vs 2.09 ± 0.16 log ms², p < 0.005), as at both low and high infusion rates (2.46 ± 0.13 to 2.14 ± 0.23 log ms², p < 0.05, and 2.92 ± 0.18 to 1.98 ± 0.06 log ms², p < 0.01, respectively). There were no significant changes of low frequency (LF) bands. Densities at LF and HF did not change significantly in control studies. As HF and LF are considered to reflect parasympathetic and mainly sympathetic control respectively, our observation of an increased LF/HF ratio (0.13 ± 0.10 vs 0.63 ± 0.13, p < 0.005) may be considered an index of relative sympathetic predominance induced by insulin infusion. We conclude that insulin affects the cardiovascular system, reducing vagal influence on the heart and inducing a relative hypersympathetic tone.     

Exendin-4改善胰岛素抵抗的作用机制研究

目的探讨exendin-4（exenatide）对高脂诱导胰岛素抵抗（IR）大鼠胰岛素敏感性（IS）改善的机制及对脂肪细胞因子的影响。方法健康雄性SD大鼠随机分为正常饮食组（NC）、高脂组（HF）和高脂＋Exenatide组（HE）。HE组给予exenatide（2μg／kg，Et二次）腹腔注射6周，用静脉胰岛素耐量试验评价各组IS变化，观察各组肌肉和脂肪组织胰岛素信号传导、脂肪细胞因子表达和血浆浓度变化。结果6周后，HE组Lee＇s指数、空腹血浆FFA、TG、TC均较NC组降低（P均〈0．01），IR明显改善；胰岛素刺激后HE组肌肉和脂肪组织IRS-1酪氨酸磷酸化升高（P〈0．05）；HF和HE组血浆内脏脂肪素（visfatin）水平明显降低（P〈0．05，P〈0．01），但HE组脂联素（APN）血浆水平和脂肪组织mRNA表达明显高于HF和NC组（P均〈0．01）。结论Exenatide明显改善了高脂大鼠IR，其胰岛素增敏机制可能与增强IRS-1酪氨酸磷酸化以及对APN、visfatin等脂肪细胞因子的影响有关。     

A mathematical model that accounts for the effects of caloric restriction on body weight and longevity

Several aspects of energy dynamics, such as energy expenditure and caloric intake, are known to affect the aging process. In this article we therefore model the aging process within a mathematical framework describing the energy dynamics of an organism. The resulting model comprises food intake, body growth and survival. The equation for the mortality rate accounts for food consumption and is suited to describe caloric restriction data. For non-growing animals, the expression for the mortality rate reduces to the well-known Gompertz equation. We successfully applied our model to growth and survival data on mice exposed to different food levels. This revised version was published online in July 2006 with corrections to the Cover Date.     

糖脉康对糖耐量减退者胰岛素敏感性的影响

目的了解糖脉康对糖耐量减退(IGT)者胰岛素敏感性的影响。方法将80例IGT患者随机分为对照组和治疗组,每组40例,在基础治疗的同时,对照组给予二甲双胍,治疗组给予糖脉康,观察两组治疗前后血糖、胰岛素、胰岛素敏感性指数(ISI)。结果两组治疗前后餐后血糖、空腹胰岛素、餐后胰岛素、ISI均较治疗前显著改善(P<0·01),两组间比较差别无显著性意义(P>0·05)。结论糖脉康可改善糖耐量减退患者的胰岛素敏感性。