追赶生长与高尿酸血症的相关性研究

目的:研究追赶生长人群代谢状况变化,探讨追赶生长是否与高尿酸血症(hyperuricemia,HUA)相关以及是否为HUA的危险因素。方法:2014年于宜昌市夷陵区进行人群调查研究,共有6 685名居民参与。对所有研究对象进行体格检查和问卷调查,同时采集空腹及糖负荷后2 h静脉血,进行血糖、血脂、尿酸等指标检测。在剔除584名资料不全者后,对余下6 101名的数据进行分析。根据是否存在低营养后营养水平提升将受试者判定为追赶生长或非追赶生长,比较2组的代谢状况,Logistic回归分析追赶生长人群发生HUA的优势比(odds ratio, OR)。结果:与非追赶生长人群相比,追赶生长人群具有更高的体质量指数(body mass index,BMI)、收缩压、三酰甘油(triglyceride,TG)水平,更低的高密度脂蛋白胆固醇(high-density lipoprotein cholesterol,HDL-C)水平;进一步亚组分析显示,在女性,追赶生长HUA患病比例和血尿酸水平明显高于非追赶生长(P0.001),而在男性,追赶生长与非追赶生长HUA患病比例和血尿酸水平差异无统计学意义(P0.1);经Logistic多元回归分析校正年龄、BMI、吸烟、饮酒、血压、空腹血糖、糖负荷后2 h血糖、TG等因素后,结果显示追赶生长女性发生HUA的风险较非追赶生长显著升高,OR值为1.415(P=0.022),95%可信区间(confidence interval, CI):1.272～2.795。结论:追赶生长人群较多出现代谢异常,且追赶生长与HUA相关,是HUA的独立危险因素。     

改良的追赶生长大鼠模型生物学特征的动态观察

动态观察改良的追赶生长大鼠模型生物学特征,发现该模型主要表现为:热卡限制期体重;体长生长抑制,恢复饮食后体重、体长、内脏脂肪快速增长,能量利用率一过性升高,与人群追赶生长变化相似,可作为一种较为理想的追赶生长研究平台.     

从追赶生长角度剖析胰岛素抵抗相关疾病高发的机制

追赶生长为胰岛素抵抗相关疾病的研究提供了新的思路.追赶生长是一个普遍存在的现象,本是生命的一种自我代偿,但与胰岛素抵抗的形成有着密切的关系.追赶生长主要是脂肪的优先和过度生长.目前在其机制、干预等方面还有许多亟待解决的问题.     

早产儿、小于胎龄儿体质量追赶生长及其与IGF－1的相关性

目的：探讨早产儿和小于胎龄儿（ SGA）体质量追赶生长的规律及其与IGF－1的相关性。方法选择早产SGA 13例、早产适于胎龄儿（ AGA）80例、足月SGA 23例、足月AGA 177例，记录各组体质量，计算标准差单位（SDS）和SDS的变化值（ΔSDS），并进行统计学分析。结果①足月SGA 42 d时体质量的ΔSDS值＞0，提示其出生后即出现体质量追赶生长。9个月时体质量与足月AGA无显著差异（ P＞0．05），提示已达到完全追赶生长。②早产AGA生后42 d时体质量SDS值降至最低，其后体质量SDS值出现缓慢上升，3月龄时体质量ΔSDS值＞0，提示42 d前存在持续宫外发育迟缓，42 d后出现体质量追赶生长。③早产SGA的体质量追赶生长出现最晚，生后SDS值在3月龄时降至最低，此后开始上升，到6月龄时体质量的ΔSDS值＞0，提示其宫外发育迟缓持续至3月龄，3月龄后出现体质量追赶生长，18月时体质量仍与足月AGA存在显著差异，提示尚未达到体质量完全追赶生长。④早产和SGA的IGF－13月龄时均出现显著上升，与其体质量追赶生长趋势相吻合。结论早产儿均存在宫外发育迟缓现象，体质量追赶生长开始的时间依次为足月SGA、早产AGA、早产SGA。1岁时足月SGA和早产儿AGA体质量基本达到完全追赶生长；IGF－1水平变化与追赶生长的趋势一致。     

追赶生长与表观遗传学

多个流行病学研究显示,亚洲糖尿病高发与经济迅速发展、营养水平快速提高相关,提示环境因素可能在亚洲糖尿病流行中发挥重要作用.营养缺乏造成的生长抑制在营养恢复后可出现代偿性快速生长现象,称为追赶生长.研究发现追赶生长与胰岛素抵抗及2型糖尿病紧密相关[1].     

重组人生长激素治疗不同生长激素分泌状态青春前期矮小患儿追赶性生长模式分析

目的 比较不同生长激素(GH)分泌状态矮小患儿重组人生长激素(rhGH)治疗后的初始追赶性生长模式,初步探讨其机制.方法 回顾性分析62例青春前期不同GH分泌状态矮小患儿对rhGH治疗1年半的追赶性生长模式并定期监测体格指标、促生长素轴的血清指标和骨龄.结果 各组在初始追赶性生长的幅度相似,特发性矮小(ISS)组比完全性生长激素缺乏症(GHD)组更早出现生长减速,并与生长激素结合蛋白(GHBP)水平降低和胰岛素样生长因子结合蛋白3的标准差分数(SDS)增值较小显著相关.GH激发峰值(Ghmax)>7μg/L的部分性GHD组与ISS组有类同的生长追赶的模式.结论 GH受体的降调节和受体后效应的降低可能是ISS组较早出现生长减速的机制.以Ghmaxμg/L作为GHD诊断的界值并相应选择rhGH治疗剂量有更充分的依据和临床意义.     

成年期追赶生长对大鼠胰岛素敏感性与应激水平的影响

目的 观察成年期追赶生长对大鼠胰岛素敏感性和应激水平的影响,并探讨其胰岛素抵抗形成的可能机制。方法 将7周龄雄性SD大鼠分为6组（共2个时间点）,即4周时间点2组：热卡限制4周组(R4),正常饮食4周组(NC4)作为R4组对照;8周时间点4组：正常饮食追赶生长组(RN4)、高脂饮食追赶生长组(RH4)、持续高脂饮食8周组（HF8）、持续正常饮食8周组(NC8)。通过先热卡限制后恢复饮食的方法建立追赶生长大鼠模型。检测大鼠高胰岛素-正糖钳夹试验过程中葡萄糖输注率和骨骼肌2-脱氧葡萄糖摄取、胰岛素刺激后的骨骼肌胰岛素信号通路、血皮质酮、骨骼肌11β-羟类固醇脱氢酶1(11β-HSD1)表达水平。结果 热卡限制4周时,R4组大鼠血皮质酮和骨骼肌11β-HSD1 mRNA表达水平明显高于NC4组(P＜0.05),骨骼肌蛋白激酶B( Akt) Ser473磷酸化和糖摄取与NC4组相比差异无统计学意义。热卡限制后恢复饮食4周时,血皮质酮和骨骼肌11β-HSD1表达水平RN4组明显高于NC8组,RH4组明显高于NC8和HF8组,而骨骼肌Akt磷酸化和糖摄取RN4组明显低于NC8组,RH4组明显低于NC8组、HF8组和RN4组（均P＜0.05）。结论正常饮食和高脂饮食追赶生长大鼠均可导致整体和骨骼肌应激水平上调及胰岛素抵抗,尤以高脂饮食追赶生长大鼠更为明显。应激和饮食状况的交互作用可能是追赶生长胰岛素抵抗形成的重要原因。     

追赶生长:胰岛素抵抗研究的新领域

2型糖尿病等胰岛素抵抗相关疾病在亚洲国家呈急速蔓延之势,这很有可能与营养水平的快速提升所带来的追赶生长现象有关.从追赶生长现象入手,研究其胰岛素抵抗发生机制,将有助于深入理解亚洲2型糖尿病的发病特点,从中寻找有效预防手段,以期在一定程度上阻遏亚洲糖尿病流行趋势.     

限食后追赶生长性肥胖与大鼠血浆葡萄糖依赖性胰岛素释放肽水平的关系

目的 探讨限食后追赶生长性肥胖与大鼠血浆葡萄糖依赖性胰岛素释放肽(GIP)水平的相关性.方法 6周龄健康雄性SD大鼠60只按随机数字表法随机分为普通饮食组(n=15,给予普通饮食)、普通饮食追赶生长组(n=15,给予同体重普通饮食组大鼠60%普通饲料限食喂养4周后饲以普通饲料)、高脂饮食组(n=15,给予高脂饮食)和高脂饮食追赶生长组(n=15,给予同体重普通饮食组大鼠60%普通饲料限食喂养4周后饲以高脂饲料),观察大鼠体重及进食量变化.分别于4、6、8周处死部分动物,检测体脂含量及血浆GIP浓度.采用配对t检验和单因素方差分析以及一元线性相关分析进行数据统计.结果 与普通饮食组相比,高脂饮食组、普通饮食追赶生长组和高脂饮食追赶生长组体脂含量[分别为(3.6±0.6)、(7.9±1.5)、(4.6±1.1)、(7.0±1.0)g;t值分别为-2.601、-2.305、-2.501,均P＜0.05]、血浆GIP水平升高[分别为(41±9)、(61±7)、(51±8)、(59±8)pmol/L;t值分别为-6.061、-3.452、-4.651,均P＜0.05].相关分析显示,体脂含量与血浆GIP水平显著相关(r2=0.9407).结论 限食后追赶生长性肥胖与大鼠血浆GIP水平高度相关,可能与追赶生长所引发的病理生理学变化有关.     

药物涂层支架的“晚期追赶”现象与中医药的干预策略

总结药物涂层支架(DES)的"晚期追赶"现象的发生机制以及中医药的干预策略。药物涂层支架的应用能够明显抑制细胞增殖,使支架内再狭窄率降低。但随着时间的推移,DES表面药物逐渐减少,DES的内膜生长会追赶上甚至超过金属裸支架的内膜增生程度,即药物支架的"晚期追赶"现象。目前西医药对于"晚期追赶"现象的干预策略无高级别循证医学证据支持,而中医药的干预则具有广阔空间。     

Roles of insulin-like growth factor-I and growth hormone in mediating insulin resistance in acromegaly

Most patients with acromegaly have some degree of insulin resistance. The principal mediator of insulin resistance in acromegaly is hypersecretion of growth hormone. Growth hormone acts at several levels to block insulin actions including inhibiting phosphorylation of the insulin receptor and one of its principal signaling molecules IRS-1 in response to insulin administration. This leads to reduced sensitivity to insulin in the periphery in stimulating peripheral glucose uptake and to increased resistance to insulin's ability to suppress gluconeogenesis. Furthermore growth hormone excess leads to mobilization of free fatty acids which inhibit insulin stimulated glucose oxidation by acting as a competitive energy source thus leading to further worsening of insulin resistance. These abnormalities can be overcome by administering agents which either lower growth hormone secretion or block growth hormone action. The role of elevated IGF-I in acromegaly in mediating insulin resistance is more difficult to analyze. Indirect inferences from the data that are available suggest that IGF-I is acting to enhance insulin sensitivity and partially counteracting the insulin antagonistic effects of growth hormone. In a recent study administration of IGF-I to acromegalics was shown to improve insulin sensitivity over and above the level that could be achieved by simply blocking growth hormone action. Therefore it appears that the net effect of IGF-I is to counterbalance some of the effects of growth hormone hypersecretion on insulin resistance.     

Fetal Growth and Insulin Resistance in Adult Life: Role of Plasma Triglyceride and Non-esterified Fatty Acids

Reduced fetal growth is associated with insulin resistance and a high prevalence of glucose intolerance in adult life. Because babies who are growth retarded have elevated levels of triglyceride and non-esterified fatty acids (NEFA), and because similar abnormalities are observed in subjects with the insulin resistance syndrome, impaired regulation of lipid metabolism could be one of the mechanisms explaining the link between reduced fetal growth and insulin resistance. We have, therefore, measured fasting plasma triglyceride and NEFA, and the insulin-mediated suppression of NEFA during an oral glucose tolerance test in 93 men and women aged 50, born in Preston, whose birthweight and body size at birth had been recorded. Elevated fasting plasma triglycerides and reduced NEFA suppression during the oral glucose tolerance test were associated with the male sex, glucose intolerance, central obesity as indicated by a high waist to hip ratio and insulin resistance as measured by a short insulin tolerance test. However there were no statistically significant relationships between the birth measurements and the circulating lipid levels. Moreover in regression analyses the relationships between thinness at birth and insulin resistance or glucose intolerance in adult life were unaffectived by the addition of triglyceride or NEFA in the models. These results suggest that the link between reduced fetal growth and insulin resistance in the adult is not mediated by an abnormal regulation of lipid metabolism.     

Adiponectin and human pregnancy

Adiponectin is an adipose tissue-derived plasma protein that is involved in regulation of insulin resistance and glucose hemostasis. Human pregnancy is characterized by an increase in insulin resistance. Therefore, it is only natural that the role of adiponectin, a modulator of insulin resistance, is subject to investigation during gestation. Furthermore, conditions associated with increased insulin resistance, such as gestational diabetes and preeclampsia, may be influenced by this hormone. Adiponectin, a key modulator of insulin action and glucose metabolism, both known to regulate fetal growth, is a plausible candidate for regulation of intrauterine fetal development. In this review, we summarize the recent studies describing the relationship between adiponectin, pregnancy, and fetal growth.     

Insulin resistance secondary to a high-fat diet stimulates longitudinal bone growth and growth plate chondrogenesis in mice

It is known that overweight children are often more insulin resistant and taller than normal-weight peers. Because it has been hypothesized that insulin is implicated in the obesity-associated growth acceleration, we aimed to determine whether insulin resistance and secondary hyperinsulinemia are the causative mechanisms of such growth acceleration. Three-week-old mice were fed with standard chow or with a high-fat diet without or with daily administration of pioglitazone. After 6 wk, high-fat mice' body and tibial growth, tibial growth plate height, and serum insulin were all greater than those of standard chow-fed mice. High-fat + pioglitazone mice were shorter, their tibial growth and the growth plate height reduced, and their insulin lower than those of high-fat mice. The addition of insulin to the culture medium of mouse metatarsal bones induced the metatarsal linear growth and increased the metatarsal growth plate height. In addition, insulin stimulated cultured chondrocyte proliferation and differentiation, with both effects being prevented by transfection with a small interfering RNA targeted to the insulin receptor. In conclusion, in high fat-fed mice, insulin resistance is causally related to accelerated skeletal growth. Our in vitro findings suggest that insulin may directly modulate skeletal growth by activating the insulin receptor directly at the growth plate.     

Influence of glucocorticoids and growth hormone on insulin sensitivity in humans

The seminal concept proposed by Sir Harold Himsworth more than 75 years ago that a large number of patients with diabetes were ‘insulin insensitive’, now termed insulin resistance, has now expanded to include several endocrine syndromes, namely those of glucocorticoid excess, and growth hormone excess and deficiency. Synthetic glucocorticoids are increasingly used to treat a wide variety of chronic diseases, whereas the beneficial effects of recombinant growth hormone replacement therapy in children and adults with growth hormone deficiency have now been well‐recognized for over 25 years. However, clinical and experimental studies have established that increased circulating levels of glucocorticoids and growth hormone can also lead to worsening of insulin resistance, glucose intolerance, overt diabetes mellitus and cardiovascular disease. Improved understanding of the physiological 24‐h rhythmicity of glucocorticoid and growth hormone secretion and its influence on the dawn phenomenon and the Staub‐Trauggot effect has therefore led to renewed interest in studies on the mechanisms of insulin resistance induced by exogenous administration of glucocorticoids and growth hormone in humans. In this review, we describe the physiological events that result from the presence of resistance to insulin action at the level of skeletal muscle, adipose tissue, and liver, describe the known mechanisms of glucocorticoid‐ and growth hormone‐mediated insulin resistance, and provide an update of the contributions of glucocorticoids and growth hormone to understanding the pathophysiology of insulin resistance and its effects on several endocrine syndromes.     

Failure of injected growth hormone to increase plasma glucose and insulin concentration in the puppy.

The resistance of puppies to the diabetogenic effect of administered growth hormone is well known. The possibility that this involves an adaptive increase in insulin secretion was explored by determining the effect of injected growth hormone on plasma insulin concentration at various age periods. Bovine growth hormone (1 mg/kg per day for 4 days) administered to 5-month-old puppies had no effect on plasma glucose or insulin levels nor on the effectiveness of injected insulin to lower plasma glucose levels. At 8 and 12 months of age the growth hormone regimen increased plasma glucose and insulin levels and produced a resistance to the hypoglycemic effect of injected insulin. It is evident that the difference between the puppy and adult in response to growth hormone is not due to excessive secretion of insulin by the puppy.     

Insulin receptors in beta-cells are critical for islet compensatory growth response to insulin resistance

Insulin and insulin-like growth factor 1 (IGF1) are ubiquitous growth factors that regulate proliferation in most mammalian tissues including pancreatic islets. To explore the specificity of insulin receptors in compensatory beta-cell growth, we examined two models of insulin resistance. In the first model, we used liver-specific insulin receptor knockout (LIRKO) mice, which exhibit hyperinsulinemia without developing diabetes due to a compensatory increase in beta-cell mass. LIRKO mice, also lacking functional insulin receptors in beta-cells (beta IRKO/LIRKO), exhibited severe glucose intolerance but failed to develop compensatory islet hyperplasia, together leading to early death. In the second model, we examined the relative significance of insulin versus IGF1 receptors in islet growth by feeding high-fat diets to beta IRKO and beta-cell-specific IGF1 receptor knockout (beta IGFRKO) mice. Although both groups on the high-fat diet developed insulin resistance, beta IRKO, but not beta IGFRKO, mice exhibited poor islet growth consistent with insulin-stimulated phosphorylation, nuclear exclusion of FoxO1, and reduced expression of Pdx-1. Together these data provide direct genetic evidence that insulin/FoxO1/Pdx-1 signaling is one pathway that is crucial for islet compensatory growth response to insulin resistance.     

Relation of birth weight, body mass index, and change in size from birth to adulthood to insulin resistance in a female twin cohort

CONTEXT AND OBJECTIVES: Because an adverse intrauterine environment is thought to induce insulin resistance, our objective was to investigate the relationships between birth weight, BMI, and change in body size over the life course and insulin resistance. SETTING, DESIGN, AND PARTICIPANTS: We conducted a cross-sectional study in a cohort of 1194 female twins aged 18-74 yr. The relationship between birth weight and insulin resistance was analyzed using a regression method allowing for a simultaneous estimation of within- and between-pair influences. The approach allows the influence of individual fetal nutrition on adult insulin resistance to be distinguished from effects that are mediated by confounding factors in the maternal environment. MAIN OUTCOME MEASURES: Insulin resistance was measured by the homeostasis model assessment. RESULTS: Individual level regression analyses showed no significant relationship between birth weight and insulin resistance. There was a significant positive relationship between insulin resistance and current body mass index (BMI) (a 26% increase in insulin resistance per sd increase in BMI; confidence interval, 22.6-29.5%). This significant relationship was accounted for in equal parts by individual-specific effects and by confounding factors in the shared environment of the twins. The relationship with birth weight became significant only after adjustment for BMI and was mediated only through between-pair differences. CONCLUSIONS: These results suggest that insulin resistance is influenced more by current body size than birth weight and that postnatal growth is potentially more important than fetal growth in the subsequent development of insulin resistance.     

参苓组方对2型糖尿病大鼠胰岛素样生长因子1干预作用的研究

目的观察参苓组方对2型糖尿病（T2DM）大鼠胰岛素样生长因子1（IGF-1）代谢途径的影响及胰岛素抵抗（IR）相关指标的改善作用。方法建立T2DM大鼠模型并分组,观察各组大鼠IGF-1、FPG、HbA1c、Fins、TG、TC的变化,比较胰岛素敏感性指数（IAI）、胰岛素抵抗指数（HOMA—IR）。结果参苓组方能升高T2DM大鼠IGF-1水平（P〈0．01）,降低FPG,HbA1c、Fins、TG、TC（P〈0．05）,使IAI升高,HOMA—IR下降（P〈0．05）。结论参苓组方能改善T2DM大鼠IR和IGF-1水平。