追赶生长胰岛素抵抗形成机制的新认识

追赶生长是机体一过性生长抑制后出现的快速生长现象,现已证实追赶生长与胰岛素抵抗存在高度相关性,但其形成的具体机制尚不明确.     

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.     

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].     

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。     

低出生体重儿童在自发性追赶生长后早期出现内脏脂肪过多

在最终将导致2型糖尿病或代谢综合征的各种病理过程中,高胰岛素血症性胰岛素抵抗和内脏型肥胖在早期即可出现.其中一种相当普遍的发病过程即开始于出生前生长受限及幼年时体重自发性追赶增长.进入这种发病过程的儿童在4岁时即使没有肥胖,也有发生高胰岛素血症和体脂增多的倾向.     

罗格列酮联合减低体重对糖耐量受损患者的影响

糖耐量受损(IGT)患者治疗3个月后,单服罗格列酮患者血糖、胰岛素、稳态模型胰岛素抵抗指数(HOMA-IR)显著降低,同时减重治疗的患者上述指标降低程度优于单服罗格列酮患者.提示罗格列酮能改善IGT和胰岛素抵抗,如同时控制体重效果更佳.     

233例非糖尿病人群空腹血浆胰岛素水平预测体重增加的前瞻性研究

目的　探讨非糖尿病人群胰岛素抵抗及血浆胰岛素水平对体重增加的影响。方法人群调查中以口服葡萄糖耐量试验 (OGTT)筛选的非糖尿病者 2 33例〔正常糖耐量 (NGT) 134例 ,糖耐量低减 (IGT) 99例〕 ,随访观察 6年。以多因素回归分析初访胰岛素水平、胰岛素抵抗与体重增加的关系。结果　在总组 ,体重增加与初访体重指数 (BMI)呈显著负相关 (P =0 .0 0 3) ,与胰岛素敏感指数及空腹血糖水平呈显著正相关 (P =0 .0 0 6 ,P =0 .0 1) ,剔除随访中演变为糖尿病者后上述相关性没有变化。仅包括体重增加者的分析显示 ,调整年龄、性别、体重指数及胰岛素敏感性影响后初访空腹胰岛素水平均值为 8.8、12 .3、19.1及 41.6mU/L组 ,在随访中体重分别增加 1.5、3.6、4.9及 7.3kg。结论　非糖尿病人群胰岛素抵抗并不利于体重增加 ,而在胰岛素抵抗相当的情况下 ,较高胰岛素水平促进体重增加     

体重指数与胰岛素抵抗及血脂异常的关系 (附260例报告)

根据体重指数将260例2型糖尿病患者分为3组,观察与胰岛素作用指数及血脂异常之间的关系.结果发现体重指数正常组,胰岛素作用指数及血脂在正常范围.而超重和肥胖组,胰岛素作用指数下降,甘油三酯和胆固醇增高,高密度脂蛋白下降.体重指数越高,后者改变越明显.说明肥胖与胰岛索抵抗及脂代谢紊乱密切相关.     

冠心病患者血清内脏脂肪素水平的变化及其影响因素的研究

目的:了解冠心病患者血清内脏脂肪素(visfatin)水平的变化及其影响因素.方法:观测70例冠心病患者(冠心病组)和18例健康对照(对照组)血清内脏脂肪素水平和其他临床生化指标,分析血清内脏脂肪素的变化及其影响因素.结果:冠心病组血清内脏脂肪素显著高于对照组;合并糖尿病的冠心病患者显著高于没有合并糖代谢异常的患者;冠心病患者血清内脏脂肪素与体重指数、高密度脂蛋白胆固醇(HDL-C)、胰岛素抵抗指数(HOMA-RI)显著正相关,与甘油三酯显著负相关;多因素回归分析显示,胰岛素抵抗指数和体重指数是血清内脏脂肪素的独立影响因素.结论:冠心病患者血清内脏脂肪素水平显著升高,胰岛素抵抗指数和体重指数是其升高的独立影响因素.     

多囊卵巢综合征患者内分泌及代谢特征研究

目的探讨多囊卵巢综合征（PCOS）患者内分泌及代谢特征，为PCOS的正确诊断、合理治疗提供依据。方法随机选择PCOS患者120例，其中体重指数（BMI）≥25kg／m^2 51例（肥胖），BMI％25kg／m^269例（非肥胖）；有胰岛素抵抗89例，无胰岛素抵抗31例；高雄激素血症67例，无高雄激素血症53例。在患者月经周期的第3～5天（月经不规律者在B超检查未见优势卵泡时）抽取肘静脉血，进行内分泌、代谢等指标检测。结果①与非肥胖者比较，肥胖者空腹和服糖后30、60、120min血糖及胰岛素、胰岛素抵抗指数（IRI）明显升高，胰岛素敏感指数（ISI）明显降低，睾酮（T）及黄体生成素（LH）明显降低。②与无胰岛素抵抗者比较，有胰岛素抵抗者BMI，空腹和服糖后30、60、120min血糖及胰岛素明显升高。③与无高雄激素血症者比较，高雄激素血症者空腹及服糖后60min胰岛素水平明显升高，ISI明显降低，而IRI明显升高；雌二醇（E2）、LH、T明显升高。结论肥胖的PCOS患者更易出现胰岛素抵抗；体重在胰岛素抵抗中起一定作用；PCOS患者胰岛素抵抗与高雄激素血症具有相关性。     

Influence of catch-up growth on IGFBP-2 levels and association between IGFBP-2 and cardiovascular risk factors in Korean children born SGA

Small for gestational age (SGA) at birth and postnatal growth pattern may have an impact on insulin resistance and body composition in their later life. Emerging evidence has indicated that insulin-like growth factor binding protein-2 (IGFBP-2) may be related to insulin sensitivity. The aim of this study was to evaluate insulin resistance and IGFBP-2 levels in SGA children, and to identify the effect of catch-up growth on IGFBP-2 concentration. Serum IGFBP-2 levels were measured in 103 Korean SGA children including 49 prepubertal and 54 pubertal subjects. Anthropometric values, fasting serum levels of metabolic parameters and insulin sensitivity indices were determined. Each prepubertal or pubertal group was subgrouped based on height or weight catch-up growth. The subgroups with weight catch-up showed higher values of BMI, body fat mass, percent body fat, and total cholesterol. Particularly in pubertal children, IGFBP-2 concentration was lower in the subgroup with weight catch-up. Catch-up growth in height did not affect insulin resistance and metabolic parameters. IGFBP-2 levels were inversely correlated with BMI, body fat mass, percent body fat, insulin and leptin levels in both prepubertal and pubertal groups. Additionally in the pubertal group, systolic blood pressure, cholesterol levels were related to IGFBP-2. A strong relationship between IGFBP-2, the insulin sensitivity index, and some cardiovascular risk factors was observed in children born SGA, suggesting that IGFBP-2 might be a promising marker for early recognition of insulin resistance, particularly in children with weight catch-up.     

Thrifty energy metabolism in catch-up growth trajectories to insulin and leptin resistance

Catch-up growth early in life (after fetal, neonatal or infantile growth retardation) is a major risk factor for later obesity, type-2 diabetes and cardiovascular diseases. These risks are generally interpreted alongside teleological arguments that environmental exposures which hinder growth early in life lead to programming of 'thrifty mechanisms' that are adaptive during the period of limited nutrient supply (or growth constraint), but which increase risks for diseases during improved nutrition and catch-up growth later in life. This paper addresses this notion of 'thrifty mechanisms' in the light of evidence that catch-up growth is characterized by a disproportionately higher rate of fat gain relative to lean tissue gain, and that such preferential catch-up fat is in part driven by energy conservation mechanisms operating via suppressed thermogenesis. It provides a molecular-physiological framework which integrates emerging insights into mechanisms by which this thrifty 'catch-up fat' phenotype cross-links with insulin and leptin resistance.     

Placental restriction of fetal growth increases insulin action, growth, and adiposity in the young lamb

Most children who are short or light at birth due to intrauterine growth restriction (IUGR) exhibit accelerated growth in infancy, termed "catch-up" growth, which together with IUGR, predicts increased risk of type 2 diabetes and obesity later in life. Placental restriction (PR) in sheep reduces size at birth, and also causes catch-up growth and increased adiposity at 6 wk of age. The physiological mechanisms responsible for catch-up growth after IUGR and its links to these adverse sequelae are unknown. Because insulin is a major anabolic hormone of infancy and its actions are commonly perturbed in these related disorders, we hypothesized that restriction of fetal growth would alter insulin secretion and sensitivity in the juvenile sheep at 1 month, which would be related to their altered growth and adiposity. We show that PR impairs glucose-stimulated insulin production, but not fasting insulin abundance or production in the young sheep. However, PR increases insulin sensitivity of circulating free fatty acids (FFAs), and insulin disposition indices for glucose and FFAs. Catch-up growth is predicted by the insulin disposition indices for amino acids and FFAs, and adiposity by that for FFAs. This suggests that catch-up growth and early-onset visceral obesity after IUGR may have a common underlying cause, that of increased insulin action due primarily to enhanced insulin sensitivity, which could account in part for their links to adverse metabolic and related outcomes in later life.     

Catch up growth in low birth weight infants: Striking a healthy balance

Catch-up growth in the first few months of life is seen almost ubiquitously in infants born small for their gestational age and conventionally considered highly desirable as it erases the growth deficit. However, recently such growth has been linked to an increased risk of later adiposity, insulin resistance and cardiovascular disease in both low income and high-income countries. In India, a third of all babies are born with a low birth weight, but the optimal growth pattern for such infants is uncertain. As a response to the high rates of infectious morbidities, undernutrition and stunting in children, the current policy is to promote rapid growth in infancy. However, with socio-economic transition and urbanization making the Indian environment more obesogenic, and the increasing prevalence of type 2 diabetes and cardiovascular disease, affecting progressively younger population, the long term adverse programming effect of fast/excessive weight gain in infancy on later body composition and metabolism may outweigh short-term benefits. This review discusses the above issues focusing on the need to strike a healthy balance between the risks and benefits of catch-up growth in Indian infants.     

Activating mutations in the gene encoding Kir6.2 alter fetal and postnatal growth and also cause neonatal diabetes

CONTEXT: Birth weight is a bioassay for fetal insulin secretion because altered insulin secretion in utero alters insulin-mediated growth. Activating mutations in Kir6.2 are the major cause of neonatal diabetes and reduce insulin secretion by altering the closure of the beta-cell ATP-sensitive potassium channel in the presence of ATP. OBJECTIVE: Our objective was to examine fetal and postnatal growth in patients with activating Kir6.2 mutations and identify whether this was modified by severity of mutation or maternal diabetes. PATIENTS AND METHODS: We used sd scores (SDS) for birth and postnatal growth in an international series of patients (n = 49) with Kir6.2 mutations and related this to their clinical phenotype. RESULTS: Birth weight was greatly reduced [-1.73 (-3.68 to 1.41), median (range) SDS], but there was postnatal catch-up because present weight was normal [-0.37 (-4.37 to 2.34) SDS]. Catch-up growth for height and weight was not seen until insulin treatment was started. Birth weight was not influenced by severity of postnatal phenotype but was increased by maternal diabetes -0.12 vs. -1.81 SDS (P = 0.037). Patients with the severe neurological developmental delay, epilepsy, and neonatal diabetes syndrome did not catch up (present weight -2.2 vs. -0.24 SDS (P = 0.003). CONCLUSIONS: Kir6.2 mutations greatly reduce fetal insulin secretion and hence fetal growth, but this is independent of mutation severity. Increased fetal growth in response to maternal diabetes suggests that either the Kir6.2 mutated fetal beta-cell is still glucose responsive or there is a non-insulin-mediated increase in fetal growth. Postnatal catch-up requires insulin treatment but is complete, except in those with epilepsy.     

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.     

Mechanism of the mitogenic influence of hyperinsulinemia

Either endogenous or exogenous hyperinsulinemia in the setting of insulin resistance promotes phosphorylation and activation of farnesyltransferase, a ubiquitous enzyme that farnesylates Ras protein. Increased availability of farnesylated Ras at the plasma membrane enhances mitogenic responsiveness of cells to various growth factors, thus contributing to progression of cancer and atherosclerosis. This effect is specific to insulin, but is not related to the type of insulin used. Stimulatory effect of hyperinsulinemia on farnesyltransferase in the presence of insulin resistance represents one potential mechanism responsible for mitogenicity and atherogenicity of insulin.     

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.