节俭基因假说与肥胖及2型糖尿病

有关节俭基因假说是解释肥胖和2型糖尿病发病原因的重要假说之一,本对节检基因假说来源、概念,有关支持节俭基因与2型糖尿病和肥胖症发病相关的实验研究及流行病学调查情况以及节俭基因假说导致2型糖尿病和肥胖症的可能机制进行了综述。     

不同运动量对肥胖症及2型糖尿病病人胰岛素敏感性的影响

随着社会经济的发展以及人口老龄化加剧，肥胖症和2型糖尿病发病率逐年升高，已成为危害人类健康的主要疾病之一，二者共同的病理基础为胰岛素抵抗，即胰岛素敏感性降低。胰岛素抵抗是多种疾病，如2型糖尿病、肥胖、高血压、高脂血症、冠心病的共同发病基础，也是其发病的中心环节，改善胰岛素敏感性对预防和治疗糖尿病有重要的意义。本文探讨了不同运动量对肥胖症及2型糖尿病胰岛素敏感性的影响。现报道如下。     

中国人载脂蛋白E基因多态性与2型糖尿病合并冠心病关系的Meta分析

目的本研究利用Meta分析的方法,综合评价中国人载脂蛋白E基因多态性与2型糖尿病合并冠心病的相关性。方法计算机及手工检索2014年12月以前中外有关中国汉族人群载脂蛋白E基因多态性与2型糖尿病合并冠心病关系的病例-对照研究。在评价纳入研究质量、提取有效数据后,采用Rev Man 5.0软件进行Meta分析。结果共纳入5个病例对照研究,包括2型糖尿病并冠心病组646例,2型糖尿病无冠心病组752例。Meta分析结果显示:文献无明显发表偏倚。携带载脂蛋白Eε3/3基因型的人群2型糖尿病并冠心病的发病风险降低(OR=0.51,95%CI:0.37~0.71),ε3/4基因型发病风险增高(OR=2.20,95%CI:1.52~3.20);ε4等位基因发病风险增高(OR=2.07,95%CI:1.49~2.87)。结论中国汉族人群载脂蛋白Eε3/3基因型、ε3/4基因型、ε4等位基因多态性可能与2型糖尿病合并冠心病的发病有关。     

腹腔镜可调节捆扎带胃减容术治疗单纯性肥胖症患者的护理

肥胖症是全球的高发病之一,可引起高血脂、原发性高血压、冠心病、2型糖尿病,并与多种恶性肿瘤的发病密切相关.     

中国人Resistin基因SNP-420C/G多态性与2型糖尿病发病风险关系的Meta分析

目的利用Meta分析的方法,综合评价Resistin基因SNP-420C/G位点多态与中国汉族人2型糖尿病发病的相关性。方法计算机检索2001年1月～2010年7月CNKI、万方、VIP、中国生物医学服务系统(SinoMed)和PubMed数据库,并手工检索相关杂志,收集有关中国汉族人群Resistin基因-420C/G位点多态的基因型频率和/或等位基因频率的独立病例对照研究。在评价纳入研究质量,提取有效数据后,采用RevMan 4.2软件进行Meta分析。结果共纳入5个病例对照研究,包括2型糖尿病组709例,对照组572例。Meta分析结果显示:以CC基因型为暴露因素,具有CC基因型的人群2型糖尿病发病风险无明显增高[OR=1.02,95%CI(0.81,1.29)];以GG基因型为暴露因素,具有GG基因型的人群2型糖尿病发病风险无明显增高[OR=1.34,95%CI(0.95,1.90)]。结论本Meta分析结果提示,中国汉族人群Resistin基因SNP-420C/G位点多态可能与2型糖尿病的发病不相关。     

2型糖尿病的发病易感基因

目的:综合分析2型糖尿病的易感基因,从基因水平阐明2型糖尿病的发生发展过程,为病因学研究提供证据。资料来源:应用计算机检索Pubmed1995-01/2005-02有关2型糖尿病遗传学及其基因扫描的文章,检索词“Type2DiabetesMellitus,genetics,association,genescan,predisposinggenes”,并限定文章语言种类为English。资料选择:对检索到的有关2型糖尿病遗传学及其基因扫描的相关信息进行整理,选取针对性强的文章,同一领域的文献则选择近期发表或权威杂志的文章。资料提炼:共检索到的2型糖尿病遗传学及基因扫描的相关文献47篇,其中15篇符合要求,排除32篇。资料综合:2型糖尿病的发病机制复杂,目前尚未完全阐明。目前对2型糖尿病的研究策略主要有两种:①基因组扫描与连锁分析。②候选基因策略的遗传关联研究:包括与糖代谢、脂代谢及其他路径关联的易感基因。结论:寻找2型糖尿病易感基因的策略主要有基因扫描、连锁分析和遗传学关联研究。近年来,应用这些遗传学分析方法发现了一些与2型糖尿病易感性关联的染色体区域和基因,并取得了很大的进步。     

青岛地区糖尿病肾病患者PC-1基因K121Q和ACE基因DI多态性的研究

目的探讨浆细胞膜糖蛋白（PC-1）基因4号外显子K121Q多态性及血管紧张素转换酶（ACE）基因与2型糖尿病肾病的相关性分析,寻找与糖尿病发病相关的致病基因。方法用多聚酶链反应（PCR）结合限制性酶切技术检测青岛地区50例2型糖尿病患者和48例正常人的PC-1基因扣ACE基因的多态性分布情况。结果正常对照组中PC-1基因KK基因型38例（79．2％）,KQ基因型10例（20．8％）,QQ基因型0例（0．00％）,K,Q等住基因频率分别为89．6％和10．4％;糖尿病患者中KK基因型41例（82％）,KQ基因型9例（18％）,QQ基因型0例（0．00％）,K,Q等位基因频率分别为91％和9％,2组人群的基因型和等位基因频率差异无统计学显著性意义（P〉0．05）。正常对照组、糖尿病组、糖尿病肾病组之间ACE基因型构成、等位基因频率以及DD型与非DD型构成均无显著性差异。但ACE基因和PC-1基因对糖尿病肾病的发展进程存在协同作用。结论PC-1基因4号外显子K121Q多态性与2型糖尿病及2型糖尿病肾病无明显相关性,QQ基因型不是2型糖尿病及2型糖尿病肾病发病的危险因子;ACE基因DI多态性与2型糖尿病及糖尿病肾病无明显相关性,DD基因型不是2型糖尿病及糖尿病肾病发病的危险因子。     

2型糖尿病的发病易感基因

目的：综合分析2型糖尿病的易感基因，从基因水平阐明2型糖尿病的发生发展过程，为病因学研究提供证据。 资料来源：应用计算机检索Pubmed 1995—01／2005—02有关2型糖尿病遗传学及其基因扫描的文章，检索词“Type 2 Diabetes Mellitus．genetics．association，genescan，predisposing genes”，并限定文章语言种类为English。 资料选择：对检索到的有关2型糖尿病遗传学及其基因扫描的相关信息进行整理，选取针对性强的文章，同一领域的文献则选择近期发表或权威杂志的文章。 资料提炼：共检索到的2型糖尿病遗传学及基因扫描的相关文献47篇，其中15篇符合要求，排除32篇。 资料综合：2型糖尿病的发病机制复杂，目前尚未完全阐明。目前对2型糖尿病的研究策略主要有两种：①基因组扫描与连锁分析。②候选基因策略的遗传关联研究：包括与糖代谢、脂代谢及其他路径关联的易感基因。 结论：寻找2型糖尿病易感基因的策略主要有基因扫描、连锁分析和遗传学关联研究。近年来，应用这些遗传学分析方法发现了一些与2型糖尿病易感性关联的染色体区域和基因，并取得了很大的进步。     

血清瘦素水平与2型糖尿病胰岛素抵抗的关系

胰岛素抵抗（IR）是2型糖尿病发病机制中的重要环节,贯穿于2型糖尿病的整个发生、发展过程中.但胰岛素抵抗的发生机制十分复杂,近年来认为肥胖症是胰岛素抵抗的危险因素.肥胖者大都存在着明显的高胰岛素血症现象.我们通过对人血清瘦素水平的测定,探讨瘦素水平与肥胖、胰岛素抵抗、2型糖尿病的关系.     

2型糖尿病合并肥胖症患者胰岛素抵抗与血清肝酶及胆汁酸的关系

<正>2型糖尿病发病机制的基本环节是胰岛素抵抗和胰岛β细胞功能缺陷。肥胖症与2型糖尿病密切相关。近年来研究发现,肝细胞功能异常与肥胖、胰岛素抵抗及2型糖尿病的发病密切相关。临床上一些肝脏血清酶学标志物如谷丙转氨酶(ALT)、谷草转氨酶(AST)和γ谷氨酰转肽酶(GGT)等可能提示肝脏脂肪聚集的程度[1]。胆汁酸(TBA)作为重要的代谢信号分子,参与了糖类、脂肪及能量代谢。我们收     

Promising new causal explanations for obesity and obesity-related diseases

Current explanations for obesity center around a predisposition in genotype and phenotype, possibly triggered by an inflammatory process or event, and exacerbated by environmental and psychological factors. It is likely that a variety of physiologic factors may act in combination to produce clinical obesity. Leptin resistance may be an important neurochemical cause of obesity; elevated leptin levels have been correlated with weight gain over extended time periods. Genetic studies support the postulate that a gene originating with our cave-dwelling ancestors, critical to survival when food was scare, has evolved into a trigger for obesity and related diseases. A variety of biochemical markers are prevalent in obesity and obesity-linked disease states. C-reactive protein, interleukin-6, and others are elevated in obesity, supporting the hypothesis that inflammation plays a role in the condition. Tumor necrosis factor-alpha is overexpressed in obesity and diabetes, suggesting that it may be part of the link between the 2 conditions.     

Mutation analysis of the preproghrelin gene: no association with obesity and type 2 diabetes

OBJECTIVE: To investigate the preproghrelin gene for variants and their association with obesity and type 2 diabetes. DESIGN AND METHOD: 82 obese probands were analyzed for mutations using single-strand conformational polymorphism, heteroduplex analyses and sequencing. Association studies were performed in 234 juvenile-onset obese and 323 lean men and in 557 type 2 diabetic and 233 glucose tolerant subjects. RESULTS: We identified two novel variants, 36C > T and IVS3 + 715delC, and 4 known variants, Arg51Gln, Leu72Met, Gln90Leu, and IVS1 + 169G > A. None of the variants showed any significant association with obesity or type 2 diabetes or estimates of glucose and lipid metabolism in glucose tolerant subjects. CONCLUSION: Variation in the preproghrelin gene is not associated with juvenile-onset obesity, type 2 diabetes or related phenotypes among the examined Danish Caucasian subjects.     

Hypertension in obesity and NIDDM. Role of insulin and sympathetic nervous system

An important link exists between obesity, noninsulin-dependent diabetes mellitus (NIDDM), and hypertension. Most patients with NIDDM are obese; the incidence of hypertension in obesity and NIDDM is substantial, approaching 50% in some studies. Furthermore, hypertension is known to contribute to the increased cardiovascular morbidity and mortality in patients with obesity and NIDDM. Despite the obvious clinical importance, the pathogenesis of hypertension in obesity and NIDDM remains poorly understood. Recent studies have identified hyperinsulinemia and insulin resistance as important threads that tie hypertension, obesity, and NIDDM together. The hypothesis is developed that insulin-mediated sympathetic stimulation contributes to blood pressure elevation in both obesity and NIDDM. Recruited as a mechanism to limit weight gain and restore energy balance, insulin resistance and sympathetic stimulation increase blood pressure by enhancing renal Na+ reabsorption and stimulating the cardiovascular system. In this article, we review the evidence on which this hypothesis is based.     

Emerging epidemic of type 2 diabetes in youth.

This review considers the epidemiologic evidence of an increasing incidence of type 2 diabetes in youth, the classification and diagnostic issues related to diabetes in young populations, pathophysiologic mechanisms relevant to the increasing incidence, the role of genetics and environment, and the community challenge for prevention and treatment. Type 2 diabetes in youth has been recognized to be frequent in populations of native North Americans and to comprise some 30 percent of new cases of diabetes in the 2nd decade of life, largely accounted for by minority populations and associated with obesity. Among Japanese schoolchildren, type 2 diabetes is seven times more common than type 1, and its incidence has increased more than 30-fold over the past 20 years, concomitant with changing food patterns and increasing obesity rates. The forms of diabetes seen in children and youth include typical type 1, occurring in all races; type 2, seen predominantly in minority youth; atypical diabetes, seen as an autosomal dominantly transmitted disorder in African-American populations; and maturity-onset diabetes of the young (MODY), seen rarely and only in Caucasians. Of the nonautoimmune forms of diabetes seen in youth, only type 2 diabetes is increasing in incidence. Proper classification requires consideration of onset (acute/severe versus insidious), ethnicity, family history, presence of obesity, and if necessary, studies of diabetes related autoimmunity. Insulin resistance predicts the development of diabetes in Pima Indians, in offspring of parents with type 2 diabetes, and in other high-risk populations. African-American children and youth have greater insulin responses during glucose tolerance testing and during hyperglycemic clamp study than do whites. There is also evidence of altered beta-cell function preceding the development of hyperglycemia. Of particular interest is the evidence that abnormal fetal and infantile nutrition is associated with the development of type 2 diabetes in adulthood. The thrifty phenotype hypothesis states that poor nutrition in fetal and infant life is detrimental to the development and function of the beta-cells and insulin sensitive tissues, leading to insulin resistance under the stress of obesity. The thrifty genotype hypothesis proposes that defective insulin action in utero results in decreased fetal growth as a conservation mechanism, but at the cost of obesity-induced diabetes in later childhood or adulthood. The vast majority of type 2 diabetes in adults is polygenic and associated with obesity. Monogenic forms (MODY, maternally transmitted mitochondrial mutations) are rare, but are more likely to appear in childhood. Linkage studies of the common polygenic type 2 diabetes have emphasized the heterogeneity of the disorder. The prevention and treatment of type 2 diabetes in children and youth is a daunting challenge because of the enormous behavioral influence, difficulty in reversing obesity, and typical nonadherence in this age-group. The emerging epidemic of type 2 diabetes in the pediatric population, especially among minorities whose proportion in the U.S. population is increasing, presents a serious public health problem. The full effect of this epidemic will be felt as these children become adults and develop the long-term complications of diabetes.     

Type II diabetes: search for primary defects.

Type 2 diabetes is a familial disease, but recent analysis of nuclear families indicates it is unlikely to be due to a single dominant gene with high penetrance and that it could be polygenic. Insulin resistance is a major feature, with obesity being a major determinant. Beta cell deficiency is a sine qua non of Type 2 diabetes. It is possible that obesity, insulin resistance independent from obesity and impaired beta cell function are independently inherited factors. None of these can be said to be 'primary' as diabetes usually results from the interaction of several geometric and environmental factors. This makes linkage analysis of Type 2 diabetes of uncertain benefit, since heterogeneity can occur within a pedigree. The only mutation so far discovered is of glucokinase producing maturity-onset diabetes of the young, that has a clearly defined and unusual phenotype. Identification of genes that cause classical Type 2 diabetes is likely to come from population association studies, molecular scanning techniques and direct sequencing of candidate genes rather than linkage analysis.     

Reduced beta-cell compensation to the insulin resistance associated with obesity in members of caucasian familial type 2 diabetic kindreds

OBJECTIVE: Both obesity and a family history of diabetes reduce insulin sensitivity, but the impact of obesity on insulin secretion among individuals predisposed to diabetes is uncertain. We used a pedigree-based approach to test the hypothesis that beta-cell compensation to the insulin resistance associated with obesity is defective among individuals predisposed to diabetes by virtue of a strong family history of type 2 diabetes before the development of diabetes or glucose intolerance. RESEARCH DESIGN AND METHODS: A total of 126 members of 26 families ascertained for at least a sib pair with type 2 diabetes with onset before age 65 years underwent a tolbutamide-modified frequently sampled intravenous glucose tolerance test (FSIGT). Family members included 26 individuals with impaired glucose tolerance and 100 individuals with normal glucose tolerance (NGT). The acute insulin response to glucose (AIRglucose) was determined and insulin sensitivity (S(I)) estimated by minimal model analysis of FSIGT data. The beta-cell compensation for insulin sensitivity was estimated from the disposition index (DI), calculated as the product of S(I) and AIRglucose. Obesity was measured by BMI. RESULTS: Among all individuals, BMI was a significant predictor of both S(I) and AIRglucose, as expected. However, BMI also significantly predicted DI (P = 0.002) after correcting for age, sex, family membership, and glucose tolerance status. The relationship of BMI and DI was confirmed in 85 individuals with NGT who were aged <45 (P = 0.002) but not in 91 unrelated control individuals without a family history of diabetes. When normoglycemic individuals aged <45 were separated into three classes by BMI (< or =27, 27-30, >30), S(I) decreased progressively and significantly with obesity whereas AIRglucose rose significantly from lean to most obese classes. In contrast to the expectation of complete beta-cell compensation with obesity D1 fell significantly (P = 0.004) among obese family members. This relationship was not observed in control subjects. CONCLUSIONS: Individuals with a genetic predisposition to diabetes show a reduced beta-cell compensatory response to the reduced insulin sensitivity associated with obesity. We propose that this impaired compensation may be one manifestation of the underlying genetic defect in susceptible individuals. This finding helps explain the multiplicative effects of family history and obesity on risk of type 2 diabetes.     

Insulin sensitivity: modulation by nutrients and inflammation

Insulin resistance is a major metabolic feature of obesity and is a key factor in the etiology of a number of diseases, including type 2 diabetes. In this review, we discuss potential mechanisms by which brief nutrient excess and obesity lead to insulin resistance and propose that these mechanisms of action are different but interrelated. We discuss how pathways that "sense" nutrients within skeletal muscle are readily able to regulate insulin action. We then discuss how obesity leads to insulin resistance via a complex interplay among systemic fatty acid excess, microhypoxia in adipose tissue, ER stress, and inflammation. In particular, we focus on the hypothesis that the macrophage is an important cell type in the propagation of inflammation and induction of insulin resistance in obesity. Overall, we provide our integrative perspective regarding how nutrients and obesity interact to regulate insulin sensitivity.     

Technology evaluation: ISIS-113715, Isis

Isis is developing ISIS-113715, an antisense inhibitor of the PTP1B gene, for the potential treatment of type 2 diabetes and obesity. ISIS-113715 is undergoing phase II clinical trials.     

Association of intrauterine exposure to maternal diabetes and obesity with type 2 diabetes in youth: the SEARCH Case-Control Study

OBJECTIVE—Limited data exist on the association between in utero exposure to maternal diabetes and obesity and type 2 diabetes in diverse youth. These associations were explored in African-American, Hispanic, and non-Hispanic white youth participating in the SEARCH Case-Control Study.RESEARCH DESIGN AND METHODS—A total of 79 youth with type 2 diabetes and 190 nondiabetic control youth aged 10–22 years attended a research visit. In utero exposures to maternal diabetes and obesity were recalled by biological mothers.RESULTS—Youth with type 2 diabetes were more likely to have been exposed to maternal diabetes or obesity in utero than were nondiabetic control youth (P < 0.0001 for each). After adjusting for offspring age, sex, and race/ethnicity, exposure to maternal diabetes (odds ratio [OR] 5.7 [95% CI 2.4–13.4]) and exposure to maternal obesity (2.8 [1.5–5.2]) were independently associated with type 2 diabetes. Adjustment for other perinatal and socioeconomic factors did not alter these associations. When offspring BMI was added, the OR for the association between in utero exposure to obesity and type 2 diabetes was attenuated toward the null (OR 1.1 [0.5–2.4]). Overall, 47.2% (95% CI 30.9–63.5) of type 2 diabetes in youth could be attributed to intrauterine exposure to maternal diabetes and obesity.CONCLUSIONS—Intrauterine exposures to maternal diabetes and obesity are strongly associated with type 2 diabetes in youth. Prevention efforts may need to target, in addition to childhood obesity, the increasing number of pregnancies complicated by obesity and diabetes.Type 2 diabetes has increasingly been reported in young adults and adolescents. The SEARCH for Diabetes in Youth Study found type 2 diabetes among youth of all major racial/ethnic groups, and high rates were noted among minority adolescents aged 15–19 years (1).A maternal diabetic intrauterine environment has consequences for future type 2 diabetes risk in the offspring (2). Among the Pima Indians, exposure to diabetes in utero was the strongest risk factor for development of type 2 diabetes in young offspring (3). This association was independent of maternal obesity, father''s diabetes, age at onset of diabetes in either parent, and offspring''s birth weight and later obesity (2,3).Recent studies have shown an association between maternal prepregnancy obesity and excessive neonatal growth and adiposity (4), independent of diabetes in pregnancy. There is increasing interest in the hypothesis that maternal obesity during pregnancy, even in the absence of frank diabetes, is also associated with lifelong metabolic abnormalities in offspring, such as the presence of obesity (5) and features of the metabolic syndrome (6). However, no study has specifically explored an association between exposure to maternal prepregnancy obesity and type 2 diabetes in youth.In the last decade an increase in the prevalence of overweight among obstetric populations has been reported (7). There is also an increasing incidence and a younger age at onset of type 2 diabetes in adults (8), and an increasing prevalence of gestational diabetes mellitus (GDM) in all major racial/ethnic groups (9). In this context, the Fifth International Workshop on Gestational Diabetes Mellitus (10) has recommended studies of in utero exposure to maternal diabetes and obesity and type 2 diabetes in youth in populations other than American Indians.Using data from the multiethnic (non-Hispanic white, African-American, and Hispanic) SEARCH Case-Control (SEARCH CC) Study, we hypothesized that youth with type 2 diabetes would be more likely to have been exposed to a diabetic and obese intrauterine environment compared with nondiabetic control youth. We also hypothesized that the association between exposure to maternal diabetes and offspring type 2 diabetes will be independent of other perinatal, early life, and familial socioeconomic factors; however, the association between maternal prepregnancy obesity and offspring type 2 diabetes will be, at least in part, accounted for by offspring BMI.     

肥胖相关蛋白 FTO 的研究进展

肥胖目前在世界范围内以极快的流行趋势和其带来的一系列相关疾病而引起全球的广泛重视。作为多因素复杂性状疾病,肥胖与遗传基因之间的相关性研究越来越深入。肥胖相关基因（fatmassandobesityassociatedgene,FTO）是首例被确认与肥胖密切相关基因,并在不同人群和动物中得到反复验证。目前针对FTO的研究越来越细致,从最初的遗传多态性研究向更深的表达调控机制及功能学研究拓展,本篇将对相关研究进展作一系统综述。