Fetal programming of obesity and type 2 diabetes

The prevalence of obesity and type 2 diabetes mellitus has increased rapidly over the past few decades, and prevention efforts have not been successful. Fetal programming involves the earliest stage of obesity development, and provides a novel concept to complement other strategies for lifelong prevention of obesity and type 2 diabetes mellitus. The World Health Organization now advocates a life-course approach to prevent/control obesity, starting with pre-conceptional and antenatal maternal health. Maternal overnutrition, gestational diabetes mellitus and excessive gestational weight gain lead to fetal overgrowth, and “programs” the offspring with an increased risk of obesity and type 2 diabetes mellitus in childhood and adulthood. This review summarizes current data on fetal programming of obesity and type 2 diabetes mellitus including potential causative factors, mechanisms and interventions to reduce its impact.     

Epidemiology and economic impact of obesity and type 2 diabetes

Obesity has become a major public health concern in the United States and the rest of the world. This disease carries significant health risks that encompass several organ systems. Type 2 diabetes mellitus is a major comorbidity of obesity that predisposes patients to significant end-organ damage. The prevalence of obesity and diabetes is increasing worldwide, and the economic impact of these diseases currently assumes a significant portion of health care expenditure. These factors mandate implementation of therapeutic medical and surgical strategies that target prevention and treatment of obesity and its related medical conditions.     

Leucine signaling in the pathogenesis of type 2 diabetes and obesity

Epidemiological evidence points to increased dairy and meat consumption,staples of the Western diet,as major risk factors for the development of type 2 diabetes(T2D).This paper presents a new concept and comprehensive review of leucine-mediated cell signaling explaining the pathogenesis of T2D and obesity by leucine-induced over-stimulation of mammalian target of rapamycin complex 1(mTORC1).mTORC1,a pivotal nutrient-sensitive kinase,promotes growth and cell proliferation in response to glucose,energy,growth factors and amino acids.Dairy proteins and meat stimulate insulin/insulin-like growth factor 1 signaling and provide high amounts of leucine,a primary and independent stimulator for mTORC1 activation.The downstream target of mTORC1,the kinase S6K1,induces insulin resistance by phosphorylation of insulin receptor substrate-1,thereby increasing the metabolic burden of β-cells.Moreover,leucine-mediated mTORC1-S6K1-signaling plays an important role in adipogenesis,thus increasing the risk of obesity-mediated insulin resistance. High consumption of leucine-rich proteins explains exaggerated mTORC1-dependent insulin secretion, increased β-cell growth and β-cell proliferation promoting an early onset of replicative β-cell senescence with subsequent β-cell apoptosis.Disturbances of β-cell mass regulation with increased β-cell proliferation and apoptosis as well as insulin resistance are hallmarks of T2D,which are all associated with hyperactivation of mTORC1.In contrast,the anti-diabetic drug metformin antagonizes leucine-mediated mTORC1 signaling.Plant-derived polyphenols and flavonoids are identified as natural inhibitors of mTORC1 and exert anti-diabetic and anti-obesity effects.Furthermore,bariatric surgery in obesity reduces increased plasma levels of leucine and other branched-chain amino acids.Attenuation of leucine-mediated mTORC1 signaling by defining appropriate upper limits of the daily intake of leucine-rich animal and dairy proteins may offer a great chance for the prevention of T2D and obesity,as well as other epidemic diseases of civilization with increased mTORC1 signaling,especially cancer and neurodegenerative diseases,which are frequently associated with T2D.     

Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes

Skeletal muscle is strongly dependent on oxidative phosphorylation for energy production. Because the insulin resistance of skeletal muscle in type 2 diabetes and obesity entails dysregulation of the oxidation of both carbohydrate and lipid fuels, the current study was undertaken to examine the potential contribution of perturbation of mitochondrial function. Vastus lateralis muscle was obtained by percutaneous biopsy during fasting conditions from lean (n = 10) and obese (n = 10) nondiabetic volunteers and from volunteers with type 2 diabetes (n = 10). The activity of rotenone-sensitive NADH:O(2) oxidoreductase, reflecting the overall activity of the respiratory chain, was measured in a mitochondrial fraction by a novel method based on providing access for NADH to intact mitochondria via alamethicin, a channel-forming antibiotic. Creatine kinase and citrate synthase activities were measured as markers of myocyte and mitochondria content, respectively. Activity of rotenone-sensitive NADH:O(2) oxidoreductase was normalized to creatine kinase activity, as was citrate synthase activity. NADH:O(2) oxidoreductase activity was lowest in type 2 diabetic subjects and highest in the lean volunteers (lean 0.95 +/- 0.17, obese 0.76 +/- 0.30, type 2 diabetes 0.56 +/- 0.14 units/mU creatine kinase; P < 0.005). Also, citrate synthase activity was reduced in type 2 diabetic patients (lean 3.10 +/- 0.74, obese 3.24 +/- 0.82, type 2 diabetes 2.48 +/- 0.47 units/mU creatine kinase; P < 0.005). As measured by electron microscopy, skeletal muscle mitochondria were smaller in type 2 diabetic and obese subjects than in muscle from lean volunteers (P < 0.01). We conclude that there is an impaired bioenergetic capacity of skeletal muscle mitochondria in type 2 diabetes, with some impairment also present in obesity.     

胃肠外科手术治疗肥胖症及2型糖尿病

肥胖症是现今社会所面临的最严重的公共健康问题之一,手术治疗是使肥胖症患者获得长期而稳定的减重效果的唯一方法。自从1954年报道第1例减肥手术以来,外科手术治疗肥胖症在全球范围内获得了很大的发展,逐渐成为治疗病态性肥胖的＂金标准＂。随着研究的不断深入,越来越多的证据表明,胃肠外科手术不仅能减重,同时可以改善甚至治愈肥胖症相关的多种代谢性疾病,尤其是2型糖尿病。目前国内外的胃肠外科医师们正致力于将手术推广到2型糖尿病的治疗中去。外科手术治疗肥胖症及2型糖尿病将有巨大的发展空间。     

手术治疗肥胖2型糖尿病的研究进展

肥胖及2型糖尿病是严重威胁人类健康的常见慢性疾病,除生活方式和内科治疗外,代谢手术以其疗效确切、并发症少等优点日益被广大医务人员所重视.代谢手术种类繁多,但目前袖状胃切除术和Roux-en-Y胃转流术应用较广,其内在机制与胃肠激素、脂肪代谢等多方面有关,尚存在诸多假说.本文就代谢手术的疗效作用、研究机制等方面进行综述.     

多学科综合治疗肥胖症合并2型糖尿病

2型糖尿病常合并肥胖症、高血压、高血脂等代谢综合征症候群。对于此类难以控制的2型糖尿病合并肥胖症的诊断和治疗,内科常用非手术如控制饮食、运动、药物方式治疗;外科则可采用手术方式,改善2型糖尿病及其代谢综合征症候群,达到“治愈”糖尿病和高脂血症的目的。中南大学湘雅三医院对1例肥胖症合并2型糖尿病患者采用多学科协作综合治疗模式,取得了较好疗效。     

Complement activation in obesity,insulin resistance,and type 2 diabetes mellitus

Amplified inflammatory reaction has been observed to be involved in cardiometabolic diseases such as obesity, insulin resistance, diabetes,dyslipidemia, and atherosclerosis. The complement system was originally viewed as a supportive first line of defense against microbial invaders, and research over the past decade has come to appreciate that the functions of the complement system extend beyond the defense and elimination of microbes, involving in such diverse processes as clearance of the immune complexes, complementing T and B cell immune functions, tissue regeneration, and metabolism. The focus of this review is to summarize the role of the activation of complement system and the initiation and progression of metabolic disorders including obesity, insulin resistance and diabetes mellitus. In addition, we briefly describe the interaction of the activation of the complement system with diabetic complications such as diabetic retinopathy, nephropathy and neuropathy, highlighting that targeting complement system therapeutics could be one of possible routes to slow down those aforementioned diabetic complications.     

肥胖症与2型糖尿病外科治疗的规范和推广

外科治疗肥胖症和2型糖尿病的临床疗效已得到国际公认。中国大陆地区的微创胃减容手术总例数已由2008年的110余例迅速增至2012年的2000余例,但由于治疗缺乏统一规范的治疗准则,致使部分患者出现疗效不佳或术后发生严重并发症等情况。由于缺乏权威的统计机构,也一直未形成属于中国的临床数据库。因此,规范和推广中国的肥胖症和2型糖尿病外科治疗势在必行。     

肥胖症伴2型糖尿病的手术与药物治疗

尽管肥胖症伴2型糖尿病的非外科疗法如控制饮食、运动、药物等能在短期内减少体质量的5％～10％．并较为有效地控制血糖,但其长期减肥及维持血糖正常的效果并不理想。因此,肥胖症伴2型糖尿病的外科治疗显得越来越重要。     

Tipping the balance: the pathophysiology of obesity and type 2 diabetes mellitus

Obesity plays a major role in the development of type 2 diabetes mellitus, and it has long been accepted that weight loss plays a significant role in diabetes therapy. This weight loss has traditionally been accomplished through lifestyle changes including diet and exercise. What has only more recently gained acceptance is that bariatric surgery may have a role to play in diabetes therapy as well. This article discusses the pathophysiology of type 2 diabetes mellitus and obesity and provides a basic understanding of these diseases, which forms the basis for understanding the importance of weight loss in their treatment.     

腹腔镜Roux-en-Y胃旁路手术治疗肥胖症和2型糖尿病

目的 探讨腹腔镜Roux-en-Y胃旁路手术（LRYGB）治疗肥胖症和（或）2型糖尿病的可行性及疗效.方法 对21例单纯性肥胖症及9例2型糖尿病患者施行LRYGB,观察肥胖症患者体质量、BMI、超重体质量减少率（EWL%）改善情况;观察糖尿病患者术后的空腹血糖和口服葡萄糖耐量试验（OGTT）变化情况;观察全组患者手术时间、术中出血量、术后恢复、术后并发症情况.结果 本组30例皆成功完成手术,无中转开放手术者,手术时间110～270（平均168）min.术中出血量10～75（平均24.0）ml.本组21例单纯性肥胖症患者术前体质量及BMI分别为（97.2±15.0）kg和35.3±3.5;术后随访2个月至5年,术后1个月体质量及BMI即显著下降[（85.1±10.1）kg和31.2±2.2,均P〈0.01],至术后2～3年降至最低水平[（66.8±9.2）kg和24.3±1.1],之后维持在此水平;EWL%则相应增高（均P〈0.05）.9例2型糖尿病患者术前空腹血糖及OGTT 2 h血糖分别为（12.6±2.6）mmol/L和（17.8±4.1）mmol/L;术后随访3～8个月,空腹血糖及OGTT2 h血糖均显著下降[（5.9±1.4）mmol/L和（7.8±1.4）mmol/L,均P〈0.05];其中合并肥胖症的4例患者BMI明显降低（P〈0.05）,而5例未合并肥胖症者BMI无明显变化（P〉0.05）.本组30例患者中5例（16.7%）术后出现并发症,其中1例因急性暴发性胰腺炎死亡外,1例因肠系膜裂孔疝致肠梗阻行再次手术治愈,余3例均经保守治疗治愈.结论 LRYGB治疗肥胖症和（或）2型糖尿病手术安全可行,术后近期减重和（或）降糖效果显著.     

手术与多学科综合治疗肥胖症及2型糖尿病

单纯性肥胖症及2型糖尿病的治疗应是多学科的综合治疗,包括饮食结构调整、增加身体活动量、行为纠正和药物治疗。一些病态肥胖患者还需要进行微创减肥手术治疗。尽管近年来微创减肥手术对于治疗单纯性肥胖症及2型糖尿病的疗效明显,但存在的问题是：缺乏相关科室的协作与多学科综合治疗以及患者随访率低,这是手术风险增加、疗效差和并发症增多的主要原因。因此,单纯性肥胖症和2型糖尿病及其合并症应该予以微创胃肠外科与相关多学科的综合治疗并进行长期随诊。     

Role of adiponectin and some other factors linking type 2 diabetes mellitus and obesity

Because of the intimate association of obesity with type 2 diabetes mellitus(T2DM), during the last two decades, extensive research work is being conducted to find out whether the coexistence of the two is a simple association or there is a positive correlating link between the two. In this article, an attempt has been made to collect and analyse the recent developments in this field and to arrive at a conclusion on the subject. The possible role of several important factors(obtained from adipocytes/not of adipocyte origin) in linking the two has been discussed in detail. Some of the agents, specifically adiponectin, are beneficial(i.e., reduce the incidence of both), while others are harmful(i.e., increase their incidence). From the analysis, it appears that obesity and T2 DM are intimately linked.     

Genetic obesity unmasks nonlinear interactions between murine type 2 diabetes susceptibility loci

Nonlinear interactions between obesity and genetic risk factors are thought to determine susceptibility to type 2 diabetes. We used genetic obesity as a tool to uncover latent differences in diabetes susceptibility between two mouse strains, C57BL/6J (B6) and BTBR. Although both BTBR and B6 lean mice are euglycemic and glucose tolerant, lean BTBR x B6 F1 male mice are profoundly insulin resistant. We hypothesized that the genetic determinants of the insulin resistance syndrome might also predispose genetically obese mice to severe diabetes. Introgressing the ob allele into BTBR revealed large differences in diabetes susceptibility between the strain backgrounds. In a population of F2-ob/ob mice segregating for BTBR and B6 alleles, we observed large variation in pancreatic compensation for the underlying insulin resistance. We also detected two loci that substantially modify diabetes severity, and a third locus that strongly links to fasting plasma insulin levels. Amplification of the genetic signal from these latent diabetes susceptibility alleles in F2-ob/ob mice permitted discovery of an interaction between the two loci that substantially increased the risk of severe type 2 diabetes.     

减重代谢手术治疗重度肥胖合并2型糖尿病术后1年疗效分析

目的:比较分析腹腔镜胃袖状切除术与腹腔镜胃转流术治疗重度肥胖合并2型糖尿病患者的短期效果。方法:回顾分析48例合并2型糖尿病重度肥胖症患者的临床资料。按手术方式分为胃袖状切除组(n=30)与胃转流组(n=18),术后随访1年,分析比较两组患者体重改善情况及相关糖脂代谢指标的变化。结果:48例均顺利完成手术。术后两组患者体质指数均明显低于术前(P<0.01),两组间差异无统计学意义(P>0.05)。术后6个月、12个月,两组患者空腹血糖、糖化血红蛋白、空腹C肽、胰岛素抵抗指数、胆固醇、甘油三酯均较术前明显改善(P<0.01)。胃袖状切除组与胃转流组糖尿病完全缓解率分别为73%与78%,两组有效率均为100%,两组缓解率相比差异无统计学意义(P>0.05)。结论:腹腔镜胃转流手术与腹腔镜胃袖状切除术均可有效治疗重度肥胖合并糖尿病,近期效果显著,且两种治疗方法临床效果相近。     

Surgical complications following operative treatment of abdominal obesity in type 2 diabetes mellitus patients

Results of surgical treatment of 211 patients consisting of 109 patients with DM2 and 102 patients without DM2 were studied. All patients underwent lipoaspiration or abdominoplasty. The aim was to assess the influence of type 2 diabetes mellitus on the frequency and structure of complications after surgery. The risk of anemia and local complications increases after surgical correction of abdominal obesity which are temporary and do not have significant influence on the clinical outcome. There were no cases of clinical manifestations of pulmonary embolism and fat embolism.     

Differential levels of diabetogenic stress in two new mouse models of obesity and type 2 diabetes

The genetic basis for the more common forms of human obesity predisposing to insulin resistance and development of type 2 diabetes is multigenic rather than monogenic in origin. New mouse "diabesity" models have been created by combining independent diabetes risk-conferring quantitative trait loci from two unrelated parental strains: New Zealand Obese (NZO/HlLt) and Nonobese Nondiabetic (NON/Lt). F1 hybrid males, heterozygous at all polymorphic autosomal loci distinguishing the two parental strains, are driven to obesity-induced diabetes (diabesity) at high frequencies. This review focuses on two new recombinant congenic strains (RCSs) developed by introgressing multiple NZO/HlLt chromosomal segments into the nominally diabesity-resistant NON/Lt strain background. Both RCSs gain more weight than NON animals. Although exhibiting comparable weight gain and adiposity, only one of the two RCSs develops diabetes. Hence, these two RCSs will be instructive in elucidating genetic and pathophysiological differences underlying uncomplicated obesity syndromes versus diabetogenic obesity (diabesity) syndromes. Unlike mice with null mutations in a single gene producing morbid obesity, the new models develop a more moderate obesity produced by the interaction of numerous genes with relatively small effects. These RCSs are differentially sensitive to adverse side effects of thiazolidinediones and thus should be particularly useful for pharmacogenetic analyses.