Weight Change and Risk of Developing Type 2 Diabetes

Objective: To examine the association between weight change and risk of type 2 diabetes and whether initial weight modifies the association. Research Methods and Procedures: This is a prospective cohort study of 20, 187 alumni from Harvard University and the University of Pennsylvania. At baseline in 1962 or 1966, men (mean age, 45.9 years) reported their weight, height, and other risk factors. They also had had their weight and height measured at university entry (mean age, 18.5 years). Participants were followed from baseline to 1998 for type 2 diabetes. Results: During follow‐up, 1223 men developed type 2 diabetes. Weight gain significantly increased the risk of this disease. The multivariate relative risks associated with BMI change from university entry to baseline of <?0.5, ±0.5, >0.5 to 1.0, >1.0 to 1.5, >1.5 to 2.0, >2.0 to 3.0, and >3.0 kg/m² per decade were 0.88, 1.00 (referent), 1.29, 2.09, 2.69, 4.67, and 7.02, respectively (p for trend < 0.0001). Even among men with a low initial BMI < 21 kg/m², weight gain significantly increased risk; the corresponding relative risks were (no cases), 1.00 (referent), 1.00, 1.93, 2.47, 4.82, and 7.68, respectively (p for trend < 0.0001). Discussion: A low initial BMI does not ameliorate the increase in risk of type 2 diabetes with weight gain. Avoidance of weight gain, even among lean individuals, is important to reduce the risk of this disease.     

Gender Differences in the Response of Plasma Leptin Concentrations to Weight Loss in Obese Older Individuals

Plasma leptin concentration is directly related to the degree of obesity and is higher in women than in men of the same body mass index (BMI). We hypothesized that fasting plasma leptin concentrations and the response of leptin to weight loss would differ in older men and women of a similar fat mass. Plasma leptin concentrations (radioimmunoassay) and fat mass (DXA) were measured in 47 older, obese (BMI=30 ± 4 kg/m²) women and 23 older, obese (BMI=31 ± 3 kg/m²) men after a 2 to 4 week period of weight and dietary stabilization, and then in 22 of the women and 18 of the men after a 6-month weight loss intervention (250–350 kcal/d deficit). Leptin correlated with fat mass in men and women (r=0.75 and r=0.77, respectively; p values<0.0001), but women had 3-fold higher leptin levels for a given fat mass than men (p=0.01). In response to the 6-month hypocaloric diet, men and women lost a similar percentage of fat mass (?13% and ?16%, respectively), but the relative decline in circulating leptin was greater in women than men (-45% and ?21%, respectively; p<0.0001). In addition, when leptin was normalized for fat mass using the ratio method, the decrease in leptin per kilogram of fat mass was greater in women than men (-0.37 ± 0.34 vs. ?0.04 ± 0.06 ng/mL/kg; p<0.01). After weight loss, the change in leptin concentrations correlated positively with the change in fat mass in men (r=0.60; p<0.01), but not in women (r=0.31; p=0.17). Furthermore, the loss in fat mass correlated negatively with baseline leptin levels in women (r=-0.47; p<0.05), but not in men (r=0.03, p=NS). These results indicate that the decline in leptin concentration with weight loss correlates with the loss in fat mass in men; but, in women, other factors affect the decrease in leptin concentration. This suggests that the role of leptin in the regulation of obesity is gender-specific and may account for gender differences in response to hypocaloric treatment and maintenance of lost weight.     

Modest Lifestyle Intervention and Glucose Tolerance in Obese African Americans

Objective: Previous studies have demonstrated the benefit of short‐term diets on glucose tolerance in obese individuals. The purpose of this study was to evaluate the effectiveness of modest lifestyle changes in maintaining improvements in glucose tolerance induced by short‐term energy restriction in obese African Americans with impaired glucose tolerance or type 2 diabetes mellitus. Research Methods and Procedures: An intervention group (n = 45; 47 ± 1 year [mean ± SE]), 105 ± 4 kg; body mass index: 39 ± 1 kg/m²) received an energy‐restricted diet (943 ± 26 kcal/d) for 1 week, followed by a lifestyle program of reduced dietary fat (?125 kcal/d) and increased physical activity (+125 kcal/d) for 1 year. Body weight and plasma concentrations of glucose, insulin, and C‐peptide during an oral glucose tolerance test were measured at baseline, 1‐week, and 4‐month intervals. A control group (n = 24; 48 ± 1 year; 110 ± 5 kg; body mass index: 41 ± 2 kg/m²) underwent these measurements at 4‐month intervals. Results: No changes in weight or glucose tolerance were observed in the control group. The intervention group had significant (p < 0.05) improvements in body weight and glucose tolerance in response to the 1‐week diet, which persisted for 4 months (p < 0.001 vs. control for change in weight). A total of 19 subjects (42%) continued the intervention program for 1 year, with sustained improvements (weight: ?4.6 ± 1.0 kg; p < 0.001 vs. control; oral glucose tolerance test glucose area: ?103 ± 44 mM · min; p < 0.05 vs. control). Discussion: A modest lifestyle program facilitates weight loss and enables improvements in glucose tolerance to be maintained in obese individuals with abnormal glucose tolerance. However, attrition was high, despite the mild nature of the program.     

Hepatic Lipoprotein Export and Remission of Human Type 2 Diabetes after Weight Loss

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Diabetes Disease Stage Predicts Weight Loss Outcomes with Long‐Term Appetite Suppressants

Objectives: Characterize degree of weight loss with stage of diabetes and describe its effect on cardiovascular disease risk factors in obese patients with and without diabetes. Research Methods and Procedures: Retrospective cohort analysis from patients participating in a long‐term weight management protocol using diet, exercise, behavioral modification, and appetite‐suppressant therapy. Patient groups, with (n = 19) and without diabetes (n = 19) were matched for age, gender, and weight before weight loss therapy. The effect of 12 months of therapy on weight, blood pressure, glycemic control, lipid profile, and medication requirements were tested. Additionally, patients were grouped or staged based upon therapy required for control of diabetes at the beginning of weight loss intervention. Analysis of covariance described relationships between diabetes disease stage and weight loss at 12 months. Results: Nondiabetic patients had greater mean reduction in BMI than the diabetic group (7.98 kg/m² vs. 4.77 kg/m², p < 0.01). A significant linear trend (p < 0.001) for decreasing weight loss with stage of diabetes was observed. Blood pressure, lipid profile, and glycemia improved significantly. The average daily glyburide‐equivalent dose decreased from 9.4 to 3.0 mg (p < 0.01). Discussion: Patients with diabetes lost less weight than similarly obese patients without diabetes. Regardless of differential weight loss between groups, cardiovascular disease risk factors improved. Hypoglycemic medication requirements decreased with weight loss therapy. A predictive relationship may exist between diabetes disease stage before weight loss therapy and future weight loss potential.     

与2型糖尿病相关糖复合物中糖链结构变化

2型糖尿病是一种全球性严重危害人类健康的慢性代谢性疾病.在2型糖尿病患者和动物的血液、尿液及受损组织中,糖链的结构均发生了不同程度的变化.本文对近年来有关2型糖尿病发生、发展过程中糖蛋白、蛋白聚糖和糖脂中糖链的结构变化进行综述,为2型糖尿病的诊断及其相关药物的研发提供有用的参考.     

2 型糖尿病治疗药物研究进展

2 型糖尿病（T2DM）是一种代谢障碍性疾病。传统抗糖尿病药物具有不同程度的副作用,如低血糖、胃肠道反应、体重增加、 心血管风险等,因此开发作用于新靶点和新作用机制的T2DM 治疗新药成为当前研究的热点。目前基于新靶点设计的糖尿病治疗新药有 些已上市,且获得良好的降糖效果,但大部分药物仍处于临床或临床前研究阶段,其疗效和安全性有待进一步临床验证。综述传统抗糖 尿病药物、T2DM 药物新靶点及基于新靶点设计的抗糖尿病新药的研究进展。     

Weight Loss Increases Soluble Leptin Receptor Levels and the Soluble Receptor Bound Fraction of Leptin

Objective: Soluble leptin receptor (sOB‐R) represents the main binding site for leptin in human blood. The aim of this study was to investigate the relationship between leptin and soluble leptin receptor and the bound/free ratio after pronounced weight reduction. Research Methods and Procedures: A total of 18 morbidly obese women participated in this prospective study. Subjects were examined for fat mass, leptin, and sOB‐R concentrations before and 1 year after Swedish adjustable gastric banding. Results: Anthropomorphic measures displayed a significant reduction of body mass index [(42.9 ± 5.6 to 32.9 ± 6.0 kg/m² (mean ± SD)]. Fat mass decreased from 56.3 ± 9.0 to 33.9 ± 12.5 kg. Plasma leptin concentration decreased from 44.6 ± 18.0 to 20.0 ± 13.1 ng/mL (p < 0.001), whereas the sOB‐R levels increased from 11.1 ± 3.6 to 16.6 ± 6.0 U/mL after weight‐reducing surgery. Thus, the sOB‐R bound fraction of leptin increased from 7% to 33%. Discussion: This work demonstrates a relationship between weight loss, leptin, and sOB‐R concentrations in vivo. During weight loss, leptin levels decreased, whereas sOB‐R levels and the receptor bound fraction of leptin increased. Thus, sOB‐R may negatively regulate free leptin.     

家族高发性2型糖尿病的遗传模式研究

对1999～2000年门诊及住院的家族高发性2型糖尿病患者为先证者的136个大家系进行研究,以探讨该病的遗传模式。对家系人群采用Falconer 法估算遗传率,用Penrose法进行多基因分析,并用S.A.G.E-REGD软件拟合A型回归Logistic模型进行复合分离分析的方法,对家族高发性2型糖尿病家系进行研究。结果表明,136个大家系的2型糖尿病遗传率为94.07%±5.84%,提示在这些家系中可能有显性主基因存在。多基因分析研究表明,在该人群中,2型糖尿病因性别不同而存在两种遗传模式。复合分离分析拒绝单纯环境模型、非传递模型、共显性模型,接受隐性模型和显性模型,但隐性模型为最佳遗传模式。因此,2型糖尿病具有高度的遗传性和遗传异质性,总体表现为多因子遗传,在部分遗传背景较一致的家系人群中可能存在由主要基因决定的常染色体显性遗传。 Abstract:This study is to explore the genetic model of type 2 diabetes mellitus (type 2 DM) among the hereditary family.One hundred and thirty-six pedigrees of familial type 2 DM were studied.The heritability of type 2 DM was estimated according to Falconer's method and the multi-factorial inheritance analyzed according to Penrose's method.Complex segregation analysis was performed using S.A.G.E-REGD.The heritability of familial type 2 DM was 9407%±5.84%.Dominant major gene might influence the genesis of type 2 DM.Analysis of multi-factorial inheritance indicated that there be two genetic patterns respectively in male and female populations.By complex segregation analysis,environment,non-transmitted and co-dominant inheritance were rejected.Autosomal dominant (AD) inheritance and autosomal recessive (AR) inheritance was accepted but AR inheritance was the best pattern.This study suggested that type 2 DM had significant heritability and genetic heterogeneity,which appeared to be a disease of multi-factorial inheritance generally and autosomal dominant (AD) inheritance in part of pedigrees.     

雌性小鼠不适于构建HFD-STZ联合诱导的2型糖尿病模型

目的 探讨雌性小鼠在高脂饲料(HFD)-链脲佐菌素(STZ)联合诱导2型糖尿病模型中的可行性.方法 分别以高脂饲料、高脂饲料-果糖饮水(HFDF)和常规饲料(对照)喂养3周龄的封闭群ICR和近交系C57BL/6J (B6)小鼠6周后,HFD和HFDF组腹腔注射STZ,对照组注射相应体积柠檬酸钠溶液,然后分别以相应饲料继续喂养6周.每周测定小鼠体重,于注射前1周和注射后1～4周测定非空腹血糖浓度.结果 实验结束时各组小鼠体重较初始体重均显著增加.ICR小鼠HFD和HFDF组体重与对照组S无差异,HFD与HFDF组间也无显著变化.虽然B6小鼠HFD与HFDF组体重组间差异不显著,但两组体重均显著低于对照组.注射STZ后1～4周,两品系小鼠HFD与HFDF组血糖水平没有显著升高,组间也没有显著差异,且均没有达到2型糖尿病小鼠成模非空腹血糖标准(11 mmol/L).结论 果糖饮水不能促进高脂饲料诱导的育肥作用,而雌性小鼠也不是HFD-STZ联合诱导2型糖尿病模型的理性选择.     

Behavioral Strategies of Individuals Who Have Maintained Long-Term Weight Losses

MCGUIRE, MAUREEN T., RENA R. WING, MARY L. KLEM, AND JAMES O. HILL. Behavioral strategies of individuals who have maintained long-term weight losses. Obes Res. Objective: The purpose of the present study was to compare the behaviors of individuals who have achieved long-term weight loss maintenance with those of regainers and weight-stable controls. Research Methods and Procedures: Subjects for the present study were participants in a random-digit dial telephone survey that used a representative sample of the U. S. adult population. Eating, exercise, self-weighing, and dietary restraint characteristics were compared among weight-loss maintainers: individuals who had intentionally lost ≥10% of their weight and maintained it for ≥1 year (n = 69), weight-loss regainers: individuals who intentionally lost ≥10% of their weight but had not maintained it (n = 56), and weight-stable controls: individuals who had never lost ≥10% of their maximum weight and had maintained their current weight (±10 pounds) within the past 5 years (n= 113). Results: Weight-loss maintainers had lost an average of 37 pounds and maintained it for over 7 years. These individuals reported that they currently used more behavioral strategies to control dietary fat intake, have higher levels of physical activity (especially strenuous activity), and greater frequency of self-weighing than either the weight-loss regainers or weight-stable controls. Maintainers and regainers did not differ in reported levels of dietary restraint, but both had higher levels of restraint than the weight-stable controls. Discussion: These results suggest that weight-loss maintainers use more behavioral strategies to control their weight than either regainers or weight-stable controls. It would thus appear that long-term weight maintenance requires ongoing adherence to a low-fat diet and an exercise regimen in addition to continued attention to body weight.     

Diphenyl Ether Derivatives as Novel GPR120 Agonists for the Treatment of Type 2 Diabetes Mellitus

Diabetes mellitus (DM) is a serious disease affecting human health. Numerous attempts have been made to develop safe and effective new antidiabetic drugs. Recently, a series of G protein-coupled receptors for free fatty acids (FFAs) have been described and characterized, and small molecule agonists and antagonists of these receptors show considerable promise for managing diabetes and related complications. FFA-activated GPR120 could stimulate the release of glucagon-like peptide-1(GLP-1), which can enhance the glucose-dependent secretion of insulin from pancreatic β cells. GPR120 is a promising target for treating type 2 DM (T2DM). Herein we designed and synthesized a series of novel GPR120 agonists based on the structure of TUG-891, which was the first potent and selective GPR120 agonist. Among the designed compounds, 18 f showed excellent GPR120 activation activity and high selectivity for GPR40 in vitro. Compound 18 f dose-dependently improved glucose tolerance in normal mice, and no hypoglycemic side effects were observed at high dose. In addition, compound 18 f increased insulin release and displayed good antidiabetic effect in diet-induced obese mice. Molecular simulations illustrated that compound 18 f could enter the active site of GPR120 and interact with Arg99. Based on these observations, compound 18 f may be a promising lead compound for the design of novel GPR120 agonists to treat T2DM.     

2型糖尿病患者尿视黄醇结合蛋白与视网膜病变的相关性

目的 探讨2型糖尿病患者尿视黄醇结合（RBP）与视网膜病变相关性。方法 采用酶联免疫法检测158例2型糖尿病患者24h尿视黄醇结合蛋白排泄（24hURBP）及24h尿白蛋白排泄（24hUAE）,并同时用眼底镜仔细检查其眼氏。结果 糖尿病视网膜病变（DR）发生率随着24hURBP、24hUAE增加而显著增高,24hURBP、24hUAE也随DR的程度加重而显著增加。结论 2型糖尿病患者DR与尿RBP、尿白蛋白呈正相关。     

老年2型糖尿病患者发生严重低血糖相关危险因素分析

目的:研究老年2型糖尿病患者发生严重低血糖的相关危险因素。方法:选取2013年7月到2014年7月我院收治的老年2型糖尿病患者200例,根据是否发生严重低血糖将患者分为非低血糖组(138例)和低血糖组(62例),比较两组临床资料。结果:低血糖组和非低血糖组体重指数、住院时间以及糖尿病病程比较差异具有统计学意义(P0.05);低血糖组心脑血管疾病药物联用率显著高于非低血糖组,二甲双胍应用率显著低于非低血糖组,胰岛素应用率以及口服降糖药(OAD)和胰岛素的联合应用率显著高于非低血糖组,两组比较差异具有统计学意义(P0.05);低血糖组低钾血症发生率显著高于非低血糖组,肾功能有关的指标显著高于非低血糖组,低血糖组白细胞和中性粒细胞显著高于非低血糖组,两组比较差异具有统计学意义(P0.05);Logistic多因素回归分析可知,病程超过10年、胰岛素应用以及和OAD联用、果糖胺低于2.5 mmol/L、白细胞升高、肾功能受损均和严重低血糖发生具有相关关系。结论:病程超过10年、胰岛素应用以及和OAD联用、白细胞升高、果糖胺低于2.5 mmol/L、肾功能受损均和严重低血糖发生有关,在行降糖治疗时应该谨慎评估上述危险因素。     

Comparison of Obese NIDDM and Nondiabetic Women: Short- and Long-Term Weight Loss

Previous research suggests that overweight patients with diabetes lose less weight than non diabetics. We compared the response of obese women with NIDDM to non diabetic controls, matched for age and weight, to a behavior weight loss program. Forty-three overweight women (20 NIDDM, 23 non diabetic) participated in the study. NIDDM and non diabetic subjects were treated together and received the same 16-week behavioral weight loss program. Dependent measures included weight, 3-day food records, physical activity, fasting plasma glucose, and questionnaires assessing eating behavior and depressive symptomatology. Weight loss of NIDDM and non diabetic subjects at posttreatment was comparable (-7.4 ± 5.3 kg vs. ?6.4 ± 3.8 kg, respectively). Changes in caloric intake, eating behavior, exercise and depressive symptomatology were also similar between the two groups. However, during the 1-year follow-up period, NIDDM subjects regained 5.4 ± 6.1 kg compared to 1.0 ± 6.7 kg for nondiabetics (p=.058). These data indicate that NIDDM subjects can lose as much weight as their nondiabetic peers during active treatment Once treatment terminated, however, NIDDM subjects demonstrated poor weight loss maintenance. Thus the added motivation that comes from having diabetes and seeing improvements in glycemic control with weight loss were not sufficient to improve long term weight loss in diabetic subjects. A continuous care model of weight control may be particularly necessary for overweight patients with type II diabetes.     

Reduction in Incidence of Diabetes,Hypertension and Lipid Disturbances after Intentional Weight Loss Induced by Bariatric Surgery: the SOS Intervention Study

SJÖSTRÖM, c. DAVID, LAUREN LISSNER, HANS WEDEL, and LARS SJÖSTRÖM. Reduction in incidence of diabetes, hypertension and lipid disturbances after intentional weight loss induced by bariatric surgery: the SOS Intervention Study. Obes Res. Objective: To examine the effect of a large, long standing and intentional weight reduction on the incidence of diabetes, hypertension and lipid disturbances in severely obese individuals as compared to weight-stable obese controls. Research Methods and Procedures: The ongoing prospective SOS (Swedish Obese Subjects) intervention consists of a surgically treated group and a matched control group obtaining conventional obesity treatment. This report is based on 845 surgically treated patients and 845 controls (BMI41. 0±4. 6 kg/m² (mean±standard deviation [S])) followed for 2 years. Results: Surgically treated patients lost 28±15 kg and controls 0. 5±8. 9 kg (p<0. 0001). Two-year incidence of hypertension, diabetes, hyperinsulinemia, and lipid disturbances was compared in the two treatment groups. Adjusted odds ratios (95% CI) for the surgically treated group versus controls were 0. 38 (0. 22, 0. 65) for hypertension, 0. 02 (0. 00, 0. 16) for diabetes, 0. 10 (0. 03, 0. 28) for hyperinsulinemia, 0. 10 (0. 04, 0. 25) for hypertriglyceridemia, 0. 28 (0. 16, 0. 49) for low HDL-cholesterol and 1. 24 (0. 84, 1. 8) for hypercholesterolemia. Compared to controls, the 2-year recovery rates from hypertension, diabetes, hypo-HDL, and hypertriglyceridemia were significantly higher in the surgically treated group. Discussion: Intentional weight loss in the obese causes a marked reduction in the 2-year incidence of hypertension, diabetes and some lipid disturbances. The results suggest that severe obesity can and should be treated.     

2型糖尿病合并下肢动脉粥样硬化的危险因素

下肢动脉粥样硬化是2型糖尿病(T2DM)患者最常见的大血管并发症之一。作为T2DM患者严重的慢并发症之一,下肢动脉粥样硬化可引起糖尿病足的发生,严重情况下可导致足坏疽。因此,阐明T2DM合并下肢动脉粥样硬化的危险因素,早期预防和治疗糖尿病合并下肢动脉粥样硬化症,不仅提高了患者的生活质量,而且减轻了家庭和社会的经济负担,具有较大的现实意义。影响T2DM患者下肢动脉粥样硬化的因素错综复杂,分为不可调控的和可调控的因素,不可调控的危险因素包括年龄、种族、遗传等,可调控的危险因素包括吸烟、高血糖、高血脂、高血压,以及近年提出的肥胖、胰岛素抵抗、高纤维蛋白血症、炎症等。本文就T2DM合并下肢动脉粥样硬化的危险因素做一综述。     

核糖代谢失衡与2型糖尿病

Diabetes mellitus(DM)is considered as a group of metabolic diseases characterized by hyperglycemia(high concentration of blood glucose)resulting from defects in insulin secretion,insulin action,or both.Many years ago,Marks[1]emphasized that pentose phosphate pathway is one of important pathways for     

妊娠期糖尿病孕妇血糖水平与新生儿体质量的相关性

目的:探究妊娠期糖尿病(GDM)孕妇产前血糖水平与新生儿质量的关系。方法:选取2012年6月至2014年6月我院分娩的GDM孕妇97例为研究对象,按照随机数字表法将患者随机分为严格组(50例)和宽松组(47例),选择同期血糖正常孕妇50例作为对照组;分析孕妇血糖水平与新生儿出生质量的关系。结果:对照组血糖水平、新生儿质量以及巨大儿的发生率均明显低于宽松组和严格组(P0.05);严格组的血糖水平、新生儿质量以及巨大儿的发生率均明显低于宽松组(P0.05);孕妇血糖水平与新生儿质量存在显著的正相关(r=0.72,P0.05)。结论:产前孕妇血糖水平与新生儿质量存在显著的正相关,对GDM患者产前进行严格的血糖控制有助于降低巨大儿的发生率,有利于母体和新生儿的健康。     

胰岛素受体变异性剪接与肿瘤和2型糖尿病

    胰岛素受体基因第11号外显子因为变异性剪接而形成两种胰岛素受体,两者与配体胰岛素、胰岛素样生长因子的结合力以及分别诱导的信号传导通路、发挥的生物学效应存在显著差异。这种差异不仅可能是导致胰岛素抵抗、2型糖尿病的重要原因,也会影响肿瘤细胞的生长、增殖、抗凋亡。虽然具体的调节机制尚不明确,但高胰岛素血症及高血糖等代谢因素是影响胰岛素受体变异性剪接的重要原因,同时基因序列敲除试验证实,胰岛素受体基因水平的改变会影响胰岛素受体的变异性剪接。