Risk Factors and Etiology of Obesity and Type 2 Diabetes

肥胖和 2 型糖尿病的危险因素和病因

• 批准号: 8741544
• 负责人: Jonathan Krakoff
• 金额: $ 20.43万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8741544
• 关键词: Accounting; Adult; Affect; Antibodies; Arousal; Autoimmunity; Biopsy; Body Composition; Body Size; Body Weight; Body Weight Changes; Body Weight decreased; Body mass index; Brain-Derived Neurotrophic Factor; Childhood; Cross-Sectional Studies; Data; Development; Diabetes Mellitus; Energy Metabolism; Etiology; Fasting; Fatty acid glycerol esters; Food Energy; Gastric Bypass; Genes; Genetic; Glucose; Goals; Gold; HLA-DRB1; Haplotypes; Hepatic; Hour; Human; Hyperphagia; Individual; Insulin; Investigation; Length; Life; Longitudinal Studies; Macronutrients Nutrition; Measurement; Measures; Mediating; Mediator of activation protein; Melanocortin 4 Receptor; Metabolic; Muscle; Mutation; Nerve; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Pancreatic Polypeptide; Peptides; Peripheral; Pilot Projects; Pima Indian; Play; Proteins; Receptor Gene; Relative (related person); Risk Factors; Role; Self Tolerance; Serum; Signal Transduction; Signaling Molecule; Stomach; Structure of beta Cell of islet; System; T-Cell Receptor; T-Cell Receptor Genes; Techniques; Testing; Thermogenesis; Time; Very Long Chain Fatty Acid; Weight; Weight Gain; Work; awake; bariatric surgery; base; cohort; cost; diabetes risk; feeding; follow-up; gastrointestinal; glucagon-like peptide; glucagon-like peptide 1; glucose uptake; insulin secretion; insulin sensitivity; long chain fatty acid; novel; respiratory; response

Decreased insulin action, impaired insulin secretion and increased adiposity are important risk factors for development of type 2 diabetes. These risk factors are present even when individuals have both normal fasting and two hour glucose concentrations indicating a very early role for decreased insulin secretion in the development of type 2 diabetes. In previous work we found that a a bimodally expressed gene in muscle tissue. HLA-DRB1, was associated with lower risk for diabetes and higher insulin secretion in Pima Indians. As this protective HLA haplotype system indicates involvement of autoimmunity in progression to type 2 diabetes in Pima Indians we performed a pilot study in individuals with and without the HLA-DRB1 locus who were also discordant for diabetes status, examining both immunoprofiling of over 9,000 potential proteins and T-cell receptor genes. From this study we have selected 80 antibodies with significantly increased concentrations in those with diabetes to investigate in a larger co-hort discordant for diabetes and the protective haplotype. . We also sequenced the complementary defining region 3 (CDR3) in the T cell receptor in these same individuals. We found that the length of the CDR3 region is shorter in those with diabetes indicating loss of self tolerance. We have subsequently sequenced CDR3 regions in a larger number of individuals without the protective HLA haplotype who also have measures of insulin action and secretion. We are continuing to investigate additional factors which control insulin secretion and insulin action. Individuals without diabetes who are undergoing bariatric surgery using the following techniques: Roux-en-Y gastric bypass (RYGBP), laporoscopic band, or gastric sleeve have undergone measures of insulin action, insulin secretion and meal tests prior to and one month following the surgery. Results indicate that individuals who underwent RYGBP had improvements in insulin action hepatic insulin sensitivity, and more rapid glucose and insulin responses during meal tests. This explains the greater improvement in glycemia seen in those with diabetes undergoing RYGBP compared with other the laporoscopic band. Although glucagon like peptide-1 (GLP-1) also increased more during the meal in those who underwent RYGBP, the timing did not indicate that this increase played a role in the increase insulin release. Other gastrointestinal peptides did not differ between the groups except for pancreatic polypeptide, a marker of vagal nerve activity, which decreased significantly during the meal following RYGBP. We are continuing to follow these individuals to examine body composition changes with relation, and determine if the glucose and insulin responses during the meals tests change with further weight loss. Previous predictors of weight gain based on this study have included, higher respiratory quotient, higher insulin mediated glucose uptake, lower free T3, and relatively lower energy expenditure. Variability in energy expenditure is a mediator of weight change, and we have continued to evaluate factors related to metabolic rate. We confirmed this association between lower energy expenditure relative to body size as a predictor of weight gain in a larger cohort with longer follow-up. Furthermore, we were able to demonstrate that lower energy expenditure also predicted gain in fat mass. The thermic effect of food and the energy cost of arousal are overlapping and difficult to measure components of energy expenditure. By examining timepoint data from our metabolic chambers, we were able to estimate these components (which we termed awake fed thermogenesis (AFT)) which accounted for approximately 10% of total energy expenditure. We found that lower AFT predicted weight gain, but only in individuals with BMI 29 kg/m. This indicates that increased insulation associated with adiposity leads to lower cost of metabolizing macronutrients. We found that very long chain fatty acid concentrations in the CSF were inversely associated with 24 hour energy expenditure indicating a role for specific long chain fatty acids as central signaling molecules with important peripheral effects. We are planning a follow-up study in which we administer a specific long chain fatty acid and determines its effect on metabolic parameters. We have also confirmed the role of relatively lower 24 hour energy expenditure as a predictor of weight and fat mass gain. Genetic factors underlie adiposity and its risk factors. Mutations in the melanocortin 4 receptor gene are associated with increased body mass index and lower 24 hour energy expenditure in humans. Inidividuals with MC4R mutations have accelerated weight gain in childhood but not in adulthood indicating a more potent effect of this mutation in early life. Furthermore, we found that presence of MC4R mutations predicted development of diabetes in childhood independent of body weight. The mechanism by which MC4R leads to hyperphagia and weight gain is not clear. One possible mediator is brain derived neurotrophic factor (BDNF) a downstream effector of MC4R signaling which has been implicated in childhood hyperphagia and weight gain. However, serum BDNF did not differ between individuals with and without MC4R mutations.

胰岛素作用减少，胰岛素分泌受损和肥胖增加是2型糖尿病发展的重要危险因素。 即使个体同时禁食和两个小时的葡萄糖浓度，也存在这些危险因素，这表明胰岛素分泌在2型糖尿病的发展中的作用非常早。 在先前的工作中，我们发现肌肉组织中的双峰表达基因。 HLA-DRB1与PIMA印第安人的糖尿病风险较低和较高的胰岛素分泌有关。由于这种保护性HLA单倍型系统表明自身免疫性参与PIMA印第安人的2型糖尿病，因此在患有和没有HLA-DRB1基因座的个体中进行了一项试验研究，这些人对糖尿病的状态也不一致，他们对9,000多个潜在的蛋白质和T-Cell受体基因进行了免疫促进剂的影响。从这项研究中，我们选择了80种具有糖尿病患者浓度显着增加的抗体，以在较大的糖尿病和保护性单倍型的较大的同伴不一致中进行研究。 。我们还测序了这些个体中T细胞受体中的互补定义区域3（CDR3）。我们发现，在糖尿病的患者中，CDR3区域的长度较短，表明失去了自耐力。随后，我们在没有保护性HLA单倍型的大量个体中测序了CDR3区域，这些个体也具有胰岛素作用和分泌的测量。 我们正在继续研究控制胰岛素分泌和胰岛素作用的其他因素。 没有糖尿病的人使用以下技术接受减肥手术：roux-en-y胃旁路（RYGBP），Laporoscopic Band或胃袖子进行了胰岛素作用，胰岛素分泌和进餐测试的措施。结果表明，接受RYGBP的个体在饮食测试期间在胰岛素作用方面有改善的胰岛素胰岛素敏感性，以及更快的葡萄糖和胰岛素反应。这就解释了与其他重镜带相比，患有RYGBP的糖尿病患者的血糖改善。尽管在接受RYGBP的患者中，例如肽-1（GLP-1）等胰腺1（GLP-1）也增加了更多，但时机并未表明这种增加在增加的胰岛素释放中起作用。两组之间的其他胃肠道肽除了胰多肽（迷走神经活性的标志）外，两组之间没有差异，在rygbp之后的餐食期间，胰神经活性的标志很大。我们将继续跟随这些人检查与关系的身体组成变化，并确定进餐期间的葡萄糖和胰岛素反应是否会随着进一步的体重减轻而变化。 基于这项研究的体重增加的先前预测因素包括更高的呼吸商，较高的胰岛素介导的葡萄糖吸收，较低的游离T3和相对较低的能量消耗。 能量消耗的变异性是体重变化的中介者，我们继续评估与代谢率有关的因素。我们证实了较低的能量消耗相对于体型的这种关联，这是较大的队列中体重增加的预测指标，随访时间更长。此外，我们能够证明较低的能量消耗还可以预测脂肪质量的增益。食物的热效应和唤醒的能量成本是重叠的，难以测量能量消耗的组成部分。通过检查我们的代谢室的时间点数据，我们能够估算这些成分（我们称为醒来的热生成（AFT）），该组件约占总能量消耗的10％。我们发现较低的AFT预测体重增加，但仅在BMI 29 kg/m的个体中。这表明与肥胖相关的绝缘材料增加会导致代谢大营养素的成本较低。我们发现，CSF中非常长的链脂肪酸浓度与24小时的能量消耗成反比，这表明特定长链脂肪酸作为具有重要外围作用的中央信号分子的作用。我们正在计划进行一项后续研究，其中我们管理特定的长链脂肪酸并确定其对代谢参数的影响。我们还证实了相对较低的24小时能量消耗的作用，作为体重和脂肪质量增加的预测指标。 遗传因素是肥胖及其危险因素的基础。黑色皮质素4受体基因中的突变与人体的体重指数增加和24小时能量消耗有关。具有MC4R突变的非个人体重在童年时期加速了体重增加，但在成年期间并未表明这种突变在早期生命中具有更有效的作用。此外，我们发现MC4R突变的存在预测了糖尿病在儿童时期的发展，而不是体重。 MC4R导致倍率和体重增加的机制尚不清楚。一种可能的介体是脑衍生的神经营养因子（BDNF），它是MC4R信号的下游效应子，该效应已与儿童的心脏和体重增加有关。但是，有MC4R突变和没有MC4R突变的个体之间的血清BDNF没有差异。