Risk Factors and Etiology of Obesity and Type 2 Diabetes

胰岛素作用降低、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。 这些风险因素存在，即使当个体具有正常的空腹和两小时葡萄糖浓度时，也表明胰岛素分泌减少在2型糖尿病发展中的非常早期的作用。 在以前的工作中，我们发现了一个在肌肉组织中双峰表达的基因。 在皮马印第安人中，HLA-DRB 1与糖尿病风险降低和胰岛素分泌增加有关。由于这种保护性HLA单倍型系统表明自身免疫参与了皮马印第安人2型糖尿病的进展，我们在具有和不具有HLA-DRB 1位点的个体中进行了一项初步研究，这些个体也与糖尿病状态不一致，检查了超过9，000种潜在蛋白质和T细胞受体基因的免疫谱。从这项研究中，我们选择了80种在糖尿病患者中浓度显著增加的抗体，以研究糖尿病和保护性单倍型的更大协方差。.我们还对这些相同个体的T细胞受体中的互补定义区3（CDR 3）进行了测序。我们发现，在糖尿病患者中，CDR 3区域的长度较短，表明自身耐受性丧失。随后，我们对大量没有保护性HLA单倍型的个体的CDR 3区域进行了测序，这些个体也有胰岛素作用和分泌的措施。 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。 使用以下技术进行减肥手术的无糖尿病个体：Roux-en-Y胃旁路术（RYGBP）、腹腔镜带或胃袖，在手术前和手术后一个月进行胰岛素作用、胰岛素分泌和膳食试验的测量。结果表明，接受RYGBP的个体在胰岛素作用肝胰岛素敏感性方面有所改善，并且在膳食试验期间葡萄糖和胰岛素反应更快。这就解释了与其他腹腔镜带相比，接受RYGBP的糖尿病患者的血糖改善更大。虽然胰高血糖素样肽-1（GLP-1）在接受RYGBP的患者中也在进餐期间增加更多，但时间并不表明这种增加在增加胰岛素释放中发挥作用。除胰多肽（迷走神经活动的标志物）外，其他胃肠道肽在两组之间没有差异，胰多肽在RYGBP后的进餐期间显著降低。我们将继续跟踪这些人，以检查身体成分的变化，并确定在膳食测试期间葡萄糖和胰岛素的反应是否会随着体重的进一步减轻而变化。 先前基于该研究的体重增加的预测因子包括较高的呼吸商、较高的胰岛素介导的葡萄糖摄取、较低的游离T3和相对较低的能量消耗。 能量消耗的变化是体重变化的一个中介，我们继续评估与代谢率相关的因素。我们在一个更大的队列中证实了相对于体型较低的能量消耗与体重增加之间的相关性，并进行了更长时间的随访。此外，我们能够证明，较低的能量消耗也预示着脂肪量的增加。食物的热效应和唤醒的能量消耗是重叠的，很难测量能量消耗的组成部分。通过检查来自我们的代谢室的时间点数据，我们能够估计这些组分（我们称之为清醒进食产热（AFT）），其占总能量消耗的约10%。我们发现，较低的AFT预测体重增加，但仅适用于BMI 29 kg/m的个体。这表明与肥胖相关的绝缘增加导致代谢大量营养素的成本降低。我们发现CSF中极长链脂肪酸浓度与24小时能量消耗呈负相关，表明特定长链脂肪酸作为具有重要外周效应的中枢信号分子的作用。我们正在计划一项后续研究，其中我们管理一种特定的长链脂肪酸，并确定其对代谢参数的影响。我们还证实了相对较低的24小时能量消耗作为体重和脂肪量增加的预测因子的作用。 遗传因素是肥胖症及其危险因素的基础。黑皮质素4受体基因的突变与人类体重指数增加和24小时能量消耗降低有关。携带MC 4 R突变的糖尿病患者在儿童期体重增加加快，但在成年期则没有，这表明这种突变在早期生活中的影响更强。此外，我们发现MC 4 R突变的存在预测了儿童期糖尿病的发展，与体重无关。MC 4 R导致食欲过盛和体重增加的机制尚不清楚。一种可能的介质是脑源性神经营养因子（BDNF），其是MC 4 R信号传导的下游效应物，其与儿童期的暴食和体重增加有关。然而，血清BDNF没有不同的个体之间有和没有MC 4 R突变。

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.