Uncovering mechanisms of pancreatic adaptability to weight cycling

揭示胰腺对体重循环的适应性机制

• 批准号: 10722086
• 负责人: Nathan C Winn
• 金额: $ 12.21万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-16 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722086
• 关键词: Address; Animals; Antioxidants; Automobile Driving; Beta Cell; Biological Assay; Blood Glucose; Blood capillaries; Blood flow; Body Weight; Body Weight decreased; Caloric Restriction; Cardiometabolic Disease; Cell Respiration; Cell Survival; Cell physiology; Cells; Chronic; Citric Acid Cycle; Closure by clamp; Compensation; Complex; Coupled; Coupling; Crista ampullaris; Data; Development; Diabetes Mellitus; Diet; Disease; Effectiveness; Exocytosis; Free Radicals; Functional disorder; Glucose; Glucose Clamp; Glucose Intolerance; Glycerides; Goals; Hemorrhage; High Fat Diet; Hormones; Human; Hyperglycemia; Hyperinsulinism; Impairment; Individual; Insulin; Insulin Resistance; Intervention; Islets of Langerhans Transplantation; Isotopes; Knowledge; Label; Link; Longevity; Measures; Membrane; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Mitochondrial Swelling; Modification; Morphology; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutrient availability; Obese Mice; Obesity; Overnutrition; Oxidation-Reduction; Oxidative Stress; Pancreas; Pattern; Peripheral; Physiological; Potassium Channel; Production; Reactive Oxygen Species; Regulation; Resolution; Risk; Risk Factors; Rodent; Sampling; Signal Transduction; Structure; Structure of beta Cell of islet; TXNIP gene; Techniques; Testing; Thinness; Tracer; Transplantation; Weight; Weight Gain; attenuation; blood glucose regulation; diet-induced obesity; energy balance; euglycemia; experimental study; genetic signature; glucose tolerance; improved; in vivo; indexing; innovation; insulin secretion; insulin sensitivity; intravenous glucose tolerance test; islet; mass spectrometric imaging; mitochondrial metabolism; mouse model; nutrient metabolism; pharmacologic; respiratory; response; small molecule inhibitor; stable isotope; weight maintenance

Project Summary Obesity is a risk factor for the development of insulin resistance (IR), a hallmark of type 2 diabetes (T2D). Weight loss improves obesity-evoked IR; however, the majority of individuals who lose weight, regain the weight within 1-5 years. This ‘weight cycling’ further increases risk of metabolic disease compared to weight maintenance. Our group developed a mouse model of weight cycling to uncover mechanisms by which weight regain poses additional risk of metabolic disease. We show that weight cycled diet-induced obese (WC-DIO) animals have worsened glucose tolerance than equally obese mice that have not weight cycled. A unique finding is that glucose intolerance in WC-DIO mice is linked to impaired insulin secretion (in vivo during a hyperglycemic clamp and ex vivo in perifused islets). This key finding indicates that β-cell compensation fails to completely adapt to the physiological IR evoked by weight regain in the same way it does during the first bout of weight gain. At the cellular level, WC-DIO mice manifest with atypical β-cell mitochondrial morphology and decreases in gene signatures linked with mitophagy, redox metabolism, and TCA cycle regulation. Mitochondrial metabolism is fundamental for normal nutrient stimulated insulin secretion. Thus, the mitochondrial alterations evoked by weight cycling support a mechanism for impaired insulin secretion. Poor functioning mitochondria are also linked with disruptions to redox control, which can increase oxidative stress and impair β-cell function. We find that a major regulator of pro-oxidant status in β-cells, thioredoxin interacting protein (TXNIP), is increased in WC-DIO islets and inversely associates with insulin secretion. Together, these preliminary studies support that in response to repeated nutrient overload, β-cells are less efficient at coupling metabolic processes to insulin secretion. The central hypothesis is that repeated nutrient overload decreases mitochondrial function and evokes oxidative impairment in β-cells. This loss of β-cell adaptation to nutrient overload impairs insulin secretion and in vivo glucose regulation. This proposal will: i) determine whether impaired mitochondrial function evoked by repeated nutrient excess is central to loss of pancreatic function and ii) examine whether TXNIP is responsible for driving oxidative stress and loss of pancreatic function with weight cycling. Stable isotopes will be used to measure metabolic flux rates in isolated islets. 13C-labeled metabolites will be administered in vivo and incorporation in β-cells quantified using imaging mass spectrometry. Pharmacological inhibition and β-cell specific deletion of TXNIP will be used to determine whether attenuation of oxidative stress restores insulin production and secretion. In vivo insulin secretion and insulin sensitivity will be determined using the frequently- sampled intravenous glucose tolerance test coupled with glucose tracers to quantify glucose fluxes. Ex vivo islet function will be determined in static culture and in perifusion assays. The experiments proposed herein will define the means by which weight cycling uncouples peripheral IR from pancreatic insulin demand, which will lead to a better understanding of the underlying mechanisms of pancreatic adaptability to excess nutrients.

项目摘要 肥胖是发生胰岛素抵抗(IR)的危险因素，IR是2型糖尿病(T2D)的标志。重量 减重可以改善肥胖引起的胰岛素抵抗；然而，大多数减重的人在 1-5年。与保持体重相比，这种“体重循环”会进一步增加患代谢性疾病的风险。我们的 该小组开发了一种重量循环的小鼠模型，以揭示体重恢复姿势的机制 代谢性疾病的额外风险。我们发现体重循环饮食诱导的肥胖(WC-DIO)动物有 与同样肥胖但没有循环体重的小鼠相比，葡萄糖耐量更差。一个独特的发现是葡萄糖 WC-DIO小鼠的不耐受与胰岛素分泌受损有关(在体内，在高血糖钳夹和EX期间 在灌流的胰岛中活体)。这一关键发现表明，β-CELL补偿未能完全适应 体重恢复引起的生理性IR的恢复方式与第一轮体重增加时的情况相同。在 在细胞水平上，WC-DIO小鼠表现为不典型的β细胞线粒体形态和基因减少 与吞丝分裂、氧化还原代谢和三氯乙酸循环调节相关的信号。线粒体新陈代谢是 营养刺激胰岛素正常分泌的基础。因此，由病毒引起的线粒体改变 体重循环支持胰岛素分泌受损的机制。功能不良的线粒体也与 氧化还原控制中断，可能会增加氧化应激，损害β细胞功能。我们发现一个 β细胞氧化状态的主要调节因子硫氧还蛋白相互作用蛋白(TXNIP)在WC-DIO中增加 胰岛，并与胰岛素的分泌成反比。总而言之，这些初步研究支持 对反复营养过载的反应，β细胞将代谢过程与胰岛素偶联的效率较低 分泌物。中心假设是反复的营养过载降低了线粒体的功能并唤醒了 β细胞的氧化损伤。这种β细胞对营养过载的适应能力的丧失会损害胰岛素的分泌和在 体内葡萄糖调节。这项建议将：i)确定线粒体功能受损是否由 反复的营养过剩是胰腺功能丧失的核心，II)检查TXNIP是否与 用于通过体重循环驱动氧化应激和胰腺功能丧失。稳定的同位素将被用于 测量孤立胰岛的代谢流率。13C标记的代谢物将在体内和 用成像质谱仪对β细胞的掺入进行定量。药物抑制与β-细胞 将使用TXNIP的特定缺失来确定氧化应激的减弱是否能恢复胰岛素 生产和分泌。在体内，胰岛素分泌和胰岛素敏感性将使用经常- 取样静脉葡萄糖耐量试验结合葡萄糖示踪剂以定量葡萄糖通量。体外胰岛 功能将在静态培养和灌流试验中确定。这里提出的实验将定义 体重循环将外周IR从胰腺胰岛素需求中分离出来，这将导致 更好地理解胰腺对过量营养的适应的潜在机制。