Uncovering mechanisms of pancreatic adaptability to weight cycling

揭示胰腺对体重循环的适应性机制

基本信息

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
项目类别：
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

项目摘要

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.

项目概要肥胖是发生胰岛素抵抗 (IR) 的危险因素，而胰岛素抵抗是 2 型糖尿病 (T2D) 的标志。减轻体重可改善肥胖引起的 IR；然而，大多数减肥者的体重会在短时间内反弹。与维持体重相比，这种“体重循环”进一步增加了代谢疾病的风险。研究小组开发了体重循环的小鼠模型，以揭示体重恢复的机制我们发现体重循环饮食诱导的肥胖（WC-DIO）动物具有额外的代谢疾病风险。与未进行体重循环的同等肥胖小鼠相比，葡萄糖耐量加快了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（在体内高血糖钳夹和前这一关键发现表明 β 细胞补偿未能完全适应。体重恢复引起的生理IR与第一次体重增加时的情况相同。细胞水平上，WC-DIO小鼠表现出非典型的β细胞线粒体形态和基因减少与线粒体自噬、氧化还原代谢和 TCA 循环调节相关的特征是。因此，线粒体的改变是正常营养刺激胰岛素分泌的基础。体重循环支持胰岛素分泌受损的机制也与线粒体功能不良有关。氧化还原控制被破坏，这会增加氧化应激并损害 β 细胞功能。 β 细胞促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 中增加胰岛和胰岛素分泌呈负相关，这些初步研究支持了这一点。由于对重复的营养超载的反应，β细胞在将代谢过程与胰岛素耦合方面效率较低中心假设是重复的营养超载会降低线粒体功能并诱发线粒体功能。 β 细胞氧化损伤 β 细胞对营养超负荷的适应能力丧失会损害胰岛素分泌。体内葡萄糖调节。该提案将： i) 确定线粒体功能是否由以下因素引起：重复的营养过剩是胰腺功能丧失的核心，ii) 检查 TXNIP 是否是造成这种情况的原因用于通过体重循环驱动氧化应激和胰腺功能丧失。测量分离胰岛的代谢通量率，将在体内施用 13C 标记的代谢物。使用成像质谱法对 β 细胞中的掺入进行定量。 TXNIP的特异性删除将用于确定氧化应激的减弱是否可以恢复胰岛素体内胰岛素分泌和胰岛素敏感性将使用经常确定的。取样静脉内葡萄糖耐量测试与葡萄糖示踪剂结合以量化离体胰岛。功能将在静态培养和灌注测定中确定，本文提出的实验将定义。体重循环将外周IR与胰腺胰岛素需求分开的方法，这将导致更好地了解胰腺适应过量营养的潜在机制。