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Role of pH-mediated metabolic reprogramming in β cell failure in Type 2 Diabetes Mellitus

pH 介导的代谢重编程在 2 型糖尿病β细胞衰竭中的作用

基本信息

批准号：
10381680
负责人：
ALEKSEY V MATVEYENKO
金额：
$ 39.75万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10381680
关键词：
Acids Address Alkalinization Animal Model Attenuated Autopsy Beta Cell Bicarbonates Buffers Cell physiology Cells Characteristics Collection Complex Coupled Coupling Data Development Diabetes Mellitus Disease Progression Endoplasmic Reticulum Environment Etiology Exposure to Failure Family Fasting Functional disorder Generations Genes Genetic Genetic Transcription Genotype Glucose Goals Health Healthcare Systems Homeostasis Human Hyperglycemia Impairment In Vitro Insulin Insulin Resistance Ion Pumps Ions Longevity MAPK8 gene Mediating Metabolic Metabolic stress Metabolism Mitochondria Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Pancreas Patients Persons Pharmacology Phenotype Physiological Prediabetes syndrome Prevalence Prevention strategy Production Proteins Regulation Rodent Role Structure of beta Cell of islet Testing Transcriptional Regulation base blood glucose regulation cancer cell combat diabetogenic extracellular functional decline gain of function glucose metabolism glucose tolerance glucose uptake improved in vivo insulin secretion islet loss of function mitochondrial metabolism novel novel therapeutic intervention obese patients oxidation pH gradient pluripotency preservation response stressor therapeutic evaluation tool transcriptomics treatment strategy

项目摘要

Type 2 diabetes mellitus (T2DM) manifests through the development of fasting and postprandial hyperglycemia the etiology of which can be distilled to failure of pancreatic β cells to maintain appropriate glucose-stimulated insulin secretion (i.e. β cell function) to compensate for the decline in insulin action (i.e. insulin resistance). Thus preservation of β cell function has been identified as a critical barrier for the development of successful preventative and treatment strategies to combat the rise in T2DM prevalence. Studies suggest that β cell dysfunction in T2DM is associated with metabolic reprogramming/shift toward increased non-oxidative glucose metabolism and reduced mitochondrial function similar to an adaptive features observed in cancer cells. Accordingly, cancer cells facilitate increased glycolytic flux and subsequent rise in metabolic acid production by upregulating expression of ion pumps/transporters that enhance cellular buffering capacity and promote cellular alkalinization (increased pHi), such as SLC4 family of bicarbonate transporters. Although, previous studies have confirmed importance of pHi for proper β cell functionality, it is unknown whether intracellular alkalinization or increased pHi buffering contributes to β cell functional decline in T2DM. Thus, the key objective of the current proposal is to test the hypothesis that aberrant induction of a novel T2DM gene SLC4A4 and its protein product (electrogenic Na+-coupled HCO3- cotransporter, NBCe1) in β cells contributes to β cell functional decline in T2DM. To address this hypothesis, Specific Aim 1 will 1) perform detailed examination of SLC4A4/NBCe1 expression using our unique collection of autopsy-derived human pancreas from patients with obesity, pre-diabetes and T2DM and 2) elucidate molecular mechanisms mediating aberrant β cell induction of SLC4A4/NBCe1 in response to diabetogenic stressors. Specific Aim 2 will utilize novel genetic gain-of-function tools to test the hypothesis that intracellular alkalinization mediated by increased β cell expression of SLC4A4/NBCe1 leads to β cell functional failure through impairment of mitochondrial metabolism and function. Finally, Specific aim 3 will utilize novel genetic loss-of-function animal models and T2DM human islets to test therapeutic potential of inhibiting SLC4A4/NBCe1 expression/activity in β cells as means to attenuate β cell failure and improve overall glucose metabolism under diabetogenic conditions. The current project will uncover novel molecular/physiological mechanisms underlying induction of β cell dysfunction and test a potentially novel therapeutic strategy to attenuate of β cell failure in T2DM.

2型糖尿病(T2 DM)表现为空腹和餐后高血糖，其病因可归结为胰腺β细胞不能维持适当的葡萄糖刺激的胰岛素分泌(即β细胞功能)来补偿胰岛素作用的下降(即胰岛素抵抗)。因此，β细胞功能的保存被认为是制定成功的预防和治疗策略以对抗T2 DM患病率上升的关键障碍。研究表明，T2 DM的β细胞功能障碍与代谢重编程/向非氧化葡萄糖代谢增加和线粒体功能降低有关，类似于在癌细胞中观察到的适应性特征。因此，癌细胞通过上调离子泵/转运体的表达来促进糖酵解通量的增加和随后代谢酸产量的增加，这些离子泵/转运体增强了细胞的缓冲能力，并促进了细胞的碱化(增加的PHI)，例如SLC4家族的碳酸氢盐转运体。尽管之前的研究已经证实了phi对正常的β细胞功能的重要性，但尚不清楚细胞内碱化或phi缓冲增加是否导致T2 DM的β细胞功能下降。因此，本研究的主要目的是验证一种新的T2 DM基因SLC4A4及其蛋白产物在β细胞中的异常诱导导致T2 DM时β细胞功能下降的假说。为了解决这一假设，特定的目标将1)使用我们独特的从肥胖症、糖尿病前期和T2 DM患者的尸检获取的人胰腺标本对SLC4A4/NBCe1的表达进行详细的检查，以及2)阐明介导异常的分子机制糖尿病应激源诱导SLC4A4/NBCe1细胞β特定目的2将利用新的遗传功能获得工具来检验这一假说，即通过增加β细胞SLC4A4/NBCE1的表达而介导的细胞内碱化通过损害线粒体代谢和功能而导致β细胞功能衰竭。最后，特殊目标3将利用新的遗传功能丧失动物模型和T2 DM人胰岛来测试抑制β细胞中SLC4A4/NBCE1表达/活性的治疗潜力，以此作为减轻β细胞衰竭和改善糖尿病条件下整体糖代谢的手段。目前的项目将揭示诱导β细胞功能障碍和测试一种潜在的新的治疗策略来减轻T2 DM患者的β细胞衰竭。