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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：
10222137
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/10222137
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 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.