The cellular molecular regulation of differing mechanisms of insulin resistance.

胰岛素抵抗不同机制的细胞分子调节。

基本信息

批准号：
10531044
负责人：
Stanley Andrisse
金额：
$ 37.88万
依托单位：
HOWARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-10 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10531044
关键词：
Adult Affect Age Androgen Receptor Androgens Animal Model Blood Cardiovascular Diseases Cell Culture Techniques Cells Clinical Collaborations Complex Diet Diglycerides Disease Energy Metabolism Fatty acid glycerol esters Female Fructokinases Fructose Functional disorder Glucokinase Glucose Glycogen Glycogen (Starch) Synthase Hepatic High Fat Diet Impairment Insulin Insulin Resistance Intake Isotopes Ketohexokinase Knock-out Knockout Mice Lipids Liver Measurement Metabolic Metabolic dysfunction Metabolic syndrome Metabolism Minority-Serving Institution Modeling Molecular Molecular Genetics Movement Mus Muscle Non obese Non-Insulin-Dependent Diabetes Mellitus Obesity Outcome PI3K/AKT Pathogenesis Pathogenicity Pathway interactions Persons Physiology Play Polycystic Ovary Syndrome Prediabetes syndrome Process Production Protein Kinase C Proteins Proto-Oncogene Proteins c-akt Regimen Regulation Research Research Personnel Resistance Role Science Technology Testing Therapeutic Intervention Tissues Tracer Training Underrepresented Minority United States Weight Work androgen excess base cardiometabolism comorbidity experimental study fatty liver disease glucose metabolism glucose production glycogenolysis hepatic gluconeogenesis insulin receptor tyrosine kinase insulin signaling male mouse model pandemic disease physical inactivity protein kinase C epsilon recruit sugar targeted treatment

项目摘要

Project Summary Molecular & Genetic Problem: Lipid-induced hepatic insulin resistance is due to diacylglyceride (DAG)-induced protein kinase C epsilon (PKCε) activation leading to inhibition of insulin receptor tyrosine kinase [4, 5]. However, nonobese hyperandrogenic (HA) female mice displayed androgen-specific hepatic insulin resistance indicating a lipid-independent pathogenic mechanism [3]. Additionally, high fructose diets (HFrD) compared to high fat diets (HFD) display differing mechanisms of insulin resistance, where high fructose impairs glucokinase and glycogen synthase but high fat lowers p-AKT [6]. Ketohexokinase (KHK, also known as liver fructokinase) is required for HFrD-induced metabolic dysfunction [7]. The Overall Aim is to establish that differing causes of insulin resistance display crosstalk between cellular, molecular, and genetic mechanisms. I will develop 3 mouse models of hepatic insulin resistance: high androgen (HA)-induced, HFD-induced, and HFrD-induced. Using various hepatic specific knockout (KO) mice to eliminate the function of certain pathways (androgen receptor (AR-KO), ketohexokinase (KHK-KO), and protein kinase C (PKC-KO)), I will examine the intersecting pathogenic mechanisms unique to each of the three insulin resistant models. Expected Outcome: I hypothesize that each model of insulin resistance (HA, HFD, and HFrD) will contain its own unique mechanistic aspect with varying aspects of crosstalk. Thus, suggesting the movement towards targeted therapeutic interventions based on the type of insulin resistance.

项目摘要分子和遗传问题：脂质诱导的肝胰岛素耐药性是由于二酰基甘油酸酯引起的（DAG）诱导的蛋白激酶C epsilon（PKCε）活化导致胰岛素受体酪氨酸的抑制激酶[4，5]。但是，非肥胖过度雄激素（HA）雌性小鼠表现出雄激素特异性肝胰岛素抵抗表明与脂质无关的致病机制[3]。此外，果糖饮食高（HFRD）与高脂肪饮食（HFD）相比显示出不同的胰岛素耐药性机制，其中很高果糖会损害葡萄糖酶和糖原合酶，但高脂肪降低P-AKT [6]。 Ketohexokinase（KHK，也是 HFRD诱导的代谢功能障碍需要称为肝脏果因酶）[7]。总体目的是确定胰岛素抵抗的不同原因显示在细胞之间的串扰，分子和遗传机制。我将开发3种肝胰岛素抵抗的小鼠模型：高雄激素（HA）诱导，HFD诱导和HFRD诱导。使用各种肝特异性淘汰（KO）小鼠消除某些途径的功能（雄激素受体（AR-KO），Ketohexokinase（KHK-KO）和蛋白激酶C（PKC-KO）），我将检查每个与每种的相交的致病机制三个抗胰岛素耐药模型。预期结果：我假设每种胰岛素抵抗模型（HA，HFD和HFRD）将包含自己独特的机械方面，具有串扰的各个方面。那暗示着向基于胰岛素抵抗的类型的靶向治疗干预措施。