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。

• 批准号: 10661826
• 负责人: Stanley Andrisse
• 金额: $ 34.6万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 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/10661826
• 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; Genetic; 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; Movement; Mus; Muscle; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; PI3K/AKT; PIK3CG gene; 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; cardiometabolism; comorbidity; current pandemic; experimental study; fatty liver disease; glucose metabolism; glucose production; glycogenolysis; hepatic gluconeogenesis; hexokinase; insulin receptor tyrosine kinase; insulin signaling; male; mouse model; physical inactivity; protein kinase C epsilon; recruit; sugar; targeted treatment

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 分子与遗传学问题：脂质诱导的肝脏胰岛素抵抗是由于二酰甘油 （DAG）诱导的蛋白激酶C ε（PKCε）激活导致胰岛素受体酪氨酸抑制 激酶[4，5]。然而，非肥胖高雄激素（HA）雌性小鼠显示雄激素特异性肝细胞凋亡。 胰岛素抵抗表明非脂质依赖性致病机制[3]。此外，高果糖饮食 与高脂饮食（HFD）相比，高脂饮食（HFrD）显示出不同的胰岛素抵抗机制，其中高脂饮食（HFD）显示出不同的胰岛素抵抗机制。 果糖会损害葡萄糖激酶和糖原合成酶，但高脂肪会降低p-AKT [6]。酮己糖激酶（KHK，也 称为肝果糖激酶）是HFrD诱导的代谢功能障碍所必需的[7]。 总体目标是确定胰岛素抵抗的不同原因显示细胞之间的串扰， 分子和遗传机制。我将开发3种肝脏胰岛素抵抗小鼠模型：高胰岛素血症小鼠模型， 雄激素（HA）诱导的、HFD诱导的和HFrD诱导的。使用各种肝特异性敲除（KO）小鼠 消除某些途径的功能（雄激素受体（AR-KO）、己酮糖激酶（KHK-KO）和 蛋白激酶C（PKC-KO）），我将研究每一个独特的交叉致病机制， 三种胰岛素抵抗模型。 预期结果：我假设每种胰岛素抵抗模型（HA、HFD和HFrD）都包含其 拥有独特的机械方面与不同方面的串扰。因此，建议向 根据胰岛素抵抗的类型进行有针对性的治疗干预。

项目成果

Liver Androgen Receptor Knockout Improved High-fat Diet Induced Glucose Dysregulation in Female Mice But Not Male Mice.

肝脏雄激素受体敲除改善了高脂肪饮食引起的雌性小鼠的血糖失调，但雄性小鼠却没有。

• DOI: 10.1210/jendso/bvae021
• 发表时间: 2024
• 期刊: Journal of the Endocrine Society
• 影响因子: 4.1
• 作者: Osei-Ntansah,Adjoa;Oliver,Trinitee;Lofton,Taylor;Falzarano,Claire;Carr,Kiana;Huang,Ruthe;Wilson,Andre;Damaser,Ella;Harvey,Guyton;Rahman,MdAhasanur;Andrisse,Stanley
• 通讯作者: Andrisse,Stanley