Hyaluronan as a mediator of intrauterine growth restriction-induced islet dysfunction in type 2 diabetes

透明质酸作为 2 型糖尿病宫内生长受限诱导的胰岛功能障碍的介质

• 批准号: 10630158
• 负责人: Cetewayo Saif Rashid
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-23 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630158
• 关键词: Accounting; Actins; Address; Adipose tissue; Adult; Affect; Age; Age Months; American; Animal Model; Appalachian Region; Applications Grants; Arteries; Beta Cell; Binding; Blood capillaries; CD44 Antigens; CD44 gene; Cell Culture Techniques; Cell Proliferation; Cell physiology; Cells; Clinical Research; Communities; Cytoskeleton; Data; Disparity; Distress; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Etiology; Extracellular Matrix; F-Actin; Family; Fetal Growth Retardation; Fetus; Flow Cytometry; Functional disorder; Future; GTP-Binding Proteins; Genes; Glucose; Glycosaminoglycans; Goals; Growth; HAS2 gene; HMMR gene; Human; Hyaluronan; Hyaluronidase; Immunohistochemistry; Impairment; In Vitro; Incidence; Individual; Inflammation; Insulin Resistance; Intervention; Islet Cell; Knowledge; Leukocytes; Ligation; Low Birth Weight Infant; Mediating; Mediator; Modeling; Molecular; Molecular Weight; Monomeric GTP-Binding Proteins; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; PTPRC gene; Peripheral; Population; Potassium; Prediabetes syndrome; Pregnancy; Primary Cell Cultures; Rattus; Regulation; Reporting; Research; Rest; Risk; Risk Factors; Role; Serum; Signal Pathway; Testing; Tissues; Uterus; Vulnerable Populations; Weaning; angiogenesis; cell type; density; epidemiology study; ethnic minority; gel electrophoresis; human tissue; improved; insulin secretion; insulin sensitivity; islet; offspring; pharmacologic; pregnant; protein activation; response; rho; transcriptome

PROJECT SUMMARY Type 2 diabetes (T2D) burden rests disproportionately on ethnic minorities and economically distressed Appalachian communities. These populations also have high rates of low birth weight (LBW), which itself is an independent risk factor for T2D. One major cause of LBW is uteroplacental insufficiency and subsequent intrauterine growth restriction (IUGR). We model uteroplacental insufficiency in late gestation pregnant rats by ligating the uterine arteries. The growth-restricted offspring display diminished glucose-stimulated insulin secretion (GSIS), reduced islet capillary density, and decreased β-cell proliferation. We recently sequenced the IUGR islet transcriptome at 2 weeks of age, revealing increased expression of Hyaluronan Synthase 2 (Has2), which makes the extracellular matrix glycosaminoglycan hyaluronan (HA), and Cd44, the principal HA receptor. HA has size-dependent opposing effects on angiogenesis and inflammation, with native high molecular weight (HMW) HA being inhibitory and its enzymatic or oxidative fragmentation to LMW-HA being activating. Previous studies show increased HA in serum and adipose tissue of humans with T2D, and attenuating HA levels or CD44 activity improves insulin sensitivity. Studies have yet to quantify islet HA in T2D despite evidence that HA and HA-binding proteins are normal islet components and HA levels are altered in T2D. To determine whether HA contributes to IUGR-mediated islet dysfunction, we will determine HA abundance, size, and cell type-specific interactions. There is a paucity of research regarding effects of HA on β-cell function. However, HA modulates actin cytoskeleton dynamics via regulation of monomeric G-proteins in a variety of cell types, which if occurring in β-cells, can have profound effects on GSIS. Taken together, I hypothesize that HA abundance and size distribution are altered in IUGR islets, and HA size-specifically modulates GSIS in vitro. The goal of Specific Aim 1 is to determine whether IUGR alters abundance, size distribution and cell type-specific binding of HA in islets. The goal of Specific Aim 2 is to determine whether HA size-specifically alters GSIS in vitro via modulation of monomeric G-proteins and associated actin dynamics. In a move toward an interventional approach, we will examine whether pharmacological modulation of HA content normalizes GSIS in IUGR islets ex vivo. Successful completion of the proposed studies will fill a key knowledge gap regarding changes in islet- associated HA in T2D and provide strong evidence that HA negatively impacts β-cell function. These data will provide rationale and demonstrate feasibility for my future R01 grant application investigating an etiological role for HA in IUGR-mediated T2D.

项目总结