权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanism of Defective Incretin Action in Beta Cells during Type 2 Diabetes Mellitus

2 型糖尿病期间 β 细胞中肠促胰岛素功能缺陷的机制

基本信息

批准号：
10619654
负责人：
Mehboob A Hussain
金额：
$ 48.35万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2021-07-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10619654
关键词：
ADRBK1 gene Ablation Acetylcholine Affect Alpha Cell Anti-Inflammatory Agents Beta Cell Binding Biochemical Cell physiology Cells Chemosensitization Chronic Circulation Coupled Cyclic AMP Diabetes Mellitus Electrophysiology (science)Endocrine Event Exocytosis Functional disorder G-Protein-Coupled Receptors GLP-I receptor GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Gastric Inhibitory Polypeptide Gene Expression Gene Expression Profile Genetic Transcription Glucose Glycerol Hormones Human In Vitro Inflammation Inflammatory Ingestion Inositol Insulin Interleukins Intestines Islet Cell Islets of Langerhans L Cells Ligands Link Macrophage Mediating Metabolism Molecular Mus Necrosis Neurotransmitters Nicotinic Receptors Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Outcome Pathway interactions Patients Peptide Receptor Peripheral Phosphorylation Phosphotransferases Physiological Proinsulin Property Receptor Signaling Regulation Resistance Role Serine Signal Pathway Signal Transduction Source Stimulus Structure of beta Cell of islet System TNF gene TNFRSF1A gene Tissues alpha-bungarotoxin receptor cholinergic cytokine diet-induced obesity glucagon-like peptide 1 glucose receptor glycemic control improved in vivo incretin hormone insight insulin secretion islet mouse model novel pharmacologic receptor recruit response signal recognition particle receptor translational impact tripolyphosphate tumor

项目摘要

PROJECT SUMMARY/ABSTRACT The incretin-mediated potentiation of glucose-stimulated insulin secretion (GSIS) accounts for 50% of postprandial insulin secretion and is essential for physiologic glycemic regulation. Upon nutrient stimulus, the two principal incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted, respectively, from intestinal endocrine K- and L-cells and reach β-cells via the circulation, where they bind their receptors, GIP receptor (GIPR) and GLP-1 receptor (GLP-1R) to amplify GSIS. While circulating incretin hormone levels are not impacted by T2DM, incretin effects on β-cell GSIS are significantly diminished in T2DM patients. However, the precise mechanisms underlying diabetes-associated blunting of incretin signaling in β-cells remain unclear. In T2DM, pharmacologic means to increase circulating GLP-1 levels improves GSIS and glycemic control. In contrast, the GIP-mediated incretin effect is notably absent in T2DM; and pharmacologic means to increase circulating GIP concentrations is not met with any GSIS improvement. The molecular mechanisms underlying diminished response to GLP-1 and absent response to GIP in T2DM remain poorly understood. T2DM is in part linked to a chronic inflammatory state with increased levels of local and circulating inflammatory cytokines that negatively impact insulin action in peripheral tissues and negatively impact the endocrine pancreas. We have therefore examined the role of pro-inflammatory cytokines that are elevated in T2DM on incretin signaling in islet -cells. Conversely, we have also interrogated the anti-inflammatory cholinergic signaling system through nicotinic acetylcholine receptors (nAchR) in modulating incretin signaling. Based on our preliminary studies, we hypothesize that TNFα - signaling through its receptor TNFR1 on β- cells - activates the Ser/Thr G-protein receptor kinase 2 (GKR2) in a non-canonical manner to suppress Gαs- activation and cAMP synthesis by ligand activated GIPR and by GLP-1R. Thus, our findings establish a mechanistic link between inflammatory cytokines in T2DM with diminished incretin signaling in β-cells. Our preliminary studies also indicate that in a murine model of T2DM, stimulating the α7 nicotinic acetylcholine receptor (α7-nAchR) reactivates GIPR signaling in β-cells to potentiate GSIS and improve glycemia. Our mechanistic studies indicate that α7-nAchR signaling phosphorylates (TNFα-activated) GRK2 at serine 670 to counteract its inhibitory effects on GIPR and GLP-1R-mediated cAMP synthesis. We now seek to expand our novel and exciting findings specifically a) to understand the role of TNFR1- GRK2-mediated signaling on in vivo β-cell function, on GIP and GLP-1R action as well as how TNFR1 signaling modulates α-cell gene expression in the context of obesity and T2DM; b) to specifically understand the role of GRK2 in mediating resistance to β-cell incretin action in T2DM; and c) to understand the beneficial role of anti- inflammatory α7-nAchR signaling in β-cells in the context of T2DM. We will use complementary in vivo and in vitro approaches to elucidate these important signaling pathways in β-cells using newly generated unique mouse models as well as in vitro in human islets and β-cells. The outcomes of our studies will yield important insights into how inflammatory cytokines of T2DM impact incretin signaling and β-cell function. Our proposed studies will also provide new insights into the effects of nicotinic acetylcholine signaling in β-cells. Finally, our studies identify potentially new receptor targets with the potential to ameliorate β-cell dysfunction in T2DM. .

项目总结/文摘