Mechanisms of Age-Related Impairments in Human Skeletal Muscle Glucose Metabolism

在接下来的40年里，65岁以上的美国人的比例将大幅增加，这意味着他们中将有数量惊人的人患有胰岛素抵抗和2型糖尿病。不幸的是，导致老年人代谢紊乱的细胞机制仍不清楚。这项研究的长期目标是确定骨骼肌中导致胰岛素抵抗的细胞机制，以便开发有效的治疗方法。该项目的中心假设是，老年人的胰岛素抵抗与骨骼肌AS160-蛋白磷酸酶1α相互作用的增加和GS位点2 2a的磷酸化障碍有关，由于PDP1调节的障碍而增强。这一假设是基于在申请人的实验室与本科生收集的初步数据而形成的。实验将包括原代人类骨骼肌细胞的机械性细胞培养实验，以及使用人类骨骼肌活组织检查和高胰岛素-正常血糖钳夹程序的临床实验。本项目的具体目的是：1)确定导致老年人胰岛素刺激的骨骼肌AS160磷酸化受损并与胰岛素抵抗敏感性相关的蛋白磷酸酶；2)确定导致老年人胰岛素刺激的骨骼肌磷酸氢脱氢酶去磷酸化受损并与胰岛素抵抗相关的细胞机制(S)；3)确定老年人中是否存在胰岛素刺激的骨骼肌糖原合成酶2 2a位的去磷酸化受损并与胰岛素抵抗有关。预计这些研究将揭示骨骼肌中导致年龄相关胰岛素抵抗的细胞机制的新见解，并为在不久的将来制定有针对性的有效治疗策略提供框架。它还将为学生提供一个独特的机会，让他们接触到转化性的生物医学研究，并有机会将课堂上学到的新陈代谢/生理学理论融入临床和桌面研究。

Over the next 40 years the percentage of Americans over the age of 65 will dramatically increase meaning an alarming number of them will be suffering from insulin resistance and type 2 diabetes. Unfortunately, the cellular mechanisms that contribute to these metabolic disturbances in older adults remain unknown. The long-term objective of this research is to identify cellular mechanisms in skeletal muscle that contribute to insulin resistance, so that effective treatments can be developed. The central hypothesis of this project is that insulin resistance in older adults is related to elevated skeletal muscle AS160-Protein Phosphatase 1α interaction and impairments in phosphorylation of GS site 2+2a, which are enhanced due to impairments in PDP1 regulation. This hypothesis has been formulated based on preliminary data collected with undergraduate students in the applicant’s laboratory. Experiments will include mechanistic cell culture experiments in primary human skeletal muscle cells, as well as, clinical experiments using human skeletal muscle biopsies and hyperinsulinemic-euglycemic clamp procedures. The specific aims of this project are to: 1) determine the protein phosphatase responsible for impaired insulin-stimulated AS160 phosphorylation in human skeletal muscle and related to insulin resistance sensitivity in aged adults; 2) determine the cellular mechanism(s) responsible for impaired insulin-stimulated skeletal muscle PDH dephosphorylation (activity) in aged individuals and associated with insulin resistance; 3) determine if insulin-stimulated dephosphorylation of skeletal muscle glycogen synthase on sites 2+2a is impaired in aged individuals and related to insulin resistance. It is anticipated these studies will reveal new insights regarding the cellular mechanisms in skeletal muscle that contribute to age-related insulin resistance, and provide the framework for targeted and efficient treatment strategies in the near future. It will also provide a unique opportunity for students to be exposed to translational biomedical research, and the opportunity to incorporate metabolism/physiology theories learned in the classroom to clinical and benchtop research.