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急剧增加，这意味着他们中有惊人数量的人将患有胰岛素抵抗和2型糖尿病。不幸的是，导致老年人这些代谢紊乱的细胞机制仍然未知。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AS 160-蛋白磷酸酶1α相互作用升高和GS位点2+2a磷酸化受损有关，这是由于PDP 1调节受损而增强的。这一假设是根据申请人实验室中本科生收集的初步数据制定的。实验将包括原代人骨骼肌细胞的机械细胞培养实验，以及使用人骨骼肌活检和高胰岛素-正葡萄糖钳夹程序的临床实验。本研究的具体目的是：1）确定负责人骨骼肌中胰岛素刺激的AS 160磷酸化受损的蛋白磷酸酶，以及与老年人胰岛素抵抗敏感性相关的蛋白磷酸酶; 2）确定负责胰岛素刺激的骨骼肌PDH去磷酸化受损的细胞机制（活性）并与胰岛素抵抗相关; 3）确定胰岛素刺激的骨骼肌糖原合酶在位点2+2a上的去磷酸化在老年个体中是否受损并与胰岛素抵抗相关。预计这些研究将揭示有关骨骼肌中导致年龄相关胰岛素抵抗的细胞机制的新见解，并在不久的将来为靶向和有效的治疗策略提供框架。它还将为学生提供一个独特的机会，接触到转化生物医学研究，并有机会将在课堂上学到的代谢/生理学理论纳入临床和台式研究。

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.