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

未来 40 年，65 岁以上美国人的比例将急剧增加，这意味着他们中患有胰岛素抵抗和 2 型糖尿病的人数将达到惊人水平。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 AS160-蛋白磷酸酶 1α 相互作用升高以及 GS 位点 2 2a 磷酸化受损有关，而 GS 位点 2 2a 磷酸化受损则因 PDP1 调节受损而增强。这一假设是根据申请人实验室本科生收集的初步数据制定的。实验将包括原代人类骨骼肌细胞的机械细胞培养实验，以及使用人类骨骼肌活检和高胰岛素-正常血糖钳夹程序的临床实验。该项目的具体目标是： 1) 确定导致人类骨骼肌中胰岛素刺激的 AS160 磷酸化受损以及与老年人胰岛素抵抗敏感性相关的蛋白磷酸酶； 2) 确定老年人中胰岛素刺激的骨骼肌PDH去磷酸化（活性）受损以及与胰岛素抵抗相关的细胞机制； 3)确定老年人中胰岛素刺激的骨骼肌糖原合酶2 2a位点的去磷酸化是否受损并且与胰岛素抵抗相关。预计这些研究将揭示有关骨骼肌中导致与年龄相关的胰岛素抵抗的细胞机制的新见解，并在不久的将来为有针对性的有效治疗策略提供框架。它还将为学生提供接触转化生物医学研究的独特机会，以及将课堂上学到的代谢/生理学理论融入临床和实验室研究的机会。

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.