Thursday, November 21, 2024
11/21/2024
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
