Expression Levels of p21‐activated kinase (PAK1) in the Skeletal Muscle Exert Feedback to Influence Pancreatic β‐cell Functionality in vivo

Abstract

Skeletal muscle accounts for ~80% of insulin‐stimulated glucose uptake. The Group I p21–activated kinase 1 (PAK1) is required for the non‐canonical insulin‐stimulated GLUT4 vesicle translocation in skeletal muscle cells. We have recently found that the abundance of PAK1 protein and its downstream effector in muscle, p41‐ARC, are significantly reduced in the skeletal muscle of human type 2 diabetic (T2D) donors. While whole body PAK1 knockout (KO) mice exhibit glucose intolerance and are insulin resistant, it remains unknown as to the relative contribution by the skeletal muscle to this phenotype. As such, we developed an inducible skeletal muscle‐specific PAK1 KO mouse model, as well as an inducible skeletal muscle‐specific PAK1 overexpressor (OE) mouse model, to discern the requirement for PAK1 in skeletal muscle insulin sensitivity, and the molecular mechanisms involved. Indeed, our skeletal muscle‐specific PAK1‐KO and ‐OE mouse studies demonstrate a requirement and role for PAK1 in skeletal muscle insulin sensitivity. Moreover, overexpression of PAK1 in GLUT4‐myc‐L6 myoblasts conferred protection of insulin‐stimulated GLUT4 translocation under insulin resistant conditions. Unexpectedly however, the skeletal muscle‐specific PAK1‐KO and ‐OE mouse models showed impact upon pancreatic function, suggesting that PAK1 expression levels in the skeletal muscle triggered release of an agent that impacted pancreatic responsiveness to blood glucose levels. Testing this concept, conditioned media (CM) collected from PAK1‐overexpressing myotubes was applied to pancreatic β‐cells in culture. Remarkably, β‐cells treated with CM from PAK1‐overexpressing cells showed enhanced glucose‐stimulated insulin release, akin to that seen in the skeletal muscle‐specific PAK1‐OE mice; this enhancement response was selective to PAK1‐derived CM and was not seen with other CM types tested. Taken together, these data suggest that PAK1 levels in the skeletal muscle can exert feedback to the pancreatic β‐cells, unveiling a new molecular mechanism by which PAK1 regulates whole body insulin sensitivity and glucose homeostasis.Support or Funding InformationThis work was supported in part by grants to DCT from the NIH (DK102233, DK067912) and a gift from the Joel Katz fund.