Skeletal muscle
insulin resistance is a major contributor to type-2 diabetes (T2D).
Pioglitazone is a potent
insulin sensitizer of peripheral tissues by targeting
peroxisome proliferator-activated receptor gamma.
Pioglitazone has been reported to protect skeletal muscle cells from lipotoxicity by promoting
fatty acid mobilization and
insulin signaling. However, it is unclear whether
pioglitazone increases
insulin sensitivity through changes in
protein-
protein interactions involving
protein phosphatase 2A (PP2A). PP2A regulates various cell signaling pathways such as
insulin signaling. Interaction of the catalytic subunit of PP2A (PP2Ac) with
protein partners is required for PP2A specificity and activity. Little is known about PP2Ac partners in primary human skeletal muscle cells derived from lean
insulin-sensitive (Lean) and obese
insulin-resistant (OIR) participants. We utilized a proteomics method to identify PP2Ac interaction partners in skeletal muscle cells derived from Lean and OIR participants, with or without
insulin and
pioglitazone treatments. In this study, 216 PP2Ac interaction partners were identified. Furthermore, 26 PP2Ac partners exhibited significant differences in their interaction with PP2Ac upon
insulin treatments between the two groups. Multiple pathways and molecular functions are significantly enriched for these 26 interaction partners, such as nonsense-mediated decay, metabolism of
RNA,
RNA binding, and protein binding. Interestingly,
pioglitazone restored some of these abnormalities. These results provide differential PP2Ac complexes in Lean and OIR in response to
insulin/
pioglitazone, which may help understand molecular mechanisms underpinning
insulin resistance and the
insulin-sensitizing effects of
pioglitazone treatments, providing multiple targets in various pathways to reverse
insulin resistance and prevent and/or manage T2D with less
drug side effects.