Mechanisms by which smoothelin-like protein 1 reverses insulin resistance in myotubules and mice

Mol Cell Endocrinol. 2022 Jul 1;551:111663. doi: 10.1016/j.mce.2022.111663. Epub 2022 May 1.


Insulin resistance (InR) is manifested in skeletal muscle by decreased insulin-stimulated glucose uptake due to impaired insulin signaling and multiple post-receptor intracellular defects. Chronic glucose-induced insulin resistance leads to the activation of Ser/Thr kinases and elevated phosphorylation of insulin receptor substrate 1 (IRS1) on Ser residues. Phosphorylation of IRS1 triggers the dissociation of IRS1 and its downstream effector, phosphatidylinositol 3-kinase. In the present study, we provide evidence for the insulin-sensitizing role of smoothelin-like protein 1 (SMTNL1) that is a ligand-dependent co-regulator of steroid receptors, predominantly the progesterone receptor. SMTNL1 was transiently overexpressed in insulin-resistant C2C12 myotubes. A proteome profiler array revealed that mTOR and Ser/Thr kinases were SMTNL1-dependent signaling pathways. In the presence of progesterone, overexpression was coupled to decreased Ser phosphorylation of IRS1 at Ser307, Ser318, and Ser612 residues. SMTNL1 also induced the expression and activity of the p85 subunit of PI3K. SMTNL1 regulated the expression of PKCε, which phosphorylates IRS1 at Ser318 residue. SMTNL1 also regulated ERK1/2 and JNK, which phosphorylate IRS1 at Ser612 and Ser307, respectively. Real-time metabolic measurements of oxygen consumption rate and extracellular acidification rate revealed that SMTNL1 improved glycolysis and promoted the utilization of alternative carbon fuels. SMTNL1 also rescued the mitochondrial respiration defect induced by chronic insulin exposure. Collectively, SMTNL1 plays a crucial role in maintaining the physiological ratio of Tyr/Ser IRS1 phosphorylation and attenuates the insulin-signaling cascade that contributes to impaired glucose disposal, which makes it a potential therapeutic target for improving InR.

Keywords: Insulin receptor substrate-1; Insulin resistance; Insulin signaling; Phosphorylation; Pregnancy; Skeletal muscle metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Glucose / metabolism
  • Insulin / metabolism
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin Resistance* / physiology
  • Mice
  • Muscle Proteins / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / metabolism*
  • Phosphorylation


  • Insulin
  • Insulin Receptor Substrate Proteins
  • Muscle Proteins
  • Phosphoproteins
  • SMTNL1 protein, mouse
  • Glucose