Abstract
Sarcopoterium spinosum (S. spinosum) is a medicinal plant, traditionally used as an antidiabetic remedy. Previous studies demonstrated its beneficial properties in the treatment of insulin resistance. The aim of this study was to further clarify the effect of S. spinosum extract (SSE) on insulin signaling. Phosphoproteomic analysis, performed in 3T3-L1 adipocytes treated with SSE, revealed the activation of insulin receptor pathways. SSE increased Glut4-facilitated glucose uptake in adipocytes, with an additive effect between SSE and insulin. While the maximal effect of insulin on glucose uptake was found at days 15–16 of differentiation, SSE-induced glucose uptake was found at an earlier stage of differentiation. Inhibition of PI3K and Akt blocked SSE-dependent glucose uptake. Western blot analysis, performed on 3T3-L1 adipocytes and L6 myotubes, showed that in contrast to insulin action, Akt was only marginally phosphorylated by SSE. Furthermore, GSK3β and PRAS40 phosphorylation as well as glucose uptake were increased by the extract. SSE also induced the phosphorylation of ERK similar to insulin. In conclusion, SSE activates insulin signaling, although the upstream event mediating its effects should be further clarified. Identifying the active molecules in SSE may lead to the development of new agents for the treatment of insulin resistance.
Highlights
The number of approved anti-diabetic medications is growing, the goal of treatment, which is maintaining a HbA1C of ≤7% remains difficult to achieve [1,2].Type 2 diabetes mellitus (T2DM) is a disease characterized by an impaired insulin action, and is considered one of the major causes for illness and premature death, which results from severe complications of the disease [3,4]
We previously found that while S. spinosum induction failed to induce Akt phosphorylation on ser473, which is known to be an important signaling event required for GLUT4 translocation and glucose transport [33], this kinase was found to be translocated to the membrane and nucleus
In order to support our previous studies demonstrating the anti-diabetic properties of spinosum extract (SSE), and to further clarify its mechanism of action, a hypothesis-free, high throughput approach for global quantification of the phospho-proteome induced by S. spinosum was employed
Summary
Type 2 diabetes mellitus (T2DM) is a disease characterized by an impaired insulin action, and is considered one of the major causes for illness and premature death, which results from severe complications of the disease [3,4]. These startling statistics illustrate the inability of current anti-diabetes drugs to retard disease progression and the continued need for further research and development of alternative drugs with novel mechanisms to slow disease progression and complications. Insulin binding to its receptor induces auto-phosphorylation of the receptor, leading to a subsequent recruitment of docking proteins and phosphorylation of various downstream substrates This cascade leads to the activation of at least two parallel pathways: the PI3K-Akt and the MAPK pathway. PI3K increases the levels of phosphatidyl-inositol (3,4,5)-triphosphate (PIP3), enabling the binding of Akt and PDK1, both possessing PH (pleckstrin homology) domains, to the membrane [5,6,7,8]
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