Insulin Sensitizing Effects of Oligomannuronate-Chromium (III) Complexes in C2C12 Skeletal Muscle Cells

Abstract

BackgroundIt was known that the insulin resistance in skeletal muscle is a major pathogenic factor in diabetes mellitus. Therefore prevention of metabolic disorder caused by insulin resistance and improvement of insulin sensitivity are very important for the therapy of type 2 diabetes. In the present study, we investigated the ability of marine oligosaccharides oligomannuronate and its chromium (III) complexes from brown alga to enhance insulin sensitivity in C2C12 skeletal muscle cells.Methodology/Principal FindingsWe demonstrated that oligomannuronate, especially its chromium (III) complexes, enhanced insulin-stimulated glucose uptake and increased the mRNA expression of glucose transporter 4 (GLUT4) and insulin receptor (IR) after their internalization into C2C12 skeletal muscle cells. Additionally, oligosaccharides treatment also significantly enhanced the phosphorylation of proteins involved in both AMP activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathways in C2C12 cells, indicating that the oligosaccharides activated both the insulin signal pathway and AMPK pathways as their mode of action. Moreover, oligosaccharides distributed to the mitochondria after internalization into C2C12 cells and increased the expression of transcriptional regulator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), carnitine palmitoyl transferase-1 (CPT-1), and phosphorylated acetyl-CoA carboxylase (p-ACC), which suggested that the actions of these oligosaccharides might be associated with mitochondria through increasing energy expenditure. All of these effects of marine oligosaccharides were comparable to that of the established anti-diabetic drug, metformin. In addition, the treatment with oligosaccharides showed less toxicity than that of metformin.Conclusions/SignificanceOur findings indicate that oligomannuonate and its chromium (III) complexes improved insulin sensitivity in C2C12 skeletal muscle cells, and acted as a novel glucose uptake stimulator with low toxicity, and could be used as dietary supplementary or potential drug for type 2 diabetes mellitus.

Maternal Chromium Restriction Leads to Glucose Metabolism Imbalance in Mice Offspring through Insulin Signaling and Wnt Signaling Pathways

“…Our results showed that a 29-week chromium-restricted diet (CD-CR group) led to obesity and hyperglycemia in a mouse model. Previous studies revealed the key role of chromium as a blood glucose and lipid regulator [17,18]. Both in a diabetic rodent model and patients, chromium supplementation could improve glucose and lipid metabolism [11,19,20,21].…”

Effects of Icariin on insulin resistance via the activation of AMPK pathway in C2C12 mouse muscle cells

“…The insulin signaling pathway is initiated via activation of the insulin receptor by insulin (Kimura et al, 2014). Insulin binding to the insulin receptor initiates a cascade of intracellular signaling events, including receptor autophosphorylation and subsequent phosphorylation and/or activation of downstream signaling molecules such as IRS-1 and PI3K (Hao et al, 2011). In an insulin-resistant state, signal transduction is impaired and the activation of downstream targets such as IRS-1 decreases dramatically, resulting in inhibition of insulin signaling (Burén et al, 2003).…”

PGC-1α, glucose metabolism and type 2 diabetes mellitus

“…Several transcription factors and coactivators are implicated in PGC-1α-induced translocation and activation of GLUT4, either dependent on or independent of insulin, including AMPK (Jager et al 2007), SIRT1 , p38 MAPK (Wright 2007), ERR (Cho et al 2013), and PPARγ (Kang et al 2013). Specifically, some antidiabetic and antioxidative agents, such as lipoic acid, oligomannuronate, metformin and selenium-enriched exopolysaccharides, can improve skeletal muscle glucose uptake through AMPK/PGC-1α/GLUT4 pathway (Wang et al 2010, Hao et al 2011. Consistently, both ER stress and oxidative stress are reported to impair GLUT4 production and glucose uptake via a PGC-1α-dependent signaling pathway (Raciti et al 2010, Aoi et al 2013.…”