In the present study, we examined the effects of free fatty acids (FFAs) on insulin sensitivity and signaling cascades in the C2C12 skeletal muscle cell culture system. Our data clearly manifested that the inhibitory effects of PKC on insulin signaling may at least in part be explained by the serine/threonine phosphorylation of IRS-1. Both oleate and palmitate treatment were able to increase the Serine 307 phosphorylation of IRS-1. IRS-1 Serine 307 phosphorylation is inducible which causes the inhibition of IRS-1 tyrosine phosphorylation by either IκB-kinase (IKK) or c-jun N-terminal kinase (JNK) as seen in our proteomic kinases screen. Furthermore, our proteomic data have also manifested that the two FFAs activate the IKKα/β, the stress kinases S6 kinase p70 (p70SK), stress-activated protein kinase (SAPK), JNK, as well as p38 MAP kinase (p38MAPK). On the other hand, the antioxidant, Taurine at 10 mM concentrations was capable of reversing the oleate-induced insulin resistance in myocytes as manifested from the glucose uptake data. Our current data point out the importance of FFA-induced insulin resistance via multiple signaling mechanisms. KeywordsFree fatty acid (FFA); Insulin resistance (IR); Skeletal muscle cell (C2C12); Protein kinase C (PKC); Insulin receptor substrate-1 (IRS-1)

Insulin Resistance occurs as a result of disturbances in lipid metabolism and increased levels of circulating fatty acids that accumulate within the insulin sensitive tissues such as muscle, liver and adipose tissues. Increased fatty acid flux has been suggested to be strongly associated with insulin resistant states such as obesity and type 2-diabetes. Fatty acids appear to cause this defect in glucose transport by inhibiting insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and reducing IRS-1 associated phosphatidyl-inositol 3-kinase activity that implicate other insulin signaling components downstream of the insulin signaling cascade. A number of different metabolic abnormalities may increase intramyocellular or intrahepatic fatty acid metabolites that induce the disease state of insulin resistance through a number of different cellular mechanisms. The current review point out the link between enhanced FFA flux and activation of PKC and how it impacts on both the insulin signaling in muscle and liver. J ou rna l o f D ia be tes & M e ta bolism

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Considerable attention has been paid to the introduction of novel naturally occurring plant-derived radiosensitizer compounds in order to augment the radiation efficacy and improve the treatment outcome of different tumors. This study was therefore undertaken to evaluate the antitumor, antiangiogeneic, and synergistic radiosensitizing effects of apigenin, a dietary flavonoid, and/or cryptotanshinone, a terpenoid isolated from the roots of Salvia miltiorrhiza, against the growth of solid Ehrlich carcinoma in female mice. Apigenin (50 mg/kg body weight) and/or cryptotanshinone (40 mg/kg body weight) was intraperitoneally (i.p.) injected into non-irradiated or γ-irradiated (6.5 Gy whole-body γ-irradiation) solid Ehrlich carcinoma-bearing mice for 30 consecutive days. Investigations included molecular targets involved in proliferation, inflammation, angiogenesis, and tumor invasiveness. Treatment with apigenin and/or cryptotanshinone significantly suppressed the growth of solid Ehrlich carcinoma tumors and demonstrated a synergistic radiosensitizing efficacy together with γ-irradiation. These effects were achieved through downregulating the expression of angiogenic and lymphangiogenic regulators, including signal transducer and activator of transcription 3, vascular endothelial growth factor C, and tumor necrosis factor alpha, suppressing matrix metalloproteinase-2 and -9 activities, which play a key role in tumor invasion and metastasis, and enhancing apoptosis via inducing cleaved caspase-3 and granzyme B levels. Histological findings of solid Ehrlich carcinoma tumors verified the recorded data. In conclusion, a synergistic radiosensitizing efficacy for apigenin and cryptotanshinone was demonstrated against Ehrlich carcinoma in the current in vivo murine model, representing therefore a potential therapeutic strategy for increasing the radiation response of solid tumors.

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