Proof from a variety of research exposed that extra FFA consumption, glucocorticoid administration, obesity, and lack of bodily exercise are some of the im portant causations leading to insulin resistance. Plethora of studies employing broad variety of cultured cells, animal models and human subjects demonstrated ceramide since the crucial intermediate linking every one of these circumstances to insu lin resistance. Preliminary proof underpinning the purpose of cer amide in insulin resistance came in the direct applica tion of ceramide to isolated skeletal muscle tissue and cultured adipocytes. These studies indicate that ceramide inhibits insulin stimulated glucose uptake and glycogen synthesis. Greater delivery of saturated FA in extra of the tissues oxidative or storage capability is probably the major causes for insulin resistance.
Prolonged ex posure of palmitate to cultured myotubes, L6 skel etal muscle cells, three T3 L1 adipocytes and cardiac myocytes increases ceramide accumulation with simultaneous inhibition of Akt. Consistent with this particular, palmitate exposure also induced a reduction in glu cose uptake and glycogen synthesis. Subsequent scientific studies applying pharmacological knowing it inhibitors or smaller inter fering RNA to block the enzymes involved in ceramide biosynthesis, have demonstrated that ceramide is surely an obligate intermediate in saturated FA induced insu lin resistance. In agreement with this, overexpression of acid ceramidase as an alternative technique to cut back the ceramide level, negated the palmitate induced ceramide accumulation and enhanced insulin signaling.
Similarly, acute application of cer amide analogue to three T3 adipocytes mimicked the palmi tate induced insulin desensitizing effect. As talked about earlier, some groups also studied the purpose of saturated FA in insulin resistance applying animal designs, which includes substantial body fat fed mice, ob/ob mice, lipid infused rats, dexamethasone handled rats and ZDF rats. A short while ago, Frangioudakis selelck kinase inhibitor et al. demonstrated that mice fed with higher extra fat diet regime displays increased expres sion of ceramide synthase. Infusion of lipid emul sion in animal model has proven to improve muscle ceramide information and decrease peripheral insulin sensi tivity. These effects had been blocked through the use of SPT in hibitors, indicating the function of ceramide. Not too long ago, Holland et al. compared the impact of lard oil and soy oil on insulin sensitivity in rats.
They observed that the two of these treatment options decreased glucose uptake and Akt activation, but ceramide enhance was observed only with lard oil infusion. Similarly, various other scientific studies also could not uncover significant improve in ceramide in response to lipid supplementation, but an elevated DAG degree was observed. When very carefully examined, some of these scientific studies were found to use lipid rich in unsaturated FA, indicating that saturated fats and unsaturated fats have distinctive mechanisms of selling insulin resist ance, and ceramide plays a purpose only in insulin resistance induced by saturated fats.