Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.2 (PDK1)
 2,238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is known that free fatty acid (FFA) contributes to the development of insulin resistance and type2 diabetes. However, the underlying mechanism in FFA-induced insulin resistance is still unclear. In the present investigation we have demonstrated that palmitate significantly (p <0.001) inhibited insulin-stimulated phosphorylation of PDK1, the key insulin signaling molecule. Consequently, PDK1 phosphorylation of plasma membrane bound PKCepsilon was also inhibited. Surprisingly, phosphorylation of cytosolic PKCepsilon was greatly stimulated by palmitate; this was then translocated to the nuclear region and associated with the inhibition of insulin receptor (IR) gene transcription. A PKCepsilon translocation inhibitor peptide, epsilonV1, suppressed this inhibitory effect of palmitate, suggesting requirement of phospho-PKCepsilon migration to implement palmitate effect. Experimental evidences indicate that phospho-PKCepsilon adversely affected HMGA1. Since HMGA1 regulates IR promoter activity, expression of IR gene was impaired causing reduction of IR on cell surface and that compromises with insulin sensitivity.
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PMID:Fatty acid represses insulin receptor gene expression by impairing HMGA1 through protein kinase Cepsilon. 1743 41

It is well known that free fatty acids (FFAs) play a key role in implementing insulin resistance and type 2 diabetes. Resources of chemical compounds that intervene the derogatory effect of FFAs are indeed very limited. We have isolated mahanine, a carbazole alkaloid, from the leaves of Murraya koenegii that prevented palmitate-induced inhibition of insulin-stimulated phosphorylation of IRbeta, PI3K, PDK1, and Akt in L6 myotubes. This was also reflected in the palmitate-induced inhibition of insulin-stimulated [(3)H] 2-DOG uptake by L6 myotubes, where palmitate adverse effect was significantly blocked by mahanine. Previous reports indicated that one of the major targets of lipid-induced damage in insulin signaling pathway resulting impairment of insulin sensitivity is insulin receptor (IR). Here, we have observed that palmitate significantly increased pPKCepsilon in both cytosol and nuclear region of L6 myotubes in comparison to control. Translocation of pPKCepsilon to the nucleus was associated with the impairment of HMGA1, the architectural transcription factor of IR gene and all these were reversed by mahanine. Palmitate-induced activation of IKK/IkappaBeta/NF-kappaBeta pathway was also attenuated by mahanine. Taken together, mahanine showed encouraging possibility to deal with lipid induced insulin resistance. In order to examine it further, mahanine was administered on nutritionally induced type 2 diabetic golden hamsters; it significantly improved hyperglycemia in all the treated animals. Our results, therefore, suggest that mahanine acts on two important sites of lipid induced insulin resistance (i) impairment of IR gene expression and (ii) activation of NF-kappaBeta pathway, thus, showing promise for its therapeutic choice for type 2 diabetes.
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PMID:Insulin resistance due to lipid-induced signaling defects could be prevented by mahanine. 1982 69