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.