Insulin resistance due to lipid-induced signaling defects could be prevented by mahanine.
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.
Biswas
Anindita
A
Cellular and Molecular Endocrinology Laboratory, Department of Zoology, School of Life Science, Visva-Bharati (A Central University), Santiniketan, 731235, West Bengal, India.
Bhattacharya
Sushmita
S
Dasgupta
Suman
S
Kundu
Rakesh
R
Roy
Sib Sankar
SS
Pal
Bikas C
BC
Bhattacharya
Samir
S
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002227:Carbazoles / Q000302:isolation & purification / Q000494:pharmacology*; D006224:Cricetinae; D003847:Deoxyglucose / Q000493:pharmacokinetics; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D008647:Mesocricetus; D032101:Murraya / Q000737:chemistry; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D018515:Plant Leaves / Q000737:chemistry; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D001786:Blood Glucose; D002227:Carbazoles; D003847:Deoxyglucose; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011972:Receptor, Insulin; C000631434:Pdk1 protein, rat; C465290:mahanine