The Immune Protective Effects Of The Pioglitazone On The Liver, Pancreas And Muscular Of The Diabetic Rats

Background:Diabetes mellitus (DM)is one of the leading causes of morbidity andmortality in the general population,which is a syndrome characterized by its severecomplications that involve multiple organs,such as kidney,heart,liver,and so on.The pathogenesis of DM and the mechanism of its complications are still unclear.Recent studies revealed that immune and inflammatory responses might playimportant roles in it.Pioglitazone (Piog),one of Thiazolidinediones,is a kind ofselective activator of the peroxisome proliferators activated receptorγ(PPARγ)andcould be used as insulin sensitizer to control hyperglycaemia.It has also beenreported that Piog may have effects on modulating immune responses andinflammatory reaction which is independent upon the regulation of glycometabolismand lipometabolism.Moreover,Piog might be able to restrain the secretion ofinflammation factors such as interleukin 1 beta (IL-1β)and nuclear factor kappa B(NF-κB),which may inhibit or alleviate the chronic inflammation of the DM.Objective:The present investigation aimed at assess the effects of Piog on thefunction and structure of liver,pancreas and muscle of STZ-induced diabetic rats andcompare its effects with cyclosporin A (CsA),a immunomodulator,and insulin (INS).Consequently,it could provide evidences whether or not Piog has protective effectson preventing those immune damages of DM mediated by IL-1βand NF-κB.At last,it could provide the theoretical proofs for the usage of the Piog in clinic.Materials and methods:Ninety-six healthy male SD rats were randomly dividedinto DM group and healthy control group (H).After the diabetic rats were made byintravenous administration of STZ,they were randomized to low dose Piog group (A),low dose Piog plus INS group (B),large dose Piog group (C),CsA group (D),CsAplus INS group (E),INS group (F),and no therapy group (G),respectively.Theweight and blood glucose were tested routinely each month.Sixteen weeks later,allrats were sacrificed.Before that,the serum and 24h urine were obtained to measurethe hepatic function,renal function,triglyceride,insulin level and the urine albumin.Hematoxylin and Eosin Stain,Masson Stain,AZON Stain and Mallory PTAH Stainwere used to observe the microstructure changes of the liver,pancreas,and muscle of the rats in each group.Furthermore,the ultramicrostructure changes of the liver andmuscle were observed by transmission electronmicroscope.The deposition ofimmunoglobulins was detected by immunohistochemistry and immunofluorescence.At last,the expression of IL-1βand NF-κB mRNA and protein were examined byRT-PCR and immunohistochemistry,respectively.Result:The triglyceride,BUN and creatinine in serum and the protein in urine ofPiog interfering groups were close to those of Group H.In Group G,there were littleabnormality in liver.As pancreatic islets became smaller and lost their regular shape,the expression of the INS decreased.The muscular tissue atrophied and degeneratedtoo.The deposition of the Ig on each organ increased significantly,so did theexpression of IL-1βand NF-κB mRNA and protein.Both microstructure andultramicrostructure changes in liver,pancreas and muscle of Group C were close toGroup H,which were better than Group A and B and showed no significant differencewith Group D and E.Although the pancreatic islet volume of the group C decreased,theshape was relatively normal and the expression of the INS accessed to that of GroupD and E,which was better than Group A and B.In each Piog interfering group,thedeposition of the Ig in liver,pancreas,and muscle decreased apparently,especially inGroup C,which had no significant difference with Group D and E.The expression ofthe mRNA and protein of IL-1βand NF-κB in the liver,pancreas and muscle tissue ofPiog interfering groups decreased apparently,especially in Group C which was lowerthan Group A and B and showed no significant difference with Group D and E.Conclusion:There were multi-organ immune injuries in STZ-induced DM rats.Piogcould lower the blood triglyceride significantly and ameliorate the renal function ofthe DM rats.Large dose of Piog had the similar effect with immunodepressant CsA,which had obvious protective effects on liver,pancreas and muscle tissues of diabeticrats.The possible mechanisms of these immunoprotective effects might be reduction inthe deposition and/or the expression of immunoglobulins in the related organs andtissues,which followed by decrease in the expression and activity of the inflammatoryfactor,such as IL-1βand NF-κB.So,in these circumstances,inflammatory responsesin these tissues alleviated and the structure and function were preserved.For theabove reasons,Piog can be used not only as INS sensitizer but also as an immunomodulator for prevention immune damage on multi-organs in DM.