A Preliminary Study On The Role Of SIRT1 In Insulin Resistance Of Scleroderma Mice

Objective:36.4% of patients with scleroderma have insulin resistance [1],but the mechanism is unknown.Studies have confirmed that SIRT1 is closely related to insulin resistance [2],and SIRT1 is also involved in the pathogenesis of SSc.SIRT1 activator resveratrol can improve SSc skin and lung fibrosis [3,4].In this experiment,we observed the expression of SIRT1,TGF-?1,and ?-SMA in the pancreatic tissue of SSc mice to investigate the possible mechanism of SIRT1 insulin resistance in SSc mice.Methods:SPF BALB/C mice,6 weeks old,female,were randomly divided into 3 groups: control group(group A),scleroderma group(group B),and resveratrol group(group C).Subcutaneous injection of bleomycin was performed in group B and C to establish a scleroderma model.At the same time,group C was injected intraperiton-eally with 50 mg/kg resveratrol.Four weeks later,2.0 g/kg glucose was given to the stomach and tail vein blood was taken at 0,30,60,90,and 120 minutes to measure blood glucose in each group.Intestinal vein blood was taken to measure fasting insulin,then insulin resistance index(HOMA-IR)was calculated.Five weeks later,the mice were sacrificed.Then the skin at the injection site of the mice was cut and the abdominal cavity was opened to rapidly separate the pancreas.HE staining was used to observe the pathological changes of the skin and the skin thickness was measured.Hydroxyproline(HYP)kit measures the HYP content in the skin and pancreas.SIRT1 levels in skin and pancreas were measured by immunohistochem-istry.Western Blot was used to measure the expression of SIRT1,TGF-?1 and ?-SMA in the pancreas.Results:1.HE staining showed that the skin in group B was obviously thickened,collagen fibers increased,inflammatory cells infiltrated,adipose tissue decreased or even disappeared,HYP content increased significantly,suggesting successful modeling of scleroderma.The HYP content in the pancreatic tissue did not differ between the three groups.2.Compared with group A,abnormal glucose tolerance,elevated blood glucose,elevated insulin levels,and elevated HOMA-IR were observed in group B and C.Compared with group B,HOMA-IR decreased in group C,and the difference was statistically significant(P< 0.05).3.Immunohistochemistry showed that compared with group A,SIRT1 expression was down-regulated in skin and pancreatic tissue of group B;compared with group B,SIRT1 expression in skin and pancreas of group C was increased,and the difference was statistically significant(P< 0.05).4.Western Blot showed that compared with group A,the expression of SIRT1 was down-regulated in group B.Compared with group B,the expression of SIRT1 in group C was increased,and the difference was statistically significant(P<0.05).However,there was no significant difference in the expression of TGF-?1 and ?-SMA in the pancreas.Conclusion:1.Decrease in SIRT1 expression in pancreatic beta cells in scleroderma mice results in insulin resistance.2.After administration of resveratrol,the expression of SIRT1 was elevated and the degree of insulin resistance in mice was improved.3.SIRT1 may be a key regulator of insulin resistance in scleroderma.