| Background:Diabetes mellitus is one of the commonest chronic diseases, characterized by its chronic complications in which a variety of organs could be involved. The pathogenesis of diabetes and its complications remains unclear up till now. Recent studies have revealed that autoimmune response and inflammation might play an important role in the pathogenesis. By biopsy, we have found the deposition of immunoglobulin complexes on the skin, kidneys and skeletal muscle in many patients with T2DM, especially those with pretibial patches. Our previous studies demonstrated that the deposition of immunoglobulins was remarkably increased on various organs of diabetic rats and cardiovascular complications of diabetes could be prevented by the administration of cyclosporine A(CsA). Recently, more and more studies indicate Thiazolidinediones (TZDs) which are currently believed to be the selective activator of the peroxisome proliferators activated receptor y (PPARy) have immunoregulatory effect. But there is no report about weather TZDs can suppress abnormal immune responses in the chronic complications of diabetes and weather they improve total body insulin sensitivity by the way of inhibiting the deposition of immunoglobulins on muscle cells.Objective:To investigate the effects of pioglitazone(PIO) at various dosage on the pathology and ultrastructure of the aorta, heart and skeletal muscle of STZ-induced diabetic rats, as well as the deposition of immunoglobulins and the protein and mRNA expression of MCP-1 and TNF-αin the same organs. To evaluate the protective effects of PIO against the multi-organ immune injuries of diabetes. In addition, to find whether there is a correlation the depositon of immunoglobulins between heart and skeletal muscle.Materials and methods:The DM rat models were made by intravenous injection of STZ. Then, they were randomly divided into seven groups, including low-dose PIO group (group PIL,4mg/kg/d), low-dose PIO combined with glargine group (group PII, PIO 4mg/kg/d and glargine 4U//kg/d), high-dose PIO group (group PIH,20mg/kg/d), CsA group (group CSA, 1mg/kg/d), CsA combined with glargine group(groupCSI, CsA 1mg/kg/d and glargine 4U//kg/d), glargine group(group INS, glargine 4U//kg/d) and no-intervention group(group DMm). Another group of normal rats (group CON) was also monitored simultaneously. Sixteen weeks later, all rats were sacrificed. The blood and the urine was obtained to test blood glucose, serous triglyceride, hepatic and renal function, and urine albumin. The hematoxylin and eosin Stain and Masson Stain were carried out to observe the pathological and the ultramicrostructural changes of the aorta, heart, and muscle of the rats in different groups. At the same time, the deposition of immunoglobulins was investigated by immunohistochemistry to show immunofluorescence. The protein and mRNA expressions of MCP-1 and TNF-αwere also studied via immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR).Result:1. The STZ-induced DM rat model were successfully established; 2. Serous triglyceride could be significantly decreased by PIO while kidney function was improved; 3. In diabetic rats with on intervention, interstitial fibrosis was clearly demonstrated along with obvious lymphocyte infiltration in the aortas and hearts, meanwhile, widespread myatrophy was also detected. However, the injuries of the aorta, heart and muscle were significantly alleviated by the intervention of PIO and CsA; 4. A significant positive correlation was found between the depositon of immunoglobulins on heart and that on skeletal muscle. The deposition of immunoglobulins on the aorta, heart and muscle tissue was significantly reduced by the intervention of PIO or CsA, moreover, high dose PIO and CsA had the proximate effect on the deposition of immunoglobulins; 5. Intervention with PIO could inhibit the protein and mRNA expressions of MCP-1 and TNF-αin the aorta, heart and muscle tissue of diabetic rats, moreover, high dose PIO and CsA had the proximate effect on the expressions of MCP-1 and TNF-α.Conclusion:STZ-induced DM rats had multi-organ immune injuries. PIO had a protective effect, which was correlated with some factors besides the regulation of glycometabolism, on the immune injuries of diabetic aorta, heart and muscle tissue. The possible mechanisim might be by reducing the deposition of immunoglobulins and inhibiting the expressions of MCP-1 and TNF-α, and thus, suppressing the immunological and inflammatory responses in the injuried organs. In addition, there was a correlation the depositon of immunoglobulins between heart and skeletal muscle, suggesting that the immune injuries of some organs whose living tissue was difficult to get (such as heart) could be decided indirectly by muscular biopsy.
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