| Objective:Insulin resistance (IR) is the key cause of many metabolic disorders diseases, including metabolic syndrome (MS) and diabetes mellitus (DM), moreover, it is always been throughout the process of these diseases. Diabetic nephropathy is not only a kind of diabetic complication, but also is an important factor in the development of end-stage renal disease (ESRD) and renal failure, which leads to death. Researches show that IR can been prevented and treated before IR not really develop diabetes or diabetic nephropathy in the irreversible stage by scientific and effective intervention means. So this research will establish an IR status mouse kidney damage model, then study the improve mechanisms of interventions on insulin resistance in kidney damage by applying different ways of interventions including differrent types of exercise, MSTN antibody treatment, and two joint interventions. Then analyze the results after the intervention, in order to explore an preventive and therapeutic way of insulin resistance and kidney injury and provide a reference for clinical prevention and treatment of diabetic nephropathy and its related diseases.Results:1. After the end of 12w high fat diet induced rat model, oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) The test results show that, HF group than in NC rats in glucose and insulin there was a significant difference (P<0.05), HF rats showed blood sugar regulation there is a "slow" phenomenon on the response sensitivity, in addition, on the 24h urine protein test results show that rats, HF group urinary protein began to appear higher than NC group 8w modeling trends in the first period, and in the 10th week, showing the difference P<0.01 is very significant, and finally through the OGTT test, ITT tests and 24h urine protein these three test results, the success of a comprehensive assessment of insulin resistance in rats kidney damage model.2. After the adoption of the intervention groups (HML group, HA group, HM group, HML+A group and HML+M group) 8w intervention period ends, HML+A group and HML+M group than in HF rats in grip, weight, retroperitoneal fat weight, and gastrocnemius weight have significantly improved trend, and between groups was significant difference (P<0.01), while the rats in Lee’s index, the weight of the soleus muscle and pancreatic weight intervention there was a significant difference in the results are not, in addition, a single factor in the intervention group (HML group, HA group and HM group) than HF group rats body weight, grip, retroperitoneal fat weight, the weight of the quadriceps, the gastrocnemius weight, and despite the weight of the pancreas improved to some extent, but on the overall degree of improvement, but not as good as joint intervention group was significantly less; by rats weighing both kidneys, the kidney hypertrophy index calculation and comparison between groups, the results show HF rats renal hypertrophy degree and kidney weights of rats were higher than other groups, and there was a significant difference (P<0.05).3. The test results showed that serum levels of indicators, HF serum levels of HDL-c content is less than the other groups, and there was a significant difference (P <0.05); and in serum LDL-c, CHO, the content of the FFA and CK, HF was generally higher than the other groups, which, HF group and NC group, HA group on the serum LDL-c content, showing a significant difference (P<0.05), HF group and HML group, HML+M group, HML+serum of rats in group A compared to CHO content, there was a significant difference (P<0.05), serum FFA and CK additional content, only NC group, HML group and HA group in serum FFA There was a significant difference (P <0.05), while the rest of the rats on serum CK content, not differences differences (P> 0.05).4. Rats kidneys tissue sections, and by HE staining, PAS staining and Masson staining showed that, out of the kidney HF group showed lesions glomerulonephritis phenomenon can be observed under the microscope glomerular severe thickening of the basement membrane, vascular loop blurred, glomerular zone appears visceral epithelial arid parietal epithelial adhesion and immune cell infiltration, and between the glomeruli and tubules, there are still a lot of fibrotic change, showing atrophy and glomerular sclerosis state, but by the results of other groups of rats kidney tissue sections were compared showed varying degrees of glomerular injury in the intervention group were improved to some extent, especially joint intervention group (HML+A group and HAML+M group) to improve the effectiveness of glomerular particularly significant; another group of rats immunized by the kidneys of the results showed that rat kidney HF group MSTN protein expression was higher than the other in each group, and compared with the NC group, there were significant differences (P <0.01).5. RT-PCR results showed that each intervention on insulin resistance were improved kidney damage some degree, which is mainly manifested in the HF group compared with either insulin upstream PI3K/Akt signaling pathway by the expression of the body, or downstream of mTOR, the expression of Glut4 signaling molecule, have shown varying degrees of regulation, and its downstream signaling molecules having on FoxO1 expression and inhibition of GSK-3β, is showing a certain downregulation degree; in addition, the amount of each intervention MSTN receptor expression in rat kidney was significantly lower than HF group, which on the other hand on the kidney of rats PI3K/Akt signaling pathway plays a certain role.Conclusion:After 8w weight-bearing treadmill, after the joint intervention of aerobic exercise, MSTN antibody intervention, and weight-bearing treadmill and aerobics/MSTN antibody on kidney tissue of rats slice results showed that the intervention group rat glomerular basement membrane glomerular sclerosis and atrophy proliferation, inflammation and fibrosis resulting have been initially improved, especially when combined intervention group, glomerular function of various aspects of the state has basically become glomerular function NC state; In addition, the rat kidney hypertrophy index and serum markers analysis showed that, although the intervention groups can kidney hypertrophy and kidney damage and lead to insulin resistance has some improvement, but still belong to the joint intervention of kidney hypertrophy improve better, but in the rat serum CHO, HDLC content, the intervention group compared with the HF group, have shown some degree of improvement; and finally for each intervention group rat kidney PI3K/Akt signaling pathway and MSTN by RT-PCR results of the body showed that the intervention on insulin resistance can damage the kidneys produce good improvement in results, which mainly for the intervention group than in the HF group, not only reduced the MSTN receptor and FoxO1, the expression of GSK-3β the amount, but also raised the expression of insulin receptor and PI3K/Akt and mTOR and its downstream signaling molecules Glut 4, which to some extent, the improvement in the IR are very favorable, summary, although each intervention can be on insulin resistance in kidney damage produces good improvement, but the degree of improvement in terms comprehensive, or joint intervention group advantages, and this significant advantage, but also reminds us that for insulin resistance prevention and treatment of kidney damage, you can ingeniously combining different treatments of multi-channel, it is bound to achieve a more comprehensive, more secure, more effective treatment, and this is, other types of clinical metabolic diseases associated with IR prevention and control work, provides a new way to improve IR. |
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