Epidemiology And Mechanism Of Iodine Intake On Insulin Resistance Induced By Oxidative Stress

Objective:With the economic development and social progress of our country,living standards have been greatly improved.The changes in life and behavior habits as well as diet structure cause the rapid increase in the prevalence of metabolic syndrome and diseases caused by metabolism disorders.Metabolic syndrome is a clinical syndrome characterized by a variety of metabolic disorders,including abdominal obesity,abnormal glucose metabolism,hypertension,dyslipidemia,etc.Its complex etiology and pathogenesis are still unclear,so further exploration is needed to provide research data for the prevention and treatment of metabolic syndrome.The core of the metabolic syndrome is insulin resistance.Improving insulin resistance is the key to treat metabolic syndrome.Glucose and fatty acids are oxidized in the mitochondria,providing energy for cellular processes and life.The loss of balance between oxidative and antioxidant systems in cell and tissues leads to the excessive production of oxygen free radical and reactive oxygen species(ROS),and the stress of nutrition caused by high-fat and high-carbohydrate diet promotes oxidative stress.Oxidative stress can impair insulin signaling,thereby increasing the risk of insulin resistance.Therefore,reducing the oxidative stress level may improve insulin resistance and play a protective role in metabolic syndrome.Iodine is an essential micronutrient,which plays its role against oxidative stress by either acting directly as an antioxidant or indirectly inducing antioxidant enzymes.Oxidized iodine can act as an electron donor to neutralize reactive oxygen species(ROS),quench free radicals such as OH· or H2O2,or attach as a free radical to double bonds of some polyunsaturated fatty acids on the cell membrane,weakening their response to ROS.Inorganic iodine acts as an antioxidant that neutralizes hydrogen peroxide,thereby preventing the formation of hydroxyl radicals.Keap1-Nrf2/ARE pathway is a key mechanism of cellular defense against oxidative stress,which can control the transcription of various antioxidant enzymes and can be used for the surveillance of the level of oxidative stress.When oxidative stress occurs,the conformational change of Keap 1 leads to the dissociation of Nrf 2,which was originally bound to Keap 1,and transfer into the nucleus,forming heterodimers with small Maf proteins,and then binding to antioxidant response elements(AREs)to initiate the transcription of various antioxidants.In this study,the risk and related indexes of metabolic syndrome,abnormal glucose metabolism,hypertension,dyslipidemia and hyperuricemia in the general population and the effects of different iodine concentrations on insulin resistance rat models induced by high sugar and fat diet were observed to explore the mechanism of iodine on insulin resistance and the prevention and treatment of metabolic syndrome.MethodsPart ⅠA total of 74100 subjects aged 20-80 years old in the Thyroid Disorders,Iodine Status and Diabetes,a national epidemiological cross-sectional study(TIDE)project were included.According to urinary iodine concentration(UIC),chi-square test compared the risk of metabolic syndrome and related metabolic diseases and indicators,and multivariate logistic regression analysis was conducted according to UIC and BMI stratification to further explore the relationship between UIC and the risk of metabolic syndrome and related metabolic diseases under different BMI stratification.Part ⅡA total of 150 4-week-old Wistar rats were divided into control group fed with normal diet and insulin resistance group(IR)fed with high sugar and fat diet.Each group was divided into normal iodine group(NI),3 times iodine group(3HI),10 times iodine group(10HI),50 times iodine group(50HI)and 100 times iodine group(100HI)according to the daily physiological iodine requirement of rats,and were fed with different concentrations of iodine water to achieve different iodine nutritional states.At week 0,week 4,week 8,week 12,week 16,weight was taken,urine was collected,serum was collected from orbital blood collection,fasting blood glucose was measured with tail tip blood,and oral glucose tolerance test(OGTT)was performed.At the end of week 16,blood was collected from heart and serum was collected,free perirenal fat,greater omental fat,inguinal fat and epididymal fat were weighed,liver and skeletal muscle tissue were collected.The concentration of urine iodine was determined by inductively coupled plasma mass spectrometry(ICP-MS),serum insulin was determined by enzymelinked immunosorbent assay(ELISA),and the activity of superoxide dismutase(SOD)and the content of reduced glutathione(GSH)in liver tissue were determined by corresponding kits.Reverse transcription-polymerase chain reaction(RT-qPCR)was used to detect the mRNA expressions of Keapl,Nrf2 and HO-1 associated with the KEAP1NRF2/ARE signaling pathway in liver,and the protein expressions of Keapl,HO-1 and NQO1 in liver were determined by Western blot.ResultPart ⅠIn the general population,there was an inverted U-shaped relationship between UIC and the risk of metabolic syndrome and male prediabetes under BMI stratification,and the risk decreased when UIC>200μg/L.The risk of diabetes mellitus,hypertension in male,hypertriglyceridemia in normal weight men,hyperLDL-C,hypercholesterolemia and hyperuricemia decreased with the increase of UIC.FBG,OGTT-2h blood glucose,HbA1c,DBP,SDP and TG increased with the increase of BMI stratification,while HDLC decreased with increased BMI stratification.FBG in male and OGTT-2h blood glucose decreased at UIC 100-300μg/L.HbA1c,SDP,TC,LDL-C,HDL-C and uric acid all showed a decreasing trend with the increase of UIC.In overweight and obese women,there was an inverted U-shaped relationship between UIC and TG,and TG decreased when UIC>200μg/L.The relationship between UIC and TC,LDL-C in obese women was inverted U-shaped.When UIC>100μg/L,TC and LDL-C decreased.Part ⅡSignificant weight increase,visceral fat accumulation,impaired glucose tolerance,fasting insulin level and HOMA-IR index were observed in IR group.Compared with the NI+IR group,the 10HI+IR group had slightly lower body weight and the 10HI+IR,50HI+IR,and 100HI+IR groups had less visceral fat,but these differences were not statistically significant.The fasting blood glucose of IR group was not significantly different from that of control group,and the fasting blood glucose of control group and 10HI+IR,50 HI+IR and 100 HI+IR groups showed a downward trend with the increase of iodine water concentration.The fasting insulin level and HOMA-IR index in the iodine water feeding group were U-shaped,and the 10HI+IR group was the lowest.HE staining of liver and skeletal muscle showed that the morphology of liver and skeletal muscle in IR group was significantly changed,while the morphological changes of liver and skeletal muscle in 10HI+IR group were light,and a few cells and structures with normal morphology were still retained.The results of transmission electron microscopy of liver and skeletal muscle showed that the morphology and quantity of mitochondria in hepatocytes and skeletal muscle cells of IR group were significantly changed,while those in 10HI+IR group were slightly changed.Liver SOD activity and GSH content in NI+IR group were significantly higher than those in NI group,and SOD activity and GSH content in IR group fed with iodine water were significantly lower than those in NI+IR group.The mRNA relative expression levels of Keapl,Nrf2 and HO-1 in NI+IR group were significantly higher than those in NI+IR group.The mRNA relative expression levels of rats in IR group fed with iodine water were significantly lower than those in NI+IR group,and the mRNA relative expression levels of HO-1 in 10HI+IR group were significantly lower than those in IR group fed with iodine water of other concentrations.The relative protein expressions of Keapl,HO-1 and NQO1 were also similar.In addition,the relative protein expression of Keapl in 10HI and 100HI groups was significantly higher than that in NI group.Conclusion:Adequate iodine intake may reduce the risk of metabolic syndrome.The risk of metabolic diseases related to metabolic syndrome,such as diabetes,prediabetes,hypertension,hypercholesterolemia,hypertriglyceridemia,hypoHDL-C,hyperldL-C and hyperuricemia,was reduced under adequate iodine nutrition,while the risk and UIC showed different trends under different BMI stratification.Adequate concentration of iodine can enhance the ability to resist oxidative stress and improve insulin resistance in insulin resistant rats.