The Effect Of Low Testosterone Levels On Insulin Resistance And Related Cognitive Dysfunction During Catch-up Growth

Object: Recent studies found that low testosterone levels in men are closely associated with insulin resistance.Catch-up growth induced by nutrition promotion after under nutrition has been shown to be an important factor for the widespread insulin resistance and related diseases in developing countries.The levels of testosterone are altered by nutritional status.Therefore,we aimed to investigate the effect of testosterone levels on insulin resistance and related cognitive dysfunction during catch-up growth.Methods: 1.Subjects and study design Subjects were selected from Risk Evaluation of c Ancers in Chinese diabe Tic Individuals: a l ONgitudinal study,REACTION study,study of Hubei branch center.1.1 Frist group of subjects included the insulin-resistant men and control individuals.Basic anthropometric parameters,biochemical indicators were analyzed,and androgen levels were detected.The differences between androgen levels in the insulin-resistant individuals and the control individuals were analyzed as a positive control of the population study.1.2 Second group of subjects included catch-up growth men who experienced the process of rapid improvement of nutrition after nutrition deficiency and control individuals,and the specific research process was consistent with the first group.1.3 Third group of subjects included the men from reaction study during 2018.Physical examination,epidemiological questionnaire,oral glucose tolerance test and Montreal Cognitive Assessment were measured.Blood samples for testing biochemical indicators and androgen levels were collected,and the correlation between androgen levels and insulin resistance was analyzed.Regression analysis was performed on androgen levels,HOMA-IR and cognitive function.2.Animals and experiment design 2.1 Male Sprague-Dawley rats were randomly divided into 3 groups: NC group,fed ad libitum with standard chow diet and corn oil injection every Monday from the 5th week;RN group(catch-up growth group),fed with 60% of weight-matched normal chow for 4?weeks then refed with weight-matched normal chow for 8?weeks and corn oil injection every Monday from the 5th week;RT group(catch-up growth rats with testosterone supplement therapy),the feeding pattern was the same as the RN group and 4 mg/kg testosterone intramuscular injection every Monday from the 5th week.2.2 The body weight and food intake of rats were recorded.Insulin resistance-related phenotypes and cognitive functions were detected: fasting blood glucose,IPITT,serum total testosterone,serum sex hormone-binding globulin(SHBG),calculated free testosterone,calculated free testosterone index(FTI),fasting insulin,ASST,tissue weight,liver oil red 0 staining.Real-time quantitative PCR was used to detect the m RNA expression levels of IRS-1,AR,NR2 A,NR2B and Western blot was used to detect the protein expression levels of AKT,p-AKT,AR,NR2 A and NR2 B in brain tissue.Results: 1.Results of population studies 1.1 The levels of total testosterone levels,free testosterone and FTI in insulin-resistant men were decreased(P <0.05)and SHBG levels were decreased.1.2 Fasting serum insulin(P <0.05),HOMA-IR(P <0.05),and triglycerides(P < 0.05)were increased and the levels of total testosterone,SHBG and free testosterone were decreased(P <0.05)in catch-up growth men.1.3 The levels of total testosterone and SHBG showed a significant negative correlation with HOMA-IR(P <0.05).Insulin resistance was an independent risk factor for cognitive dysfunction(P <0.05).Total testosterone(r =-0.237 P = 0.046)and SHBG(r =-0.234,P = 0.047)was negatively correlated with cognitive dysfunction,but they were not independent risk factors for cognitive dysfunction.2.Results of animal experiments 2.1 Catch-up growth caused visceral fat accumulation(P <0.05),insulin resistance(P <0.05),cognitive dysfunction(P <0.05)and significant decrease in the levels of total testosterone(P <0.05),free testosterone(P <0.05).Testosterone replacement therapy increased the levels of total testosterone and free testosterone(P <0.05)and improved visceral fat accumulation(P <0.05),insulin resistance(P <0.05),hepatic lipid deposition and cognitive dysfunction(P <0.05).2.2 Compared with the NC group,p-AKT protein expression levels in the brain of the RN group were decreased(P <0.05),IRS-1 m RNA expression levels were decreased,The m RNA and protein expression levels of NR2 A,NR2B were decreased(P <0.05);Compared with the RN group,IRS-1 m RNA expression levels in RT group were increased(P <0.05),p-AKT protein expression levels and the m RNA and protein expression levels of NR2 A,NR2B were increased(P <0.05).Conclusions: 1.Catch-up growth men were accompanied with hyperinsulinemia,insulin resistance and their levels of total testosterone,SHBG and free testosterone were decreased;2.The levels of total testosterone and free testosterone were decreased in catch-up growth rats characterized by visceral fat accumulation,hepatic lipid deposition,insulin resistance and cognitive dysfunction;3.Testosterone supplement therapy increased the levels of total testosterone and free testosterone in catch-up growth rats and improved visceral fat accumulation,hepatic lipid deposition,insulin resistance and cognitive dysfunction;4.Low testosterone levels may promote the occurrence of insulin resistance and cognitive dysfunction during catch-up growth by interfering the IRS-1 / AKT / NRs signaling pathway.