Preliminary Study On The Increased Susceptibility To Diabetes Melitus Mediated By Hyperlipidemia In CG-IUGR Rats

Objective: After intrauterine growth retardation with catch-up growth(CG-IUGR)rats were duplicated and intervened with atorvastatin calcium,the levels of glucose and lipid metabolism,the related molecules expression and/or activity of insulin signal transduction,glycogen synthase(GS)and biological clock were detected in liver and/or skeletal muscle,which aims to analyse the possible relationship between hyperlipidemia and the increased susceptibility to DM in CG-IUGR rats.Methods: The SD rats were divided into control group,CG-IUGR group and CG-IUGR+atorvastatin calcium group.The CG-IUGR rat model was established by the low-calorie diet,and were intervened by atorvastatin calcium.1.The growth and development of rats from birth to 8 weeks were assessed,including body weight,body length and body growth index(BMI).2.The state of glucose and lipid metabolism in 8-week-old rats were detected,including the changes of serum total cholesterol(TC),triglyceride(TG),low density lipoprotein cholesterol(LDL-C)and high density lipoprotein cholesterol(HDL-C),the weight of perirenal fat,and the levels of fasting blood glucose(FBG),fasting insulin(FINS)and insulin resistance index(IRI),the state of glucose tolerance and insulin tolerance,and the level of serum insulin(INS)at the 15 minutes after glucose load.3.The related molecules expression and/or activity of insulin signal transduction and glycogen synthase were detected in8-week-old rats,including the mRNA and protein expression of insulin receptor substrate(IRS),glucose transporter 4(GLUT4)and GS in liver and skeletal muscle,and the activity of GS in liver and skeletal muscle.4.The circadian rhythm of glycometabolism-related tissues were tested in 8-week-old rats,including the protein expression of nuclear receptor subfamily1(Rev-Erbα),circadian locomotor output cycles kaput(CLOCK)and brain and muscle Arnt-like protein-1(BMAL1)in liver.Results: 1.The growth rate of body weight,body length and BMI were significantly increased during the growth and development of CG-IUGR rats(P<0.05),and these changes were improved by atorvastatin calcium.2.The following changes can be observed in 8-week-old CG-IUGR rats.The levels of serum TG,TC,and LDL-C were increased while that of HDL-C were decreased significantly(P<0.05).The weight of perirenal fat was obviously increased(P<0.05).The levels of FINS,FBG,IRI and serum insulin at the 15 minutes after glucose load are all distinctly increased(P<0.05).The glucose tolerance and insulin tolerance are both impaired(P<0.05).These changes were all improved by atorvastatin calcium.3.The mRNA and protein expression of GYS1,IRS1,GLUT4 in skeletal muscle and GYS2,IRS2 in liver were significantly down-regulated,and GS activity in these tissue were simultaneously decreased in 8-week-old CG-IUGR rats(P<0.05).These changes were improved by atorvastatin calcium.4.The protein expression of Rev-Erbα were up-regulated while that of CLOCK and BMAL1 were down-regulated significantly in liver of8-week-old CG-IUGR rats(P<0.05).These changes were improved by atorvastatin calcium.Conclusions: 1.Hyperlipidemia can increase susceptibility to DM in CG-IUGR rats by attenuating the effect of insulin signal transduction and glycogen synthesis.2.The increased susceptibility to DM may be related to the circadian clock disturbance in the liver mediated by hyperlipidemia in CG-IUGR rats.