The Association Of Famine Exposure During Fetal Life And Gene With Adulthood Glucose Metabolism

Background In recent years,the prevalence of diabetes has rapidly increased,which has become one of the most serious and critical public health problems in China.According to thrifty phenotype hypothesis,the fetal or early infancy life is a critical period for the development of pancreatic and pancreatic islet beta cells.Malnutrition can impair the structure and function of the pancreas and islet beta cells,and these dysfunctional structural changes can increase the risk of developing diabetes in adulthood.A growing animal experimental and epidemiological evidence suggests that malnutrition during embryonic life does increase the risk of developing diabetes in adulthood.Diabetes is a polygenic hereditary disease,genome-wide association studies have identified at least 100 polymorphic sites associated with diabetes.For example,the rs2943641 polymorphism on IRS1 is associated with the type 2 diabetes,insulin resistance and hyperinsulinemia,Prol2Ala(rs1801282)polymorphism site on PPARy may affect insulin sensitivity and so on.The study to explore the interaction between famine and genetics among Dutch famine cohort found that the relationship between diabetes genes and adulthood diabetes was more significant among people who experienced famine in early life.From 1959 to 1961,a serious and massive famine broke out in China,people born during the famine period generally experienced malnutrition,providing an opportunity to study the relationship between famine and genes in developing type 2 diabetes in adulthood for Chinese populationObjective The main purpose of our current study was to explore whether exposure to famine in fetal life increased the risk of diabetes in adulthood,to explore the relationship between multiple diabetes related genes and diabetes by using the genetic scoring method,and to explore whether famine exposure in fetal life interacted with diabetes related gene risk score on developing type 2 diabetes in adulthood.The first part:Fetal famine exposure and glucose metabolism in adulthoodMethods The data from cross-sectional 2010-2012 China National Nutrition and Health Surveillance was utilized.The subjects born between 1960 and 1961 were selected as exposed group,those born in 1963 were selected as unexposed group.A total of 7830 subjects were used.The general information,physical examination data,physical activity data,food intake and blood biochemical test results were utilized.In the description for general characteristics,t test was used to compare the mean of continuous variables between two groups,Wilcoxon test to compare the median of continuous variables,chi-square test to compare the rate of categorical variables between two groups.The multiple linear regression or logistical regression was performed to explore the association between the exposure to famine in fetal life and fasting plasma glucose or abnormal glucose metabolism in adulthood by adjusting gender,famine severity,economic status,education level and other confounding factors.Results The medians of fasting plasma glucose both in exposed and control group were 5.2mmol/L.The prevalences of diabetes in those two groups were 6.4%and 5.1%,prevalences of impaired glucose tolerance were 5.3%and 5.0%,prevalences of impaired fasting glucose were 7.0%and 6.4%,respectively.The difference in prevalence of diabetes between these two group was significant(P=0.016).There were no significant differences in fasting plasma glucose,impaired glucose tolerance and impaired fasting glucose.Adjusting for confounding factors,the risk of diabetes in adulthood of famine exposed group was 1.25 times higher than that in control group,with a 95%confidence interval of 1.03-1.53.There were no associations between fetal famine exposure and fasting plasma glucose,impaired glucose tolerance,impaired fasting glucose in whole subjects.In severe famine area,more stronger associations between fetal famine exposure and fasting plasma glucose(β=0.08,P=0.014),diabetes(OR=1.40,95%CI 1.11-1.76,P=0.004)were observed.After adjusted by confounding factors,famine exposure during fetal period could increase the fasting plasma glucose in female subjects(P=0.08,P=0.037).The association between fetal famine exposure and diabetes in adulthood was only found in female subjects(OR=1.33,95%CI 1.01-1.75,P=0.040)when adjusting the confounding factors mentioned above except for the BMI.No associations between fetal famine exposure and fasting plasma glucose,abnormal glucose metabolism in adulthood were observed in male subjects.The second part:Diabetes related gene risk score and glucose metabolismin adulthoodMethods From the total subjects of first part,1000 subjects were selected both in exposed group and control group.The blood samples of 1982 subjects were detected successfully on 46 newly reported diabetes-related single nucleotide polymorphism(SNP)in Asian population by using Mass Array.And loci detection rate of 1907 subjects were greater than 50%.Finally,the geneticl data from 1907 subjects were analyzed.Diabetes related gene risk scores were calculated by summing up the numbers of the risk alleles weighted by the P-coefficients of the effect allele reported gene-diabetes association study.To generate the diabetes related gene risk score classification variable,the subjects were divided into four groups based on quantiles of diabetes related gene risk score.The Hardy Weinberg equilibrium test was performed on 46 loci of subjects without diabetes mellitus by using chi-square test.The relationship between diabetes related gene risk scores and fasting plasma glucose or abnormal glucose metabolism was analyzed by using multiple linear regression or logistical regression adjusted for confounding factors including gender,age,economic status,education level and other confounding factors.Results The minimum diabetes related gene risk score of current subjects was 10.70,the median was 46.68,and the maximum was 64.79.When taking diabetes related gene risk score as continuous variable,for per unit of diabetes related gene risk score increase,fasting plasma glucose increased by 0.009mmol/L(P=0.037),the risk of diabetes increased by 3%(OR 1.03,95%CI 1.01-1.05),the risk of impaired glucose tolerance increased by 2%(OR 1.02 95%CI 1.00-1.04),no significant increase in the risk of impaired fasting glucose,after adjusting for confounding factors.In female subjects,for per unit of diabetes related gene risk score increase,fasting plasma glucose increased by 0.010mmol/L(P<0.001),the risk of diabetes increased by 3%(OR=1.03,95%CI 1.00-1.06).No significant increases in fasting plasma glucose and risk of abnormal glucose metabolism were observed in male subjects.When diabetes related gene risk score was defined as classification variable,after adjusting for the above confounding factors,the fasting plasma glucose in the second group(P25-P50),the third group(P50-P75)and the fourth group(P75-P 100)were 0.141mmol/L(P=0.046),0.161 mmol/L(P=0.024)and 0.233mmol/L(P=0.001)higher than the first group(P0-P25),respectively.The risk of diabetes in the third group and the fourth group were 2.36 times(95%CI,1.16-4.82)and 2.40 times(95%CI,1.18-4.90)than that of first group,respectively.The risk of impaired glucose tolerance in the fourth group were 1.85 times(95%CI,1.04-3.29)than that of first group.The risk of impaired fasting glucose in the second group were 1.77 times(95%CI,1.00-3.14)than that of first group.In female subjects,fasting plasma glucose in the fourth group was 0.286mmol/L(P=0.002)higher than the first group,the risk of diabetes and impaired glucose tolerance in the fourth group were 3.10 times(95%CI,1.19-8.08)and 2.26 times(95%CI,1.09-4.69)than that of first group.In male subjects,fasting plasma glucose in the second group was 0.254mmol/L(P=0.028)higher than the first group,the risk of impaired fasting glucose in the fourth group was 2.86 times(95%CI,1.05-7.76)than that of the first group.The third part:The interaction between fetal famine exposure and diabetesrelated gene risk score on glucose metabolism in adulthoodMethods The methods of subject’s selection,experiment conduction and diabetes related gene risk score computation were the same as those of the second part.The stratified analysis was performed to explore the relationship between fetal famine exposure and fasting plasma glucose or abnormal glucose metabolism in adulthood among different diabetes related gene risk score levels(high and low level defined by the median of gene risk score),and to explore the relationship between diabetes related gene risk score and fasting plasma glucose or abnormal glucose metabolism in famine exposure group and control group.In the multiple linear regression model,the coefficient of interaction term between famine and diabetes related gene risk score was compared with 0 using t test to explore whether there was an interaction between fetal famine exposure and diabetes related gene risk score on fasting plasma glucose in adulthood.In the logistic regression model,the coefficient of interaction term between famine and diabetes related gene risk score was compared with 0 using t test to explore whether there was an interaction between fetal famine exposure and diabetes related gene risk score on abnormal glucose metabolism in adulthood.Results After adjusting for confounding factors,the associations between fetal famine exposure and fasting plasma glucose,abnormal glucose metabolism in adulthood were not found both in diabetes related gene risk score high and low level.In exposed group,the fasting glucose(P=0.045)and the risk of diabetes(OR=1.94,95%CI 1.01-3.72)were significantly increased,the risk of impaired glucose tolerance and impaired fasting glucose were not changed,as increasing in diabetes related gene risk score.No association between diabetes related gene risk score and fasting plasma glucose,abnormal glucose metabolism was found in control group.No interaction was found between fetal famine exposure and diabetes related gene risk score on fasting plasma glucose and abnormal glucose metabolism in adulthood.However,with the increase of the diabetes related gene risk score,the fasting plasama glucose,the risk of diabetes and the risk of impaired fasting blood glucose in exposed group were always higher than those in control group.The difference in fasting plasama glucose between two groups increased gradually,and the difference in risk of diabetes and impaired fasting glucose decreased gradually.Conclusion Fetal exposure to famine can increases fasting plasma glucose,risk for developing diabetes and impaired glucose tolerance in adulthood among female.It was stronger observed that diabetes related gene risk score is related to fasting plasma glucose,diabetes and impaired glucose tolerance among female.The relationships between diabetes related gene risk score and fasting plasma glucose,abnormal glucose metabolism were relative weak among male.Although we did not find the interaction between fetal famine exposure and diabetes related gene risk score in fasting plasma glucose and abnormal glucose metabolism in adulthood.However,the interaction plots implicated that larger sample size study may be needed to further explore.