The Association Between Exposure To Famine In Early Life And Glucose And Lipid Metabolism Dysregulation,and Study On The Preliminary Underlying Mechanisms

Background and Aim:Human life can be divided into early,middle and late life.Whether exposure to negative events in the early life can affect noncommunicable diseases in later life is a not very clear but hot research field.DOHaD theory postulates that responsiveness to malnutrition in early life or in utero leads to metabolic and structural changes.This responsiveness might be useful to survive in early life but also increases the risk of diabetes in later life.In China,diabetes,metabolic syndrome and NAFLD（non-alcoholic fatty liver disease）are prevalent and are supposed to be associated with rapid economic growth during the most recent three decades.However,the observation that the diabetes prevalence in China exceeds that in the United States cannot be explained simply by economic factors.The famine in China from 1959 to 1962,called China’s Great Famine,maybe another factor.We aimed to explore whether exposure to famine in early life was associated with diabetes,metabolic syndrome and NAFLD in later life,and to observe the metabolic changes in rat model exposed to energy restriction in early life using isotope tracer technique.Methods:Our data of 6897 adults were from a cross-sectional Survey on Prevalence in East China for Metabolic Diseases and Risk Factors study in 2014（ChiCTR-ECS-14005052,www.chictr.org.cn）.6899 subjects were included in the SPECT-China study.Exposure to famine was based on a proxy,the year of birth.Subjects were categorized into five groups according to their life stages when exposed to famine from January 1,1959,to December 31,1962:fetal period（current age 52-55 y）born between 1959 and 1962,childhood（current age 56-65 y）born between 1949 and 1958,adolescence and young adult（current age 66-93 y）born between 1921 and 1948,non-exposed（current age 40-51 y）born between 1963 and 1974,and non-exposed（current age≤39 y）born after 1975.Current economic status was assessed by the gross domestic product per capita in 2013 at each site.Each site was categorized into high and low economic status according to the GDP per capita of the whole nation in 2013.Diabetes is diagnosed according to the American Diabetes Association 2014 criteria.Metabolic syndrome is diagnosed according to the International Diabetes Federation 2015criteria.After excluding a history of excessive consumption（>20 g/d）of pure alcohol,schistosomal hepatic disease,or self reported viral hepatitis,using medications associated with secondary NAFLD,The diagnostic criteria for fat accumulation（steatosis）by ultrasonography.To analyze the relationship between life stages when exposed to famine and risk of diabetes,metabolic syndrome and NAFLD in adulthood,logistic regression analyses were used.For the different life stages,the non-exposed group（1963-1974）was the reference.The interaction between life stages when exposed to famine and other factors was tested by adding a multiplicative factor in the logistic regression model.Data were expressed as ORs（95%CI）.Sprague Dawley rats were divided into 4 groups:refed-normal diet group（50%of the diet intake of ad libitum-fed group for 4 weeks and normal diet for 9 weeks）（n=7）,weight-mached ad libitum normal diet-fed group（n=7）,refed-high fat diet group（50%of the diet intake of ad libitum-fed group for 4 weeks and high fat diet for 9 weeks）（n=7）and weight-mached ad libitum high fat diet-fed group（n=7）.Metabolic parameters including blood glucose,insulin and body fat rate weredetermined.2-deoxy-1-¹⁴C₁-glucose was used to measure glucose uptake in quadriceps muscle.Results:（1）Compared with non-exposed subjects,famine exposure during the fetal period（OR1.53,95%CI 1.09,2.14）and childhood（OR1.82,95%CI 1.21,2.73）was associated with diabetes after adjusting for age and gender,adiposity,height,the lipid profile and blood pressure.Subjects living in areas with high economic status had a greater diabetes risk in adulthood（OR 1.46,95%CI 1.20,1.78）.In gender-specific analyses,fetal-exposed men（OR 1.64,95%CI,1.04,2.59）and childhood-exposed women（OR 2.81,95%CI 1.59,4.97）had significantly greater risk of diabetes.（2）Famine exposure during the fetal period（OR 1.53,95%CI 1.08,2.17）and childhood（OR 1.95,95%CI 1.30,1.93）was associated with higher risk of metabolic syndrome in women after adjusting for age,smoking,urban/rural residence and current economic status,but not in men.（3）Famine exposure during the fetal period（OR 1.77,95%CI 1.22,2.57）and childhood（OR 1.82,95%CI 1.35,2.46）was associated with an increased prevalence of moderate-severe NAFLD in women after adjusting for age,rural/urban residence,economic status,BMI,diabetes,dyslipidemia and hypertension.（4）high fat diet group and refed-high fat diet group had significantly higher HOMA-IR than normal diet group and refed-high fat diet group（P<0.05）.HOMA-IR had significant increasing trend through normal diet group,refed-normal diet group,high fat diet group and refed-high fat diet group（P<0.05）.Refed-normal diet group,high fat diet group and refed-high fat diet group had significantly lower glucose uptake rate in quadriceps muscle than normal diet group（P<0.05）.Also,glucose uptake rate in quadriceps muscle had significant decreasing trend through normal diet group,refed-normal diet group,high fat diet group and refed-high fat diet group（P<0.05）.Conclusions:（1）The rapid increase in the prevalence of diabetes in middle-aged and elderly people in China is associated with the combination of exposure to famine during the fetal stage and childhood and high economic status in adulthood（2）Exposure to famine in early life had sex-specific association with metabolic syndrome and moderate-severe NAFLD.（3）It also suggests the adverse effects of malnutrition might extend beyond the’first 1000days’and last 9 years.（4）Exposure to energy restriction in early life may induce insulin resistance in early stage of metabolic disorder,partly through decreased muscle glucose uptake.