Study Of Correlation Between Oxidative Stress Activation, Pancreatic Islet Function And Acute Glycemic Excursion In Subtypes Of Impaired Glucose Regulation

Objective To analyze correlation of oxidative stress activation,pancreatic islet function and acute glucose fluctuations in subtypes of impaired glucose regulation by continuous glucose monitoring system(CGMS).Methods 1.From January to July in 2008,according to ADA 2003 diagnostic criteria,81 individuals were divided into 4 groups:normal glucose tolerance(NGT,n=18),isolated impaired fasting glycemia(I-IFG,n=12),isolated impaired glucose tolerance(I-IGT,n=19), combined IFG/IGT(n=11),and newly diagnosed type 2 diabetes mellitus(T2DM, n=21).And then continuous glucose monitoring system(CGMS) was used for 72 hours to monitor the blood glucose(BG) level before drug intervention.2. Assessed by oral glucose tolerance test(OGTT) repeated twice,98 individuals were divided into 3 groups:NGT(n=15),impaired glucose intolerance(IGR,n=47) and 36 T2DM.And their BG levels were monitored by CGMS for three consecutive days.Intraday glycemic excursions were assessed by mean amplitude of glucose excursions(MAGE);From 48h to 72h during CGMS period,24h urine samples were collected and free 8-iso prostaglandin F_2α(8-isoPGF_2α) were measured by ELISA to evaluate oxidative stress.Fasting and OGTT 2 hours venous blood samples were collected to measure plasma insulin and C peptide levels.Moreover,HOMA insulin resistance index(HOMA-1R) were calculated to evaluate insulin sensitive.HOMAβ-cell function index(HBCI) andâ–³I₁₂₀/â–³G₁₂₀ to evaluate the insulin response to a stimulus.Repeated CGMS were given after three months Lispro 25 interventions in T2DM group.Periodical interview included life style intervention directions and insulin regulations.Glucose excursions,oxidative stress,insulin index and other metabolic readouts before and after intervention were compared by one-way ANOVA.Possible factors effected on the deterioration of pancreatic islet function were analyzed by Pearson correlation coefficient and multivariate stepwise regression.Results 1. Characteristics of glycemic excursion in different subtypes of impaired glucose intolerance:â‘ The levels of largest amplitude of glycemic excursions(LA(?)E), mean blood glucose(MBG),and standard deviation of mean level of blood glucose fluctuation(SDBG) increased gradually with the deterioration of glucose tolerance.The MAGE readout of the I-IGT group was(3.16±1.15) mmol/L, significantly higher than that of the NGT group[(1.62±0.49) mmol/L,P＜0.05], and significantly lower than that of the T2DM group[(5.23±1.88) mmol/L, P＜0.05].The level of frequency of glucose excursion(FGE) decreased along with the decrease of glucose tolerance:NGT group[(6.06±3.42)]＞IGT/IFG group [(5.54±2.50)]＞T2DM group[(4.81±1.83)].Among the three components of IGR,the I-IGT group showed highest MAGE(3.16±1.15) mmol/L and lowest NGE level(4.89±1.79).â‘¡The level of absolute mean of daily difference (MODD) increased in the following order:NGT group[(0.76±0.29) mmol/L], I-IGT group[(1.06±0.36) mmol/L],IFG/IGT group[(1.16±0.39) mmol/L], and T2DM group[(1.95±0.95) mmol/L](all P＜0.05).â‘¢The fasting glucose level deteriorated the most rapidly in the I-IFG group,while it reached the highest postprandial peak in the IFG/IGT group.The blood glucose curve increased along the order of NGT,I-IGT,IFG/IGT,I-IFG,and T2DM.â‘£When the level of glycosylated hemoglobin A1c(HbA_1C) level was less than 7%,the fasting phase of curve virtually coincided with each other among individual groups with different HbA_1C levels;however,the postprandial peak separated slightly.When the HbA_1C level was between 7.0%and 7.9%,the postprandial peaks of individual groups with different HbA_1C levels dispersed markedly.When the HbA_1C level was higher than 8%,the fasting blood glucose curve moved upwards significantly with increasing postprandial excursion.2.Correlation of oxidative stress activation and acute glucose fluctuations:â‘ Mean(SD) urinary excretion rates of 8-isoPGF_2α(1706±477)pg/mg of creatinine)in T2DM group significantly increased compared with it in IGR group((216±65)pg/mg) and NGT group((269 4-60)pg/mg)(F=27.304,P＜0.05).And levels of MAGE(6.04mmol/L) in T2DM group also elevated compared with it in IGR group((2.70±1.22)mmol/L)) and NGT group((1.73±0.50)mmol/L))(F=67.729,P＜0.05).â‘¡With Lispro 25 interventions in T2DM group,urinary excretion rates of 8-isoPGF_2α,MAGE, glycosylated hemoglobin(HbA_1C) and triglyceride(TG) read(?)ts decreased by 34.53%,31.81%,18.50%and 28.79%respectively(F values were 6.108,18.378, 39.322 and 5.942,all P＜0.05).Moreover,the level of systolic blood pressure(SBP),diastolic blood pressure(DBP),fasting blood glucose(FBG) and 2h postprandial blood glucose(2hPBG) also significantly decreased(F values were 7.879,11.684,38.952 and 61.207 respectively,all P＜0.01).â‘¢Pearson correlation analysis:urinary excretion rates of 8-isoPGF_2α was positively correlated with MAGE(r=0.593,P＜0.01).No significant correlation were found between HbA_1C and urinary excretion rates of 8-isoPGF_2α(r=0.186,P＞0.05);â‘£With urinary excretion rates of 8-isoPGF_2α as dependent,and positive correlation factors in Pearson correlation analysis as independent,multivariate stepwise regression analysis showed MAGE and HDL-c entered final two models(r² value was 0.354 and 0.346 respectively,all P＜0.01);and same results were found by Partial correlation analysis.3.Correlation of Pancreatic Islet Function and Acute Glucose Fluctuations:â‘ HOMA-IR of T2DM group were 2.7 times and 3.8 times higher than that of IGR group and NGT group respectively(F=4.07,P＜0.05).â‘¡With corrected by HOMA-IR,HBCI/IR of T2DM group were 17.2 percent and 25.5 percent as that of NGT group and IGR group respectively(F=21.19,P＜0.01). And FBCI/IR of T2DM group were 34.4 percent and 42.9 percent as that of NGT group and IGR group respectively(F=89.62,P＜0.01).Moreover,â–³I₁₂₀/â–³G₁₂₀/IR of T2DM group were 6.2 percent and 15.5 percent than that of NGT group and IGR group respectively(F=21.19,P＜0.01).â‘¢Significant correlation by Partial correlation analysis was found only between FBCI/IR and 8-isoPGF_2α/Cr,but not between HBCI,HBCI/IR,â–³I120/â–³G120,fasting C peptide and 8-isoPGF_2α/Cr after FBCI/IR controlled analysis(r value was 0.20,0.27,-0.03 and 0.05 respectively,P＞0.05).Furthermore,statistical significant was also found in the correlation between FBCI/IR,â–³I120/â–³G120 and MAGE, but not between HOMA-IR,HBCI,HBCI/IR,â–³I120/â–³G120/IR and MAGE after FBCI/IR controlled analysis(r value was 0.03,-0.11,0.21 and -0.05 respectively, P＞0.05).These conclusions were further evaluated and validated by multivariate stepwise regression analysis.â‘£Pearson correlation analysis:HOMA-IR was positively correlated with blood glucose before lunch with most significance; dinner postprandial glucose spike mainly reflected islet beta cell secretion function.And there were significantly correlation between basal islet function and dinner postprandial glucose spike,fasting blood glucose and 3am blood glucose; Stimulated pancreatic islet function had correlation with blood glucose two hours after breakfast.⑤All subjects were grouped by the level of quartile blood glucose in special time and insulin resistance and pancreatic islet function indices were compared by one-way ANOVA.Then the reference threshold of fasting blood glucose,two hours after breakfast and blood glucose before lunch were 5.8mmol/L,7.9mmol/L and 7.3mmol/L respectively.The cut-off points of dinner postprandial glucose spike depending on the index.It was 7.3mmol/L to assess HBCI/IR and 8.1mmol/L to assess FBCI/IR(all P＜0.01).Conclusionâ‘ With the deterioration of glucose regulation,the intraday and day-to-day blood glucose excursion levels became increasingly fluctuant,therefore,the oxidative stress became more activated.â‘¡The amplitude of glycemic excursion was lower in the NGT group than in the T2DM group,however,the frequency of glycemic excursion was higher in the NGT subject than that in the T2DM subjects.The glucose excursion profile of the IGR subjects was between the NGR and T2DM subjects.â‘¢The characteristics of glucose excursion of the I-IGT group were similar to those of the T2DM group,and the characteristics of the I-IFG group was similar to those of the NGT group.â‘£The loss of postprandial glycemic control preceded evident deterioration in fasting phase of IGR.⑤The activation of oxidative stress in T2DM were positive correlation with glucose fluctuations and some lipoprotein metabolism.â‘¥With insulin treatment,glucose excursions and oxidative stress were both improved obviously.⑦Pre-diabetes and type 2 diabetes had various degrees of pancreaticβ-cell secreting dysfunction,and this tendency became more obvious with insulin resistance factors taken into account.⑧Acute glucose fluctuations may contribute to pancreaticβ-cell secreting dysfunction through activation of oxidative stress in T2DM.⑨According to the level of blood glucose in special time,we had a preliminary evaluation of diabetic patients' pathophysiology conditions and it may be helpful to choose oral hypoglycemic agents.