Metabolic Profiles And Insulin Resistance And Insulin Secretion In Subjects With The New Criteria For Impaired Fasting Glucose And Impaired Glucose Tolerance

Aims/hypothesis:Pre-diabetes represents an intermediate stage between normal glucose tolerance (NGT) and diabetes.It is the state that occurs when a person's blood glucose levels are higher than normal but not high enough for a diagnosis of diabetes. Pre-diabetes can be defined either by impaired fasting glucose (IFG; defined as a fasting plasma glucose concentration of 5.6-6.1mmol/L) or impaired glucose tolerance (IGT; defined as a 2-h oral glucose tolerance test [OGTT] plasma glucose concentration of 7.8-11.1 mmol/L), depending on the method used to detect it. In 2003, the ADA established a new cutoff for IFG by reducing plasma glucose level from 6.1mmol/L to 5.6mmol/L. This choice was based on epidemiological predictive data from different populations showing that decreasing the lower limit of IFG would optimize its sensitivity and specificity for predicting the risk of diabetes. However, this change has raised controversy and was challenged as to its appropriateness. At present, it is unclear whether IFG1(5.6 mmol/L≤FPG<6.1 mmol/L) and IFG2(6.1 mmol/L≤FPG <7.0 mmol/L) have the same prediction value for diabetes and cardiovascular events. Secondly, whether insulin resistance and insulin secretion are significantly different in the IFG1 and IFG2 aslo remains unknown.Moreover, although both IFG and IGT increase the risk of diabetes, available data suggest that they may have different pathophysiological mechanisms, and their prognosis may be also different. Despite that some studies showed that IGT is a better predictor than IFG for all-cause mortality and/or cardiovascular morbidity/mortality, however this conclusion has not been unanimously accepted. The question thus arises whether IFG and IGT are fundamentally different conditions. The answer to this question could have important implications for their treatment and for interventions aimed at preventing the progression to diabetes.In this study, we first examined whether the metabolic and cardiovascular risk factor profile as well as insulin resistance and secretion differ in subjects with the new threshold of IFG (IFG1) as compared with subjects with the old threshold of IFG (IFG2) in a cohort of nondiabetic Chinese. Secondly, we compared the pathophysiology of IFG and IGT with regard to insulin sensitivity and insulin secretion.methodsAmong a cohort with unknown diabetes, examanition was undertaken in our hospital. According to the results, normal glucose tolerance (NGT, n=834), isolated impaired fasting glucose (IFG, n=422; IFG1 n=241, IFG2 n=181), isolated impaired glucose tolerance (IGT, n=148), combined IFG and IGT (IFG+IGT, n=72),were selected. Height, weight, waist circumference, blood pressure, fasting plasma triglyceride, total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol(LDL-C), fasting and 30-min,120-min plasma glucose, serum insulin in a standard oral glucose tolerance test (75-gOGTT) were measured. The prevelance of metabolic syndrome and its component diseases were diagnosed by NCEP-ATPIII(2001) and Chinese diabetes society respectively. Homeostasis model assessment (HOMA-IR) was applied to assess the status of insulin resistance, Homeostasis model assessment (HOMA-B) was applied to assess the basic function of islet B cell, while insulinogenic index (the ratio of the increment of insulin to that of plasma glucose 30min after a glucose load:ΔI30/ΔG30) was performed to evaluate the early phase of insulin secretion. Categorical variables were compared byχ2 test. Logistic regression analysis with adjustment for age and gender was used to test for association between groups and post- challenge hyper-glucose, metabolic syndrome or its individual components. Multivariable Logistic analysis was used to analyse the risk factors related to IFG.and IGT.Results 1. Among 494 subjects with impaired fasting glucose,14.6% had abnormal postprandial glucose, whereas 67.3% of 220 subjects with increased post-chellenge glucose had normal fasting glucose.2. By lowering the cutoff value of FPG from 6.1mmol/L to 5.6mmol/L, the number of subjects falling into the category of IFG rose from 181 to 422, and the prevalence of IFG increased more than doubled.3. Compared with NGT group, age, waist-hip ratio, body mass index (BMI), blood pressure, total cholesterol and low density lipoprotein (LDL) cholesterol, triglyceride, fasting and 2-h post-challenge plasma glucose were elevated in IFG1 and IFG2 groups. IFG2 group had a significant higher 2-h plasma glucose level than IFG1 group. Adjusted with age, sex, BMI, HOMA-IR increased in subjects with IFG1 and IFG2 groups, while IFG2 group had higher HOMA-IR than IFG1 group. Compared with subjects in NGT, subjects with IFG1 and IFG2 had lower HOMA-B. However, there was no significant difference between IFG1 and IFG2 groups. In a logistic regression analysis with adjustment for age and gender, IFG1 and IFG2 were associated with comparable risk of metabolic syndrome, whereas the suggestion of Chinese medicine science diabetic branch was employed, the risk of metabolic syndrome was higher with IFG2 than with IFG1. At th same time, IFG2 was associated with higher risk of post-challenge glucose intolerance as compared with IFG1(OR 6.3(95%CI 3.4-10.27) VS OR 2.1(95%CI 1.3-3.52)].4. Compared with NGT group, age, waist circumference, body mass index (BMI), blood pressure, were elevated in other groups, and the level of plasma triglyceride also increased in IGT group.30-min plasma glucose increased gradually in IFG, IGT, IFG+IGT groups, However, there was no significant difference among the three groups. Compared with NGT group,120-min plasma glucose also increased in IFG, IGT, IFG+IGT groups, while the level were higher in IGT, IFG+IGT groups than that in IFG group, there was no significant difference between IGT group and IFG+IGT group. Fasting insulin was higher in IGT group than that in NGT,IFG, IFG+IGT groups,and there was no significant difference among the three groups. There was no significant difference with 30min insulin level among the four groups. Compared with NGT group,120-min insulin increased in IFG, IGT, IFG+IGT groups, at the same time, the level was higher in IGT group than that in IFG,IFG+IGT groups. In IGT group, age,120-min plasma glucose and serum insulin level in OGTT were higher than that in IFG.. Fasting glucose level in IFG+IGT group is higher than that in IGT group,while there was no significant difference between IFG group and IFG+IGT group. The subjects with IFG+IGT had higher 120-min plasma glucose level than that with IFG, while the level was similar to that in IGT group.5. After adjustment with age, sex, systolic blood pressure, and BMI, etc, HOMA-IR increased in IFG, IGT, and IFG+IGT groups. However, there was no difference among the three groups. HOMA-B decreased significantly in IFG and IFG+IGT groups than in NGT and IGT, meanwhile, there was no difference between NGT and IGT. Compared with NGT group,ΔI30/ΔG30 was lower in IGT and IFG+IGT groups, but no significant difference was found among IFG and NGT (P>0.05). Multivariable Logistic analysis showed age, BMI, insulin resistance were independent risk factors related to IFG, while basal insulin secretion was a protective factor of IFG..The predominant determinants of IFG were insulin resistance and disorder of basal insulin secretion. Age, BMI were independent risk factors associated with IGT. With aging, overweight or obesity and disorder of early insulin secretion, the individual was at higher risk for developing IGT. Aging, overweight or obesity had more impact on IGT development than early insulin secretion impairment.Conclusions1. By lowering the cutoff value of FPG from 6.1mmol/L to 5.6mmol/L, the prevalence of IFG increased more than doubled.2. IFG2 was associated with a worse metabolic profile and insulin resistance than IFG1, IFG2 subjects are more likely to have post-challenge hyper-glycemia and metabolic syndrome.3. Both insulin resistance and insulin secretion deficiency were present in subjects with IFG, IGT. The subjects with IFG may have liver insulin resistance and defect of baseline B cell function, but the early phase of insulin secretion is maintained. The subjects with IGT may have peripheral insulin resistance and defect of the early phase of insulin secretion, but baseline B cell function is miantained. IFG and IGT represents two distinct status of impaired glucose metabolism.