PANG Can Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Center of Diabetes, Shanghai 200233, China; BAO Yu-qian Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Center of Diabetes, Shanghai 200233, China; WANG Chen Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Center of Diabetes, Shanghai 200233, China; LU Jun-xi Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Center of Diabetes, Shanghai 200233, China; JIA Wei-ping Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Center of Diabetes, Shanghai 200233, China; XIANG Kun-san Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Center of Diabetes, Shanghai 200233, China
Correspondence to: JIA Wei-ping Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China (Tel:86-21-64369181 ext 8922 Fax:86-21-64368031 Email:email@example.com ) This study was supported by : Key Project from Science and Technology Commission of Shanghai(No. 01ZD002(1)) Program for Outstanding Medical Academic Leader of Shanghai(No. LJ06010) National Basic Research Program of China (973 Program)(No. 2006CB503901) Keywords: fasting plasma glucose·beta cell failure·diabetes mellitus Abstract: Background Type 2 diabetes is a chronic disease characterized by a progressive loss of beta cell functions. However, the evaluation of beta cell functions is either expensive or inconvenient for clinical practice. We aimed to elucidate the association between the changes of insulin responsiveness and the fasting plasma glucose (FPG) during the development of diabetes.Methods A total of 1192 Chinese individuals with normal blood glucose or hyperglycemia were enrolled for the analysis. The early insulinogenic index (ΔI30/ΔG30), the area under the curve of insulin (AUC-I), and homeostasis model assessment were applied to evaluate the early phase secretion, total insulin secretion, and insulin resistance respectively. Polynomial regression analysis was performed to estimate the fluctuation of beta cell functions.Results The ΔI30/ΔG30 decreased much more rapidly than the AUC-I accompanying with the elevation of FPG. At the FPG of 110 mg/dl (a pre-diabetic stage), the ΔI30/ΔG30 lost 50% of its maximum while the AUC-I was still at a compensated normal level. The AUC-I exhibited abnormal and decreased gradually at the FPG of from 130 mg/dl to higher (overt diabetes), while the ΔI30/ΔG30 almost remained at 25% of its maximum value. When hyperglycemia continuously existed at >180 mg/dl, both the ∆I30/ΔG30 and AUC-I were totally lost.Conclusion The increased fasting plasma glucose reflects progressive decompensation of beta cell functions, and could be used to guide the strategy of clinical treatments.
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Type 2 diabetes is a chronic disease characterized by a progressive loss of beta cell functions, which is an initial defect in early secretion phase of insulin, followed by an impaired late secretion phase, and a eventually complete beta cell failure.1,2 Proper evaluation of beta cell functions would guide a successful strategy of clinical therapy. In recent years, various experimental methods and modeling approaches have been developed to precisely evaluate beta cell functions, including ultradian oscillation of insulin secretion,3 hyperglycemic clamp4,5 and arginine stimulation test,6 intravenous glucose tolerance test,7-9 and homeostasis model assessment (HOMA).10,11 In addition, the insulin response to an oral glucose load, such as oral glucose tolerance test (OGTT), was used to evaluate beta cell functions.12,13
However, there is still lack of a proper way to conveniently and quickly evaluate the beta cell functions, for even the OGTT is not easy enough to broadly apply in clinical practice. As a diagnostic marker of diabetes, the level of fasting plasma glucose (FPG) also somehow reflects beta cell functions and serves as a predictor for the incidence of diabetes.14,15 The close relationship between fasting or postprandial beta cell responsiveness and FPG had been demonstrated in a Caucasian diabetic population.16 However, there is no direct evidence to support the relationship of FPG and the early phase or total secretion of insulin. In the present study, we investigate whether FPG could be used in screening the various statuses of beta cell functions, both in non-diabetic subjects and diabetic patients without treatment history.
Study subjectsA total of 1192 subjects aged 20–86 years (553 men and 639 women) from the outpatient department of Shanghai Sixth People's Hospital and Shanghai communities were included in our analysis between 1992 and 2002. The study was designed in compliance with the Helsinki Declaration and approved by the local ethical committee, and informed consent was obtained from each participant. Individuals who suffered from cancer, severe disability, severe psychiatric disturbance or having a history of anti-diabetic therapy were excluded.
Anthropometric indicesHeight and weight were measured and body mass index (BMI) was calculated as weight in kilograms divided by the square of the height in meters (kg/m2). Waist circumference was measured at the point between the costal margin and iliac crest, which yielded the minimum measurement. Hip circumference was measured around the buttocks at the level that yielded the maximum measurement. Waist-to-hip ratio was calculated as the ratio of the waist circumference to the hip circumference. Blood pressure measurements were taken three times using a sphygmomanometer and then averaged.
OGTT, insulin secretion and sensitivity determinationAll participants were examined by a 75 g oral glucose test, together with a simultaneous insulin releasing test over 180 minutes. The diagnoses of diabetes mellitus and impaired glucose regulation (IGR) (i.e. impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT), and normal glucose tolerance (NGT)) were based on the 1999 WHO criteria.17 Obesity (OB) and overweight (OW) were diagnosed according to the 1998 WHO criteria.18 Beta cell functions were assessed by the following indices. (1) Insulinogenic index, which represents the early phase insulin secretion, was calculated from increments of serum insulin measured at 30 minutes and 30-minute plasma glucose by the equation as follows: insulinogenic index = (insulin level at 30 minutes – basal insulin)/ (glucose level at 30 minutes – basal glucose), or =∆I30/ΔG30 ((μU/ml)/(mmol/L)).19 (2) Total area under the curve of insulin in 180 minutes (AUC-I). (3) Insulin sensitivity status was determined by homeostasis model assessment of insulin resistance (HOMA-IR). It was calculated as HOMA-IR=(basal insulin (μU/ml)×basal glucose (mmol/L)/22.5.5
MeasurementsBlood samples for insulin, total cholesterol, high density lipoprotein (HDL) cholesterol, and triglyceride levels were collected after an overnight fasting. Plasma glucose levels were measured using the glucose oxidase method. The serum true insulin assay used bio-antibody technique (LINCO kit, USA). Serum total cholesterol, triglyceride, HDL-cholesterol, and low density lipoprotein (LDL)- cholesterol were measured with Hitachi Model 7600 Series Automatic Analyzer (Hitachi High-Technologies Corporation, Japan).
Statistical analysis Statistical analyses were performed using the SPSS11.5 statistical software. Data were given as mean ± standard deviation (SD) unless otherwise stated. The one-way analysis of variance (ANOVA) test was applied to compare differences among subgroups. Polynomial regression was used for tendency analysis. A P value less than 0.05 was considered statistically significant.
Characteristics of the study population Table shows the clinical and metabolic characteristics of the study subjects. The average age and BMI were 51 (range from 20 to 86 years) and 25.9 (range from 15.1 to 42.1 kg/m2), respectively. A total of 385 subjects had newly diagnosed type 2 diabetes, 222 subjects with IGR, and 585 subjects with NGT. As expected, FPG, 2-hour postprandial plasma glucose (P2HG), fasting serum insulin, total cholesterol, and LDL-cholesterol together with systolic blood pressure and diastolic blood pressure were significantly higher in subjects with diabetes or IGR than those with NGT. HDL-cholesterol was found higher in subjects with NGT than those with type 2 diabetes and IGR. Among all the groups, subjects with diabetes had the highest level of FPG, P2HG, total cholesterol, LDL-cholesterol, and triglyceride, while subjects with IGR were the most obese population according to the level of BMI.
view in a new window Table. Characteristics of the study population
Comparison of beta cell functions and insulin sensitivity among NGT, NGR, and DM with or without obesityAs shown in Figure 1A, the insulinogenic index, a measure of early-phase insulin secretion, decreased progressively from NGT to diabetes with the more pronounced decrease in diabetic patients (P <0.01). This holds true with normal weight (NW), OW, and OB subjects (P <0.01). OB subjects with NGT had significantly higher early-phase insulin secretion than those of their NW and OW counterparts, the same phenomena was observed in OW subjects. However, in diabetic OB subjects, there were no differences in insulinogenic index among NW, OW, and OB diabetic patients. Thus, the decrease of early-phase insulin secretion from NGT to diabetes in OB subjects was more pronounced than those of NW and OW diabetes.
AUC-I, the measurement of total insulin secretion, only significantly decreased in OW and OB diabetic patients (Figure 1B), compared with their NGT counterparts. No significant difference could be found between NGT and IGR subjects regardless of whether they were obese or not. Similar to the insulinogenic index, AUC-I was positively correlated with BMI (P <0.01; Figure 1B).
view in a new window Figure 1. Insulinogenic index (A), AUC-I (B), and HOMA-IR (C) by subgroups of various categories of glucose tolerance and body mass index. Numbers of subjects were in parenthesis. NGT: normal glucose tolerance; IGR: impaired glucose regulation; NW: normal weight; OW: overweight; OB: obesity. *P <0.05, #P <0.01 represent comparison between subgroups.
The HOMA-IR index, measurement of insulin sensitivity, exhibited a significant correlation with the increase of BMI (P <0.01) and the severity of glucose intolerance (P <0.01).
Changes of insulin secretion and insulin resistance with the increase of FPGFigure 2 shows the relationships between FPG levels and insulin secretion in our study groups, which were analyzed by polynomial regression with the quartic parabola regression equation for insulinogenic index (r=0.9647) and cubic parabola regression equation for AUC-I (r=0.9798, P <0.01). The relationship between FPG and P2HG/HOMA-IR were also included. The ∆I30/ΔG30 increased and reached its maximum before at the FPG of 80 mg/dl. Then the ∆I30/ΔG30 began to decrease rapidly, and fell to 50% and 25% of its maximum value at the FPG of 110 mg/dl and 130 mg/dl, respectively. In contrast, the AUC-I increased and reached its maximum at the FPG of 100 mg/dl. The decrease of AUC-I was much slower than that of ∆I30/ΔG30. It gradually reached 50% maximum level at the FPG of 170 mg/dl, where the ∆I30/ΔG30 was quite low. The curves of ∆I30/ΔG30 and AUC-I levels among NW, OW, and OB had a similar shape and were correlated positively with the increase of BMI (data not shown). There were positive correlations between FPG levels and the mean of the P2HG or HOMA-IR index (r=0.989, P <0.0001; r=0.946, P <0.0001, respectively).
view in a new window Figure 2. Fluctuation of insulinogenic index and AUC-I with increment of fasting plasma glucose. Data were expressed as mean±SD. FPG: fasting plasma glucose; AUC-I: the area under the curve of insulin.
As the insulin resistance caused by obesity may influence insulin secretion, we further compared the curve patterns of insulin secretion by subgroups of BMI. In the normal range of FPG less than 110 mg/dl, the insulinogenic index was apparently the highest in obese patients and was comparable between NGT and IGR subjects. Among the three subgroups of BMI, the ∆I30/ΔG30 values decreased rapidly in a similar pattern when FPG was greater than 80 mg/dl and remained in the same extremely low level at a FPG level of from 130 mg/dl to higher. Distinctively, the AUC-I levels increased with the BMI subgroups (P <0.01) and such differences were maintained across the levels of FPG, even though the decreasing trend of AUC-I was similar among the three BMI subgroups (Figure 3).
view in a new window Figure 3. Fluctuation of insulinogenic index (A) and AUC-I (B) with increment of fasting plasma glucose by subgroups of body mass index. Data were expressed as mean values. FPG: fsting plasma glucose; AUC-I: area under the curve of insulin.
The evaluation of beta cell functions is critical for clinical therapy. There is a 75% loss of beta cell functions when the FPG level of 140 mg/dl is exceeded.1 However, there is still a lack of an easy and fast way for doctors to make an evaluation of beta cell functions. Though FPG is designated as an indicator of beta cell functions20 and is much more convenient than other delicate tests, few studies have drawn the whole diagram of the FPG-related insulin releasing model during the development of diabetes.
In the present study, ∆I30/ΔG30 and AUC-I derived from the OGTT were used to determine the early phase secretion of insulin and total insulin secretion, respectively. The level of FPG indicates different beta cell functions and could guide the strategy of clinical treatments. For example, when FPG reached 100 mg/dl, the ∆I30/ΔG30 was still normal, but began to decrease from a compensated high level; whereas AUC-I still maintained at a high compensation level. The corresponding P2HG level (from 117 mg/dl to 173 mg/dl) was elevated to an abnormal status, known as IGT. Since the early phase secretion of insulin plays a pivotal role in the maintenance of postprandial glucose homeostasis,21-23 the elevation of P2HG (from 173 mg/dl to 198 mg/dl) may be due to the decrease of the ∆I30/ΔG30 and the increase in insulin resistance. In regard of this, the treatment of IGT with FPG ranged from 80 mg/dl to 100 mg/dl may suggest improving insulin sensitivity, such as changing life style or the use of an insulin sensitizer.
The defective early phase secretion appeared earlier and collapsed much more rapidly than that of total insulin secretion. At the FPG of 110 mg/dl, a status defined as IFG, the loss of ∆I30/ΔG30 was 50% and AUC-I was still within normal range. In that case, the use of insulin secretagogues to recover the early phase secretion was necessary. If FPG was higher than 170 mg/dl, and both early and total insulin secretion were lost, subcutaneous injection of insulin was preferred.
In summary, in the early stage of type 2 diabetes or pre-diabetes, abnormalities in insulin secretion are already encountered, with very often compensated hyperinsulinemia and then a loss of the early phase insulin secretion, even if FPG is within the normal range. Fasting hyperglycemia reflects decompensation of beta cell functions. Therefore, we could utilize the level of FPG to primarily estimate the different combined status of early phase secretion and total insulin secretion during the development of diabetes and guide the proper strategy of treatments.
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