Beta-cell function and insulin sensitivity at various degrees of glucose tolerance in Chinese subjects

diabetes research and clinical practice 100 (2013) 391–397

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Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres

Beta-cell function and insulin sensitivity at various degrees of glucose tolerance in Chinese subjects Jiunn-Diann Lin a, Yen-Lin Chen b, Chun-Hsien Hsu c, Chung-Ze Wu a, An-Tsz Hsieh a, Chang-Hsun Hsieh d, Jin-Biou Chang e, Yao-Jen Liang f, Dee Pei g,* a

Division of Endocrinology and Metabolism, Department of Internal Medicine, Shuang Ho Hospital, School of Medicine, College of Medicine, Taipei Medical University, Taiwan, ROC b Department of Pathology, Cardinal Tien Hospital, Medical School, Catholic Fu-Jen University, Taipei, Taiwan, ROC c Department of Family Medicine, Cardinal Tien Hospital, Medical School, Catholic Fu-Jen University, Taipei, Taiwan, ROC d Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical School, Taiwan, ROC e Department of Pathology, National Defense Medical Center, Division of Clinical Pathology, Tri-Service General Hospital, Taipei, Taiwan, ROC f Department and Institute of Life Science, Fu-Jen Catholic University, New Taipei City, Taiwan, ROC g Department of Internal Medicine, Cardinal Tien Hospital, Medical School, Catholic Fu Jen University, Taipei, Taiwan, ROC

article info

abstract

Article history:

Aims: The aim of this study was to evaluate the relative importance of insulin sensitivity (SI),

Received 6 August 2012

and the first (1st ISEC) and second phase insulin secretion (2nd ISEC) in the development of

Received in revised form

type 2 diabetes (T2D) in Chinese subjects.

19 December 2012

Methods: A total of 96 subjects, including 19 with normal fasting glucose, 21 with pre-

Accepted 14 March 2013

diabetes, and 56 with T2D were enrolled. Subjects underwent a modified low dose graded

Published on line 13 April 2013

glucose infusion (M-LDGGI; a simplified version of Polonsky’s method) and frequently

Keywords:

the changes of plasma insulin against the glucose levels. By observing the respective

sampled intravenous glucose tolerance test. The results were interpreted as the slope of First phase insulin secretion

percentage reduction, the deterioration rate of each parameter was compared.

Second phase insulin secretion

Results: As fasting plasma glucose (FPG) levels increased, SI decreased mildly and non-signifi-

Type 2 diabetes

cantly, while the 1st and 2nd ISECs decreased more dramatically and significantly. More importantly, the decrease of the 1st ISEC from baseline was greater than that of the 2nd ISEC. Conclusions: Since the 1st ISEC decreased the most with increasing FPG levels, it is concluded that the 1st ISEC is the key trigger of T2D development. On the contrary, the 2nd ISEC remained more stable across increasing FPG levels. This latter finding may explain the effectiveness of insulin secretagogues during the early stage of T2D. The results of this study can be helpful in the development of interventions aimed at stopping the progression and/or treating T2D in Chinese populations. # 2013 Elsevier Ireland Ltd. All rights reserved.

* Corresponding author at: Dept. of Internal Medicine, Cardinal Tien Hospital, No. 362, Chung Cheng Rd., Xindian City, Taipei County 23137, Taiwan, ROC. Tel.: +886 2 22193391; fax: +886 2 22195821. E-mail address: [email protected] (D. Pei). Abbreviations: SI, insulin sensitivity; 1st ISEC, first insulin secretion phase; 2nd ISEC, second insulin secretion phase; IR, insulin resistance; FPG, fasting plasma glucose; NFG, normal fasting plasma glucose; PreDM, pre-diabetes; T2D, type 2 diabetes; AIRg, acute insulin response after the glucose load; FPI, fasting plasma insulin; HOMA-IR, homeostasis model assessment of insulin resistance; HOMA-B, homeostasis model assessment of beta-cell function; M-LDGGI, modified low dose graded glucose infusion test; FSIGT, frequent sample intravenous glucose tolerance test. 0168-8227/$ – see front matter # 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.diabres.2013.03.022

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1.

diabetes research and clinical practice 100 (2013) 391–397

Introduction

Impaired insulin sensitivity (SI) and reduced insulin secretion (ISEC) are the two major pathophysiologic abnormalities underlying type 2 diabetes (T2D) [1]. It is generally agreed that beta cell secretion increases in order to maintain normal glucose homeostasis among subjects with insulin resistance (IR) [2]. However, beta cell secretion eventually reaches a level of decompensation in many of these subjects, leading to clinically evident diabetes [1,2]. ISEC is composed of two phases: the 1st phase (1st ISEC) and 2nd phase (2nd ISEC) [3,4]. Conceptually, the 1st ISEC consists of the stored insulin within the granules of beta cells that is secreted within 10 min of an acute elevation in plasma glucose levels. On the other hand, the 2nd ISEC phase comprises the secretion of newly produced insulin from the beta-cells, which reaches a plateau within 2–3 h [4]. Whether impaired SI or ISEC is the major contributor for diabetes or whether both factors contribute equally remains controversial. Using surrogate markers derived from an oral glucose tolerance test (OGTT), IR has been found to be the major factor determining the deterioration of plasma glucose levels in Europeans while deterioration of ISEC was the predominant factor in Asians [5–7]. The reasons behind these contradictory findings have not been fully clarified. Additionally, evidence suggests that the 2nd ISEC is maintained for a longer period than the 1st ISEC during the natural progression of diabetes. The remaining 2nd ISEC after the diagnosis of diabetes may determine the time period of the oral hypoglycemic drugs, particularly the insulin secretagogues, can effectively control glucose levels. Despite the important role of the 2nd ISEC in the pathophysiology of diabetes, most recent studies have only focused on the 1st ISEC [8]. In this study, we simultaneously measured SI, and the 1st and 2nd ISECs in order to elucidate their respective roles in the pathogenesis of diabetes among 96 Chinese subjects with varying levels of glucose tolerance.

2.

Materials and methods

2.1.

Subjects

We enrolled 96 individuals between the ages of 40 and 70 years who presented at our out-patient clinic in 2011. Subjects were either self-referred or referred by health professionals for purposes of screening for diabetes and had a body mass index (BMI) between 20.0 kg/m2 and 30.0 kg/m2. Subjects were free of any other significant medical diseases, had no history of diabetes or diabetic ketoacidosis, nor had taken any medications known to influence SI and/or beta-cell function (including oral hypoglycemic agents) during the study period. Subjects were categorized into three groups according to their fasting plasma glucose (FPG) as follows: normal fasting plasma glucose (NFG; FPG < 5.6 mmol/l), pre-diabetes (PreDM; 5.6  FPG < 7.0 mmol/l) and T2D (FPG  7 mmol/l). These FPG categories were based on the 2012 American Diabetes Association (ADA) recommendation [9]. On the first day of study, a complete routine work-up was performed to exclude

the presence of cardiovascular, endocrine, renal, hepatic and respiratory disorders. The study protocol was approved by the hospital’s institutional review board and ethics committee. All subjects provided written informed consent prior to participation. BMI was calculated as body weight (kg)/height (m)2. Systolic and diastolic blood pressures were measured on the right arm with subjects seated using a standard mercury sphygmomanometer. Blood samples were drawn from the antecubital vein for biochemical analysis.

2.2.

Patients and protocols

Each participant undertook 2 tests: the modified low dose graded glucose infusion test (M-LDGGI) and the frequently sampled intravenous glucose tolerance test (FSIGT). The two tests were performed in random order, separated by a minimum interval of three days. The tests were performed at 8:00 am following a 10-h overnight fast with subjects in the sitting position. An intravenous catheter was placed in each forearm: one for blood sampling and one for glucose infusion. The sampling catheters were kept patent through the slow infusion of 0.9% saline.

2.2.1.

FSIGT

After the catheters were inserted, a bolus of 10% glucose water (0.3 g/kg) was given. Twenty minutes later, a bolus of regular human insulin (Novo Nordisk Pharmaceutical, Princeton) 0.05 units/kg was injected. Blood samples for plasma glucose and insulin levels were collected at 0, 2, 4, 8, 19, 22, 30, 40, 50, 70, 100 and 180 min. Subsequently, the SI, and acute insulin response after the glucose load (AIRg) were obtained using Bergman’s Minimal Model [10]. AIRg was regarded as the 1st ISEC. Subjects with higher SI and AIRg were considered to have better glucose metabolism.

2.2.2.

M-LDGGI

This test is a simplified version of the low dose graded glucose infusion proposed by Polonsky [11], which we have used in a previously published study [8,12]. On the day of the test, catheters were placed as described above, and a stepped intravenous infusion of glucose (20% dextrose) was started at a rate of 2 mg/kg/min, followed by 6 mg/kg/min. Each infusion rate was maintained for 80 min. Blood samples were drawn every 20 min for the measurement of plasma insulin and glucose levels. The results were graphed as the slope of change of plasma insulin levels (y-axis) versus plasma glucose levels (x-axis), essentially reflecting insulin secretion in response to a certain level of plasma glucose. This slope was regarded as the 2nd ISEC.

2.2.3.

Metabolic tests

Homeostasis model assessment of insulin resistance (HOMAIR) and homeostasis model assessment of beta-cell function (HOMA-B) were calculated according to Matthew’s equations [13]. Blood samples were centrifuged immediately and stored at 30 8C until the time of analysis. Plasma insulin was measured by a commercial solid phase radioimmunoassay kit (Coat-A-Count insulin kit, Diagnostic Products Corporation, Los Angeles, CA, USA). Intra- and inter-assay coefficients

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diabetes research and clinical practice 100 (2013) 391–397

Table 1 – The demographic data of the three groups.

n Gender (M/F) Age (years) Body mass index (kg/m2) Waist circumference (cm) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Fasting plasma glucose (mmol/l) Total cholesterol (mmol/l) HDL-cholesterol (mmol/l) Triglyceride (mmol/l) log (Fasting plasma insulin (mU/l)) SI (10 4 min 1 pmol 1 l 1) log (1st ISEC (mU/min)) log (2nd ISEC) log HOMA-IR log HOMA-B

Normal fasting plasma glucose

Pre-diabetes

Type 2 diabetes

19 9/10 54.1  8.8 26.3  3.2 86.7  9.1 118.5  12.1 74.8  7.7 4.8  0.4c 4.4  0.8 1.2  0.5 1.4  0.4 1.4  0.5 2.1  1.2 2.0  0.6b,c 0.74  0.06b,c 0.2  0.5 1.7  0.5b,c

21 13/8 54.5  14.2 24.6  2.9 84.1  7.2 122.1  11.0 75.9  9.3 6.1  0.3c 4.4  0.6 1.2  0.3 1.2  0.7 1.2  0.4 2.6  1.7 1.5  0.4a 1.13  0.48a,c 0.2  0.7 1.2  0.7a,c

56 28/28 50.6  8.6 24.9  2.9 82.1  10.9 122.1  17.3 76.6  10.9 10.3  3.0a,b 4.4  1.0 1.2  0.3 1.4  0.7 1.3  0.5 1.8  1.5 1.1  0.5a 1.48  0.49a,b 0.1  0.6 0.9  0.6a,b

SI: insulin sensitivity; 1st ISEC: first phase insulin secretion, the acute insulin response after glucose load derived from FSIGT; 2nd ISEC: second phase insulin secretion, the slope of the changes of plasma insulin levels (y-axis) against the plasma glucose levels (x-axis) during the modified low dose graded glucose infusion test; HOMA-IR: homeostasis model assessment of insulin resistance, HOMA-B: homeostasis model assessment of beta-cell function. Data are expressed in mean  SD. a p < 0.05 against group 1. b p < 0.05 against group 2. c p < 0.05 against group 3.

2.3.

Statistical analysis

Data are presented as mean  standard deviation. One-way ANOVA tests were used to compare the demographic data, clinical characteristics, and test parameters between the three FPG groups. A Bonferoni test was used for post hoc examination. The distributions of HOMA-IR, HOMA-B, 1st ISEC, 2nd ISEC, and fasting plasma insulin (FPI) were normalized using log transformations. Correlations were evaluated by Pearson correlation. All statistical tests were two-sided and a p value < 0.05 was considered to be significant. Statistical analysis was performed using SPSS 10.0 software for windows (SPSS, Chicago, IL).

3.

Results

group. There was no significant difference between the three groups in log FPI, SI, and Log HOMA-IR. Fig. 1 depicts the changes in plasma insulin levels against plasma glucose levels of the M-LDGGI. The slopes of these lines represent the 2nd ISEC. Fig. 2 shows the changes of mean plasma glucose and insulin levels during the FSIGT. Fig. 3 shows the correlations between FPG levels and SI, log 1st ISEC, or log 2nd ISEC. Significant correlations were observed between FPG and log 1st ISEC (r = 0.421, p = 0.000, panel B), log 2nd ISEC (r = 0.552, p = 0.000, panel C), but not SI (r = 0.181, p = 0.098, panel A). Since the units and scales were different for each of these three lines, it was difficult to compare their slopes, which represent the rate of

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of variance for insulin were 3.3 and 2.5%, respectively. Plasma glucose was measured via a glucose oxidase method (YSI 203 glucose analyzer, Scientific Division, Yellow Spring Instrument Company Inc., Yellow Spring, OH, USA). Serum total cholesterol (TC), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) were measured by the dry, multilayer analytical Slide method using the Fuju DR-Chem 3000 analyzer (Fuji Photo Film Corporation Minato-Ku Tokyo, Japan).

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A 8 Normal fasting plasma glucose Pre-diabetes Type 2 diabetes

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deterioration of each parameter. In order to solve this problem, rather than plotting each parameter against FPG using the original units (e.g., mU/min for the 1st ISEC), we used uniquely designed lines to compare the rate of deterioration. Using the SI as an example, a regression equation was first obtained from Fig. 3A (SI = 2.745 – 0.088  FPG). The lowest value of FPG (3.94 mmol/l) was entered into the equation and the corresponding SI value (2.493  10 4  min 1 pmol 1 l 1) was obtained. This value was taken to represent the 100% SI value. Next, the percentage of SI of the highest FPG (1.363  10 4  min 1 pmol 1 l 1, 15.71 mmol/l, respectively) was calculated against the 100% SI value, which was 54%. Then, a line of SI changes according to different FPG levels was drawn from the 100% of the lowest FPG to the 54% of the highest FPG (Fig. 4). Similar methods were repeated for evaluating the relationship between FPG and the 1st and 2nd ISECs so that the changes of data across the same range of FPG could be more readily compared. Fig. 4 clearly shows that as the glucose levels increased, the SI decreased but did not reach a significant difference, meanwhile both the 1st and 2nd ISECs reduced dramatically. Furthermore, the percent decrease of the 1st ISEC from baseline was greater than that of the 2nd ISEC.

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4.

Discussion

T2D has two major defects: decreased SI, or conversely IR, and decreased ISEC. When IR first emerges, euglycemia can be maintained by a compensatory increase in ISEC by the betacell. However, as the disease progresses, the beta-cell becomes gradually exhausted. Finally, decompensation ensues and clinically evident T2D develops. There is a variable period of

diabetes research and clinical practice 100 (2013) 391–397

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Fig. 4 – A comparison of decreasing SI, first phase and second phase insulin secretion from baseline according to plasma glucose levels.

time between the diagnosis of T2D and the need for insulin therapy. Oral hypoglycemic agents, mainly insulin secretagogues, can effectively control blood glucose within an acceptable range during this time due to an intact 2nd ISEC. Despite the importance of the 2nd ISEC in the pathophysiology of T2D, most studies have only focused on 1st ISEC. The limited information on 2nd ISEC may be related to the fact that this phase is more difficult to measure. The study of van Haeften et al. was the first to shed light on the changes of 1st and 2nd ISECs as well as SI in subjects with different stages of glucose metabolism [14]. Although these authors used the sophisticated hyperglycemic clamp technique, they merely compared these three parameters between different groups of subjects, rather than directly exploring their relationships. In our study, two novel methods were used to further investigate this issue. First, as illustrated in Fig. 3, correlation analyses were performed between FPG and the other three parameters. Thus, we were able to study the independent changes in ISEC and SI associated with FPG increases. Secondly, the relative reductions in ISEC and SI from lowest to the highest FPG were plotted in Fig. 4, which allowed us to further compare the relative slopes between the three lines. Thus, we believe our results further the understanding of the natural course of diabetes pathogenesis. Other studies have also focused on the relative importance of ISEC and SI in the progression of T2D, but generally only consider the 1st ISEC. For instance, Fukushima et al. and Kim et al. suggested that the defect in ISEC may be more important than IR in the development of T2D among Japanese and Korean subjects, respectively [5,6]. In contrast, earlier studies from Western countries demonstrated equivocal findings. Two of these studies showed that SI deteriorated more than did ISEC as subjects progressed from normal glucose tolerance (NGT) to T2D [7,15]. Conversely, the opposite was reported in studies by Mari et al. and van Haeften et al. [14,16]. These conflict findings between studies may be attributed to many factors, including different races, genetic backgrounds, study designs, methods and even different grouping criteria [7,14– 16]. Although van Haeften et al. and Mari et al. made similar

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conclusions to ours, the findings concerning the role of SI were different. In both of these studies, SI was found to decline significantly as FPG increased. However, as illustrated in Fig. 4, this was not observed in the current study. These divergent results are not completely surprising given that the clinical backgrounds between Caucasians and Asians are different [17,18]. For instance, Asians are more insulin resistant and at higher risk of development of T2D at a lower BMI by comparison with Caucasians [17,18]. Whether our data could be extrapolated to other ethnic group is an important question. Based on the above discussion, it appears that the relative decrease in SI is lower among Asians than Caucasians. On the other hand, all the studies unanimously illustrate that the 1st ISEC disappears early in the natural course of T2D, regardless of race. Finally, very few studies have evaluated the 2nd ISEC. The purpose of our study was to compare the contribution of deteriorations in SI, and 1st and 2nd ISECs to the progression of T2D. Due to the inconsistent results pertaining to SI, we suggest that caution should be exercised when our results are being generalized to other ethnic groups. Further studies with a larger cohort and longer observational time are necessary. Although important, the role of the 2nd ISEC in the development of T2D is not only rarely studied but also controversial. After adjusting for age and BMI, van Haeften et al. observed a marked decrease of both phases of ISEC from NFG to PreDM, but no further decline from PreDM to T2D [14]. Furthermore, the same authors noted that the 1st ISEC deteriorated more severely than the 2nd ISEC in the progression from NFG to T2D [14]. In agreement with their findings, we also found that 1st ISEC decreased more dramatically than the 2nd ISEC as glucose levels increased (Fig. 4). However, contrary to their study, we found a significant decline of 2nd ISEC when progressing from PreDM to T2D. Although this minor divergence might be due to the aforementioned confounding factors such as race, other factors might also play a role. First, our study divided subjects into three groups according to 2012 ADA criteria [9] while van Haeften et al. stratified their subjects according to 1997 ADA classification, including NFG as an FPG  6.1 mmol/l [19]. Second, subjects in our T2D group had higher average FPG levels than did T2D subjects in van Haeften’s study (10.3 mmol/l versus 6.6 mmol/l, respectively). The wider range of FPG indicates more severe deterioration of beta-cell function in our T2D subjects. Hence, a greater decline of 2nd ISEC in our study is to be expected. On the other hand, if the SI did not change even in this much wider range of FPG, the less important role of deteriorating SI is further confirmed. Thirdly, it is well-documented that higher BMI is associated with increased beta-cell function [20]. Subjects in the study by van Haeften et al. had higher average BMIs than those in our study (26.7 kg/m2 versus 24.9 kg/m2), which suggests that the former group may have had better beta-cell reserve to prevent further loss of the 2nd ISEC. Our data show that SI does not decrease during the course of developing T2D. However, this finding does not imply that SI has a less important role. On the contrary, IR is the most important factor responsible for the initiation of glucose intolerance. Without IR, decompensation of the beta-cell would not occur. Interestingly, evidence suggests that IR is

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more severe in healthy Asians than in Caucasians, which confirms that it is still an important determinant of T2D pathogenesis [17,21]. In addition to IR, both phases of ISEC also differ between ethnic groups [21]. For instance, Torrens et al. observed that the ability of beta cells to compensate for IR is more pronounced in Africans than in Chinese [17]. The combined effect of a higher IR and lower beta cell response could partially explain the greater deterioration of beta cell function than SI during T2D development in Chinese subjects. However, the physiological basis of this hypothesis requires verification. A major strength of the present study is the simultaneous measurement of both the 1st and 2nd ISECs. Moreover, we evaluated the relationship between FPG levels and three components associated with T2D pathogenesis (SI, 1st ISEC, and 2nd ISEC). Thus, we were able to separately observe the changes in beta cell function and IR with increasing hyperglycemia as well as compare these changes using the same scale. Nevertheless, the current study has a number of limitations that must be mentioned. First, body fat content and distribution, and plasma free fatty acid levels, which are known to be associated with SI and betacell function, were not measured in this study [22]. However, evidence has shown that the correlation between waist circumference and SI might even be stronger than the relationship between intra-abdominal fat and SI (r = 0.63, p = 0.003 versus r = 0.59, p = 0.006) [23]. Han et al. also demonstrated that waist circumference could explain 77.8% variance of intra-abdominal fat [24]. Secondly, since an OGTT was not performed, post-challenge plasma glucose levels were not available for these patients. Thus, the relationships between post-challenge plasma glucose levels and either SI, or both phases of ISEC were not assessed. Further investigations focusing on these relationships could help define the precise role of SI and beta cell function in T2D pathogenesis. Since the 1st ISEC decreased most drastically with increasing FPG levels, it can be concluded that the 1st ISEC is the key trigger of T2D development. On the contrary, the 2nd ISEC remained more stable regardless of FPG level. This latter finding may explain the effectiveness of insulin secretagogues in managing the early stage of T2D. The results of this study can be helpful in the development of interventions aimed at stopping the progression and/or treating T2D in Chinese populations.

Funding None.

Authors contributions Hsieh Chang-Hsun analysed the data. Lin Jiunn-Diann wrote the manuscript. Wu Chung-Ze and Chen Yen-Lin reviewed and edited the manuscript. Pei Dee contributed to the discussion and edited the manuscript. Hsu Chun-Hsien, Chang Jin-Biou and Liang Yao-Jen helped with data analysis and contributed to the discussion.

Conflict of interest The authors declare that they have no conflict of interest.

Acknowledgements The authors thank all subjects who participated in the study.

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