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

Jiunn-Diann Lin a, Yen-Lin Chen b, Chun-Hsien Hsu c, Chung-Ze Wua, An-Tsz Hsieh a,Chang-Hsun Hsieh d, Jin-Biou Chang e, Yao-Jen Liang f, Dee Pei g,*aDivision of Endocrinology and Metabolism, Department of Internal Medicine, Shuang Ho Hospital, School of Medicine, College of Medicine,

Taipei Medical University, Taiwan, ROCbDepartment of Pathology, Cardinal Tien Hospital, Medical School, Catholic Fu-Jen University, Taipei, Taiwan, ROCcDepartment of Family Medicine, Cardinal Tien Hospital, Medical School, Catholic Fu-Jen University, Taipei, Taiwan, ROCdDivision of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical School,

Taiwan, ROCeDepartment of Pathology, National Defense Medical Center, Division of Clinical Pathology, Tri-Service General Hospital, Taipei, Taiwan, ROCfDepartment and Institute of Life Science, Fu-Jen Catholic University, New Taipei City, Taiwan, ROCgDepartment of Internal Medicine, Cardinal Tien Hospital, Medical School, Catholic Fu Jen University, Taipei, Taiwan, ROC

d i a b e t e s r e s e a r c h a n d c l i n i c a l p r a c t i c e 1 0 0 ( 2 0 1 3 ) 3 9 1 – 3 9 7

a r t i c l e i n f o

Article history:

Received 6 August 2012

Received in revised form

19 December 2012

Accepted 14 March 2013

Published on line 13 April 2013

Keywords:

First phase insulin secretion

Second phase insulin secretion

Type 2 diabetes

a b s t r a c t

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

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

type 2 diabetes (T2D) in Chinese subjects.

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

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

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

sampled intravenous glucose tolerance test. The results were interpreted as the slope of

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

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

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

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: peidee@gmail.com (D. Pei).

Abbreviations: SI, insulin sensitivity; 1st ISEC, first insulin secretion phase; 2nd ISEC, second insulin secretion phase; IR, insulinresistance; FPG, fasting plasma glucose; NFG, normal fasting plasma glucose; PreDM, pre-diabetes; T2D, type 2 diabetes; AIRg, acuteinsulin 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

Contents available at Sciverse ScienceDirect

Diabetes Researchand Clinical Practice

journal homepage: www.elsevier.com/locate/diabres

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

d i a b e t e s r e s e a r c h a n d c l i n i c a l p r a c t i c e 1 0 0 ( 2 0 1 3 ) 3 9 1 – 3 9 7392

1. 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. Addition-

ally, 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 hypogly-

cemic 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 medica-

tions known to influence SI and/or beta-cell function (includ-

ing 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 partici-

pation. 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. FSIGTAfter 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-LDGGIThis 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 testsHomeostasis model assessment of insulin resistance (HOMA-

IR) 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 Corpora-

tion, Los Angeles, CA, USA). Intra- and inter-assay coefficients

Table 1 – The demographic data of the three groups.

Normal fasting plasma glucose Pre-diabetes Type 2 diabetes

n 19 21 56

Gender (M/F) 9/10 13/8 28/28

Age (years) 54.1 � 8.8 54.5 � 14.2 50.6 � 8.6

Body mass index (kg/m2) 26.3 � 3.2 24.6 � 2.9 24.9 � 2.9

Waist circumference (cm) 86.7 � 9.1 84.1 � 7.2 82.1 � 10.9

Systolic blood pressure (mmHg) 118.5 � 12.1 122.1 � 11.0 122.1 � 17.3

Diastolic blood pressure (mmHg) 74.8 � 7.7 75.9 � 9.3 76.6 � 10.9

Fasting plasma glucose (mmol/l) 4.8 � 0.4c 6.1 � 0.3c 10.3 � 3.0a,b

Total cholesterol (mmol/l) 4.4 � 0.8 4.4 � 0.6 4.4 � 1.0

HDL-cholesterol (mmol/l) 1.2 � 0.5 1.2 � 0.3 1.2 � 0.3

Triglyceride (mmol/l) 1.4 � 0.4 1.2 � 0.7 1.4 � 0.7

log (Fasting plasma insulin (mU/l)) 1.4 � 0.5 1.2 � 0.4 1.3 � 0.5

SI (�10�4 min�1 pmol�1 l�1) 2.1 � 1.2 2.6 � 1.7 1.8 � 1.5

log (1st ISEC (mU/min)) 2.0 � 0.6b,c 1.5 � 0.4a 1.1 � 0.5a

log (2nd ISEC) �0.74 � 0.06b,c �1.13 � 0.48a,c �1.48 � 0.49a,b

log HOMA-IR �0.2 � 0.5 �0.2 � 0.7 0.1 � 0.6

log HOMA-B 1.7 � 0.5b,c 1.2 � 0.7a,c 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.

Plasma gluc ose level ( mmol/l)

4 6 8 10 12 14 16 18 20

Pla

sm

a in

su

lin le

ve

l (p

mo

l/l)

0

50

100

150

200

250

300

Normal f asting plasma glucose

Pre-d iabetes

Type 2 diabetes

0'

20'

40'

60'

80'

100'

120'

140'

160'

0'

20'

40'

60'80 '100'

120'

140'

160'

0' 20'

40'

60'

80'

100'

120' 140'160'

Fig. 1 – Plasma glucose and insulin concentration at various

time points during a modified low dose graded glucose

infusion test in each group.

d i a b e t e s r e s e a r c h a n d c l i n i c a l p r a c t i c e 1 0 0 ( 2 0 1 3 ) 3 9 1 – 3 9 7 393

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 Instru-

ment Company Inc., Yellow Spring, OH, USA). Serum total

cholesterol (TC), triglyceride (TG), and high-density lipopro-

tein 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).

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 examina-

tion. 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

The SI, 1st ISEC, 2nd ISEC, and other clinical characteristics of

the three groups are shown in Table 1. No significant

differences were observed in the demographic data among

the three groups. However, the NFG group had significantly

higher log1st and log 2nd ISECs and log HOMA-B levels than

the other two groups. Similarly, the PreDM group had a higher

log 2nd ISEC and log HOMA-B levels than those in the T2D

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

A

Fasting plas ma glu cose (mm ol/l)

2 4 6 8 10 12 14 16 18

Insu

linse

nsitiv

ity (

10

-4xm

in-1

xp

mo

l-1xl-1

)

0

2

4

6

8

r = -0.181, p=0 .098

B

C Fasting plasma gluco se (mmol /l)

2 4 6 8 10 12 14 16 18

Lo

g (

firs

t p

ha

se

in

su

lin s

ecre

tio

n (

U/m

in))

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

r = -0.4 21, p = 0.0 00

υ

Fasti ng plas ma glucose (m mol /l)

2 4 6 8 10 12 14 16 18

Log (

second p

hase insulin

secre

tion)

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0r = - 0.552, p = 0.00 0

Fig. 3 – The relationship between fasting plasma glucose

level and either insulin sensitivity, first phase and second

phase insulin secretion.

A

B

Time (min)

0 20 40 60 80 10 0 12 0 14 0 16 0 18 0 20 0

Pla

sm

a g

luco

se

le

ve

l (m

mo

l/l)

2

4

6

8

10

12

14

16

18

20

22

24

Normal fasting pla sma glu cose

Pre- diabetes

Type 2 diabetes

Time (min)

0 20 40 60 80 10 0 12 0 14 0 16 0 18 0 20 0

Pla

sm

a insulin

level (p

mol/l)

0

500

1000

1500

2000

2500

Norma l fas ting p las ma glu cose

Pre-diabetes

Type 2 diabetes

Fig. 2 – Plasma glucose and insulin concentration at various

time points during a frequently sampled intravenous

glucose tolerance test in each group.

d i a b e t e s r e s e a r c h a n d c l i n i c a l p r a c t i c e 1 0 0 ( 2 0 1 3 ) 3 9 1 – 3 9 7394

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.

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 beta-

cell. 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

Fasting plasma glucose (mmol/ l)

2 4 6 8 10 12 14 16 18

De

cre

ase

fro

m b

ase

line

(%

)

-60

-40

-20

0

20

40

60

80

100

120

Insulin sensitivity

Second pha se o f insulin se cretion

First pha se o f insulin se cretion

Fig. 4 – A comparison of decreasing SI, first phase and

second phase insulin secretion from baseline according to

plasma glucose levels.

d i a b e t e s r e s e a r c h a n d c l i n i c a l p r a c t i c e 1 0 0 ( 2 0 1 3 ) 3 9 1 – 3 9 7 395

time between the diagnosis of T2D and the need for insulin

therapy. Oral hypoglycemic agents, mainly insulin secretago-

gues, can effectively control blood glucose within an accept-

able 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 tech-

nique, 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 reduc-

tions 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

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 progres-

sion 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 diver-

gence 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

d i a b e t e s r e s e a r c h a n d c l i n i c a l p r a c t i c e 1 0 0 ( 2 0 1 3 ) 3 9 1 – 3 9 7396

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 beta-

cell 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.

r e f e r e n c e s

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