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Diabetes Research and Clinical Practice 76 (2007) 397–403

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Insulin secretion and insulin resistance in newly diagnosed,


drug naive prediabetes and type 2 diabetes patients
with/without metabolic syndrome
Sang Youl Rhee a,b, Suk Chon a,b, Seungjoon Oh a,b, Sung Woon Kim a,b,
Jin-Woo Kim a,b, Young Seol Kim a,b, Jeong-taek Woo a,b,*
a
Department of Endocrinology and Metabolism, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
b
Research Institute of Endocrinology, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
Received 6 June 2006; accepted 19 September 2006
Available online 1 December 2006

Abstract
The relationships between insulin secretion and resistance in subjects with newly diagnosed prediabetes (preDM) and type 2 DM
according to the presence of metabolic syndrome (MS) were controversial. We performed OGTT on 322 drug naive subjects with a
history of hyperglycemia of 3 months, and divided into three groups, NGT, preDM (IFG and/or IGT), and T2DM. We also
diagnosed these subjects with respect to MS according to ATP III criteria modified by Asia-Pacific guidelines and compared IGI and
HOMA-IR. When compare groups stratified by the presence of MS, preDM and T2DM groups with MS showed significantly higher
mean HOMA-IR and IGI than those without. When compare groups with respect to glucose tolerance, NGT, preDM, and T2DM
subgroups in MS group showed significant higher HOMA-IR and lower IGI according to glucose tolerance. However, NGT, preDM,
and T2DM subgroups in non-MS group showed a significant decrease in IGI but no significant difference in HOMA-IR as glucose
tolerance worsened. In conclusion, deterioration in IGI and aggravation of HOMA-IR are both important in the primary
pathogenesis of diabetes in those with MS. However, IGI deterioration may be the only important factor in the primary
pathogenesis of T2DM in the absence of MS.
# 2006 Elsevier Ireland Ltd. All rights reserved.

Keywords: Asian diabetes; Type 2 diabetes; Insulin resistance; Insulin secretion

1. Introduction deterioration in insulin secretion and an aggravation of


insulin resistance are known to be essentials in the
The pathogenesis of diabetes is complicated by primary pathogenesis of type 2 diabetes mellitus (DM)
several metabolism-related problems. In particular, a [1].
A deterioration in insulin secretion is caused by
glucose toxicity, b-cell dysfunction, an impaired pro-
* Corresponding author at: Department of Endocrinology and Meta- insulin biosynthesis, and lipotoxicity [2]. Of these, b-
bolism, College of Medicine, Kyung Hee University, #1 Hoegi-dong, cells dysfunction is considered common trait in type 2
Dongdaemoon-ku, Seoul, Republic of Korea.
DM [3,4]. Absolute b-cell function decline due to
Tel.: +82 2 958 8199/8200/8128; fax: +82 2 968 1848.
E-mail addresses: jtwoomd@khmc.or.kr, bard95@hanmail.net disease aggravation leads to a deterioration of insulin
(J.-t. Woo). secretion and causes diabetes.

0168-8227/$ – see front matter # 2006 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.diabres.2006.09.035

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398 S.Y. Rhee et al. / Diabetes Research and Clinical Practice 76 (2007) 397–403

Insulin resistance can be defined as resistance to the in these subjects were determine using specific
metabolic effects of endogenous insulin secretion. equations and the study subjects were divided into
Physiologically, endogenous insulin secretion allows three groups, which were additionally subdivided based
the body’s glucose metabolism to maintain an on the presence or absence of MS, and differences
equilibrium [5]. However, aggravation of insulin between these subgroups were analyzed.
resistance interrupts normal physiologic actions of
insulin and causes hyperinsulinemia, which is not only 2. Subjects and methods
important in progression of type 2 DM but is also
important in other diseases such as hypertension, 2.1. Subjects
dyslipidemia, atherosclerosis, and malignancy [6,7].
Several cross-sectional and longitudinal studies have This study was carried out from January 2002 to November
showed that a deterioration in insulin secretion and an 2004 inclusive on 322 subjects suspected of having type 2 DM
at the Department of Endocrinology and Metabolism, Kyung
aggravation of insulin resistance occur simultaneously
Hee University Hospital. In order to avoid severe b-cell
before clinically overt hyperglycemia appears [8,9].
dysfunction and to exclude any change in insulin secretory
This means that during the onset of type 2 DM, function or insulin resistance due to artificial intervention,
increases in insulin secretion occurs complementary to study subjects were confined to have a history of hypergly-
rising insulin resistance, and that as a result patients cemia of less than 3 months and no history of taking a
show normal glucose tolerance. However, as endogen- medication that might affect glucose metabolism.
ous insulin production falls, there is not enough insulin
to compensate for the increasing insulin resistance. This 2.2. Methods
process explains the primary pathogenesis of type 2 DM
[1,2]. The medical histories of the study subjects were reviewed
The aggravation of insulin resistance is also known to ensure that they fulfilled the enrollment criteria. Height,
weight, body mass index (BMI), abdominal circumference,
to be closely related to metabolic syndrome (MS) [10].
resting blood pressure, and other anthropometric data were
MS is not a definitive disease entity but rather a cluster
also recorded. To diagnose type 2 DM, we used oral glucose
of diseases, which include obesity, hyperglycemia, and tolerance test (OGTT). Total cholesterol, HDL-cholesterol,
disorders of glucose tolerance and dyslipidemia [11]. LDL-cholesterol, triglyceride, and HbA1c were measured
According to NHANES III, the prevalence of MS before carrying out OGTT.
among American adults of over 20 years old is 20%, Before OGTT, basal plasma glucose (Glc0), insulin (Ins0),
while among for those over 60 years old its prevalence is and C-peptide (Cpep0) levels were measured after an 8 h fast.
as high as 40% [12]. After a 75 g of glucose loading, plasma glucose concentra-
In terms of insulin resistance, type 2 DM and MS are tions at 30, 60, 90, and 120 min (Glc30, Glc60, Glc90, and
closely related. The Botnia study showed that 84% of Glc120) and the insulin (Ins30) and C-peptide (Cpep30) con-
men and 78% of women with type 2 DM had centrations at 30 min were measured. According to OGTT
results, subject were divided into three groups; a normal
accompanying MS. For patients with prediabetes,
glucose tolerance (NGT) group, a prediabetes (preDM) group,
64% of men and 42% of women had MS, and for
comprised of an impaired fasting glucose (IFG) group and/or
NGT groups, only 15% of men and 10% of women had an impaired glucose tolerance (IGT) group, and a type 2
MS [13]. Not all type 2 DM patients have MS and diabetes mellitus (T2DM) group. Study subjects were diag-
neither do all MS patients have accompanying type 2 nosed according to the American Diabetes Association 2004
DM. This signifies that even though these two diseases [14]. And, HOMA-IR (the insulin resistance index) and IGI
have much in common, that they differ pathophysio- (Insulinogenic index, which means the insulin secretion abil-
logically. ity index) were calculated for all subjects who underwent
For these reasons, we undertook this study to OGTT [15].
compare differences in type 2 DM according to the co- Ins0  Glc0
HOMA-IR ¼
existence of MS with respect to insulin secretion and 22:5
insulin resistance. To exclude the effect of artificial
Ins30  Ins0
intervention or severe b-cell dysfunction, the subjects IGI ¼
enrolled in this study were confined to newly diagnosed 18 ðGlc30  Glc0 Þ
and drug naive. Thus, the 322 study subjects had no where Ins0 is the fasting plasma insulin (mIU/L), Ins30 the
drug history that may have affected glucose metabolism insulin 30 min after glucose intake (mIU/L), Glc0 the fasting
and had a relatively short medical history of hypergly- plasma glucose (mmol/L), and Glc30 is the plasma glucose
cemia. Insulin resistance and insulin secretory indexes 30 min after glucose intake (mmol/L).

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S.Y. Rhee et al. / Diabetes Research and Clinical Practice 76 (2007) 397–403 399

Table 1
Modified ATP III diagnostic criteria of metabolic syndrome incorpor-
ating the Asia-Pacific abdominal obesity guideline
Abdominal obesity Waist circumference
(by Asia-Pacific guideline)
Men >90 cm
Women >80 cm
Triglyceride 150 mg/dL (1.7 mmol/L)
HDL cholesterol
Men <40 mg/dL (1.03 mmol/L)
Women <50 mg/dL (1.3 mmol/L)
Blood pressure 130 mmHg/85 mmHg or
anti-hypertensive agent Fig. 1. Prevalence of metabolic syndrome among study subjects.
Fasting plasma glucose 110 mg/dL or diabetes

Study subjects were stratified according to the presence of with impaired fasting blood glucose and/or impaired
MS, and were diagnosed according to adult treatment panel glucose tolerance, and 178 with type 2 DM. According
(ATP) III diagnostic criteria of MS of the National Cholesterol to ATP III criteria modified in-line with the Asian-
Education Program (NCEP) by using basic anthropometric Pacific guidelines, 218 subjects (67.7% of total) were
data, OGTT results, and lipid profiles [11]. However, for MS
diagnosed with MS. When subjects in the three main
diagnosis, abdominal circumference thresholds were taken as
groups were compared, 34.9% of the NGT group had
90 cm for men and 80 cm for women, according to the Asian-
Pacific abdominal obesity guidelines [16] (Table 1). MS, whereas 60.5% of the prediabetes group, and
By using the indices mentioned above, the three subject 82.6% of the type 2 DM group had MS (Fig. 1). By
groups were subdivided into six subgroups, i.e., NGT, preDM, gender, 41.3% of men and 29.4% of women in the NGT
and T2DM each with/without MS. The clinical characteristics, group, 56.5% of men and 65.7% of women in the
insulin secretory functions, and insulin resistances of these prediabetes group, and 75.7% of men and 90.3% of
subgroups were compared. women in the type 2 DM group had MS.
For raising a reliability of subject’s selection, we also When the three groups were compared according to
investigated the possibility of including inappropriate subjects the presence or not of MS, and excluding the factors that
with genetic defects (i.e., MODY) or immune mediated diabetes were used to diagnose the MS, most variables such as
(i.e., type 1DM or SPIDDM) that might fall into the error of
age, fasting blood glucose, blood glucose 2 h after
interpreting study results. To exclude this possibility, we
glucose load, HbA1c, total cholesterol, and LDL were
reviewed all pedigree of study subjects and exclude subjects
whose first-degree relatives had diabetes less than 25 years old or not statistically significant in the individual groups
a tendency of autosomal dominant hereditary pattern. We also (Table 2). But in the type 2 DM group, the prevalence of
measured islet autoantibody (GAD Ab and IA-2 Ab) of all women was significantly high, and in the prediabetes
preDM and T2DM subjects by radioimmunoassay (Linco Rese- and type 2 DM groups, the concentrations of insulin and
arch, MO, USA) and exclude autoantibody positive subjects. C-peptide at the time of glucose loading (Ins0, Cpep0)
and 30 min (Ins30, Cpep30) after loading were sig-
2.3. Data analysis nificantly higher for MS subgroups.
Statistical analysis and data management were carried
using the Statistical Package for the Social Sciences (SPSS,
3.2. Comparisons of HOMA-IR and IGI according
Version 12.0; SPSS Inc., Chicago, Illinois). In order to confirm
to glucose tolerance and metabolic syndrome
statistical significances between subgroups, the Student’s
t-test, one-way ANOVA, and the Chi-square test were used.
The three groups (NGT, preDM, and type 2 DM)
were stratified by the number of MS components and
3. Results HOMA-IR and IGI were compared (Table 3). HOMA-
IR increased significantly as the number of MS
3.1. Clinical characteristics of the study subjects components increased in the preDM and type 2 DM
groups. However, IGI significantly increased as the
According to OGTT results, 63 subjects were number of MS components increased only in the preDM
diagnosed with normal glucose tolerance, 81 subjects group, whereas in the type 2 DM group, IGI showed no

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400 S.Y. Rhee et al. / Diabetes Research and Clinical Practice 76 (2007) 397–403

Table 2
Clinical characteristics of the study subjects
NGT Prediabetes New T2DM
MS No MS p MS No MS p MS No MS p
Subjects (M/F) 22 (12/10) 41 (17/24) 0.321 49 (26/23) 32 (20/12) 0.402 147 (72/75) 31 (23/8) 0.011
Age (years) 48.7  13.3 44.9  12.4 0.259 51.4  10.5 51.6  10.4 0.924 52.9  11.7 49.7  12.5 0.171
BMI (kg/m2) 26.5  3.4 24.3  5.0 0.075 27.1  3.3 25.0  2.6 0.004 26.6  3.3 23.3  2.5 <0.001
AC (cm) 91.5  5.1 85.5  11.1 0.001 93.0  7.8 86.5  6.4 0.002 92.1  8.7 85.0  6.4 <0.001
SBP (mmHg) 138.8  20.2 120.9  14.8 <0.001 132.3  20.7 123.7  17.4 0.054 131.1  18.6 119.1  14.6 0.001
DBP (mmHg) 89.1  12.4 78.1  9.4 <0.001 84.7  13.2 77.9  11.4 0.019 84.3  12.8 77.7  11.7 0.010
HTN med 9 (40.91%) 4 (9.76%) 0.004 15 (30.61%) 9 (28.13%) 0.811 67 (45.58%) 2 (34.2%) <0.001
Smoker 6 (27.27%) 12 (29.27%) 0.867 10 (20.41%) 10 (31.25%) 0.269 38 (25.85%) 14 (45.16%) 0.032
FPG (mmol/L) 5.01  0.58 5.20  0.47 0.164 5.68  0.68 5.59  0.69 0.529 8.40  3.50 8.37  2.78 0.979
pp2 H (mmol/L) 6.39  1.14 5.93  1.18 0.143 8.92  1.26 8.98  1.20 0.835 16.49  5.12 16.29  3.98 0.838
Ins0 (mIU/L) 8.3  5.4 7.7  6.0 0.698 10.5  5.2 7.2  3.8 0.003 9.6  6.5 5.5  3.0 <0.001
Ins30 (mIU/L) 70.6  46.4 55.2  39.8 0.174 62.2  48.9 38.3  24.3 0.004 24.5  24.5 13.5  9.1 <0.001
C-pep0 (nmol/L) 0.67  0.23 0.53  0.30 0.119 0.77  0.43 0.53  0.23 0.010 0.73  0.40 0.50  0.30 0.005
C-pep30 (nmol/L) 2.33  0.90 1.86  0.73 0.031 1.96  0.83 1.50  0.67 0.004 1.10  0.70 0.80  0.47 0.002
HbA1c (%) 5.00  0.76 5.03  0.54 0.886 5.47  0.77 5.70  0.81 0.250 7.87  2.01 7.56  2.09 0.447
T-chol (mmol/L) 5.00  1.01 5.05  1.06 0.858 5.40  1.39 5.23  1.33 0.564 5.46  1.13 5.27  0.73 0.246
TG (mmol/L) 2.13  1.39 1.31  0.77 0.016 2.70  2.91 1.34  0.66 0.003 2.39  1.58 1.52  1.18 0.004
HDL (mmol/L) 1.07  0.20 1.33  0.28 <0.001 0.98  0.19 1.26  0.35 <0.001 1.05  0.24 1.21  0.23 <0.001
LDL (mmol/L) 2.93  1.00 3.03  0.94 0.799 3.00  0.80 3.30  1.18 0.296 3.15  0.97 3.08  0.62 0.800
IGI 1.25  0.97 0.91  0.74 0.124 0.91  0.77 0.55  0.63 0.031 0.24  0.40 0.10  0.01 0.001
HOMA-IR 1.83  1.12 1.80  1.42 0.919 2.68  1.39 1.79  0.91 0.001 3.45  2.49 2.37  1.37 0.003
Values are mean  S.D. Bold values means statistically significant ( p < 0.05).

significant increase. Meanwhile, in the NGT groups HOMA-IR and lower IGI according to glucose
HOMA-IR and IGI showed no significant differences. tolerance (Fig. 3). On the other hand, the NGT, preDM,
On comparing the three groups stratified by the and type 2 DM subgroups in non-MS group showed a
presence of MS, mean HOMA-IR and IGI were higher significant decrease in IGI but no significant difference
in those with MS (Fig. 2). However, in the case of the in HOMA-IR as glucose tolerance worsened.
prediabetes and type 2 DM groups those with MS,
showed significantly higher HOMA-IR and IGI values 4. Discussion
than those without, whereas in the NGT subgroup,
HOMA-IR and IGI levels were not dependent on the Like other studies, this study shows that MS and type
presence of MS. 2 DM have much in common. Unlike the majority of
When the three groups were subdivided according to studies carried out in the West, which found higher
the presence of MS and examined with respect to prevalences for MS in men than in women, this study
glucose tolerance, the NGT, preDM, and type 2 DM shows that women had the higher prevalence [12,13].
subgroups in MS group showed significant higher This dissimilarity in prevalence is probably caused by

Table 3
Change of IGI and HOMA-IR according to the number of MS components among study subjects
0–2 3 4 5 p Total
Change of IGI according to the component number of MS
NGT 0.91  0.74, n = 41 1.28  1.05, n = 18 1.10  0.57, n = 4 0.448 1.03  0.83, n = 63
Prediabetes 0.55  0.63, n = 32 0.86  0.71, n = 28 0.91  0.59, n = 14 1.12  1.28, n = 7 0.019 0.77  0.73, n = 81
T2DM 0.10  0.10, n = 31 0.16  0.24, n = 48 0.31  0.56, n = 56 0.22  0.26, n = 43 0.051 0.21  0.26, n = 178
Change of HOMA-IR according to the component number of MS
NGT 1.80  1.42, n = 41 1.75  0.88, n = 18 2.19  2.04, n = 4 0.641 1.81  1.32, n = 63
Prediabetes 1.79  0.91, n = 32 2.32  1.06, n = 28 3.06  1.71, n = 14 3.35  1.57, n = 7 0.005 2.33  1.29, n = 81
T2DM 2.06  1.48, n = 31 2.75  1.94, n = 48 3.16  2.31, n = 56 4.59  2.90, n = 43 <0.001 3.20  2.40, n = 178
Values are mean  S.D. Bold values means statistically significant ( p < 0.05).

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S.Y. Rhee et al. / Diabetes Research and Clinical Practice 76 (2007) 397–403 401

Fig. 2. IGI and HOMA-IR differences according to the presence of Fig. 3. Differences in IGI and HOMA-IR according to glucose
MS in the three glucose tolerance subgroups. Both IGI and HOMA-IR tolerance in patients with/without MS. In MS subjects, IGI values
were significantly elevated in MS subgroups. progressively decreased and HOMA-IR values progressively
increased with increased glucose tolerance aggravation. However,
though IGI values progressively decreased in patients without MS
ethnic differences and the different diagnostic criteria with increasing glucose tolerance aggravation, HOMA-IR values were
used. According to a study carried out on normal unaffected.
subjects presenting for a health examination, the
prevalence of MS in Korea is 6.8% (5.2% for men HOMA-IR levels than the corresponding non-MS
and 9.0% for women) according to the ATP III criteria, subgroups, which mean that a change in insulin
and 10.9% (9.8% for men and 12.4% for women) secretion (IGI) occurred as insulin resistance
according to the modified Asian-Pacific criteria. Here (HOMA-IR) was aggravated by the presence of MS
again women showed somewhat higher prevalence [17]. within each group. However, this tendency was not clear
However, we also believe there are other external in NGT subjects, but as the difference in insulin
factors that may have contributed to this female resistance shows no statistical significance, neither does
predominance, especially since Korean men of 40–50 the secretion of insulin show any significant difference.
years old have two to three times the mortality rate of However, when comparing the prediabetes and type 2
women, as this increased survival of women per se DM groups in terms of number of MS diagnostic
probably affected the higher prevalence observed in components, IGI showed no significant changes in the
women [17]. type 2 DM group. HOMA-IR levels in both groups
On comparing the three study groups, i.e., NGT, increased as the number of diagnostic components
preDM, and type 2 DM, according to the presence or increased. But IGI showed a significant decrease with
absence of MS, variables such as fasting blood glucose, increased number of components only in the prediabetes
plasma glucose 2 h after glucose loading, and HbA1c group. This means that in the prediabetes group, insulin
show no statistical significance. However, MS sub- secretion increases compensatory to an aggravation of
groups in the prediabetes and type 2 DM groups showed insulin resistance, whereas in the type 2 DM group, this
significantly higher Ins0, Ins30, Cpep0, Cpep30, IGI, and compensatory insulin secretion is insufficient. Therefore,

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402 S.Y. Rhee et al. / Diabetes Research and Clinical Practice 76 (2007) 397–403

according to the Asian-Pacific abdominal obesity


guidelines when diagnosing MS. Lastly, HOMA-IR
and IGI are only surrogates of insulin resistance and
secretion, so we could not reflect exact status of insulin
resistance and secretion in vivo.
However, regardless of its limitations, this study is
the first to compare the relationship between the
presence of MS and insulin secretory function and
insulin resistance in early stage drug naive patients,
such that no severe b-cell exhaustion or artificial
intervention could have caused changes in insulin
secretory function or insulin tolerance. Moreover,
Fig. 4. Hypothesis concerning primary metabolic changes during the importantly the study demonstrates the existence of
development of type 2 DM. In patients with MS, IGI (compensatory early stage type 2 DM patients that show no close
insulin secretion) deterioration and HOMA-IR (insulin resistance)
aggravation are both important in the primary pathogenesis of dia-
relation between insulin secretion deterioration and
betes. However, HOMA-IR aggravation may not be an important insulin resistance aggravation. Prospective studies that
factor in the pathogenesis of diabetes in those without MS. overcome the present study’s limitations, comparative
studies between races, and work at the molecular level
our results imply that a deterioration in insulin secretory would empower us to present a clearer view of the
function may be more important than an aggravated comparative characteristics, relationships, and patho-
insulin resistance in early stage type 2 DM. physiologies of MS and early stage type 2 DM.
The most noticeable result of our study is that even
though decreasing IGI was statistically significant in Acknowledgement
non-MS subjects, HOMA-IR did not change signifi-
cantly as glucose tolerance worsened (Fig. 3). Type 2 This study was supported by a grant of the Korea
DM subjects with accompanying MS showed the same Health 21 R&D Project, Ministry of Health &Welfare,
significant effect as insulin resistance was aggravated Republic of Korea (Grant No. A050463). The authors
and insulin secretory function deteriorated. However, in appreciate the efforts of Young Ji Yoon in preparation of
type 2 DM subjects without MS, only insulin secretory the manuscript.
function significantly decreased; insulin resistance
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