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without metabolic syndrome
Diabetes Research and Clinical Practice 76 (2007) 397–403 www.elsevier.com/locate/diabres
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 The pathogenesis of diabetes is complicated by several metabolism-related problems. In particular, a
* Corresponding author at: Department of Endocrinology and Metabolism, College of Medicine, Kyung Hee University, #1 Hoegi-dong, Dongdaemoon-ku, Seoul, Republic of Korea. Tel.: +82 2 958 8199/8200/8128; fax: +82 2 968 1848. E-mail addresses: [email protected], [email protected] (J.-t. Woo).
deterioration in insulin secretion and an aggravation of insulin resistance are known to be essentials in the primary pathogenesis of type 2 diabetes mellitus (DM) [1]. A deterioration in insulin secretion is caused by glucose toxicity, b-cell dysfunction, an impaired proinsulin biosynthesis, and lipotoxicity [2]. Of these, bcells dysfunction is considered common trait in type 2 DM [3,4]. Absolute b-cell function decline due to disease aggravation leads to a deterioration of insulin 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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Insulin resistance can be defined as resistance to the metabolic effects of endogenous insulin secretion. Physiologically, endogenous insulin secretion allows the body’s glucose metabolism to maintain an equilibrium [5]. However, aggravation of insulin resistance interrupts normal physiologic actions of insulin and causes hyperinsulinemia, which is not only important in progression of type 2 DM but is also important in other diseases such as hypertension, dyslipidemia, atherosclerosis, and malignancy [6,7]. Several cross-sectional and longitudinal studies have showed that a deterioration in insulin secretion and an aggravation of insulin resistance occur simultaneously before clinically overt hyperglycemia appears [8,9]. This means that during the onset of type 2 DM, increases in insulin secretion occurs complementary to rising insulin resistance, and that as a result patients show normal glucose tolerance. However, as endogenous insulin production falls, there is not enough insulin to compensate for the increasing insulin resistance. This process explains the primary pathogenesis of type 2 DM [1,2]. The aggravation of insulin resistance is also known to be closely related to metabolic syndrome (MS) [10]. MS is not a definitive disease entity but rather a cluster of diseases, which include obesity, hyperglycemia, and disorders of glucose tolerance and dyslipidemia [11]. According to NHANES III, the prevalence of MS among American adults of over 20 years old is 20%, while among for those over 60 years old its prevalence is as high as 40% [12]. In terms of insulin resistance, type 2 DM and MS are closely related. The Botnia study showed that 84% of men and 78% of women with type 2 DM had accompanying MS. For patients with prediabetes, 64% of men and 42% of women had MS, and for NGT groups, only 15% of men and 10% of women had MS [13]. Not all type 2 DM patients have MS and neither do all MS patients have accompanying type 2 DM. This signifies that even though these two diseases have much in common, that they differ pathophysiologically. For these reasons, we undertook this study to compare differences in type 2 DM according to the coexistence of MS with respect to insulin secretion and insulin resistance. To exclude the effect of artificial intervention or severe b-cell dysfunction, the subjects enrolled in this study were confined to newly diagnosed and drug naive. Thus, the 322 study subjects had no drug history that may have affected glucose metabolism and had a relatively short medical history of hyperglycemia. Insulin resistance and insulin secretory indexes
in these subjects were determine using specific equations and the study subjects were divided into three groups, which were additionally subdivided based on the presence or absence of MS, and differences between these subgroups were analyzed. 2. Subjects and methods 2.1. Subjects This study was carried out from January 2002 to November 2004 inclusive on 322 subjects suspected of having type 2 DM at the Department of Endocrinology and Metabolism, Kyung Hee University Hospital. In order to avoid severe b-cell dysfunction and to exclude any change in insulin secretory function or insulin resistance due to artificial intervention, study subjects were confined to have a history of hyperglycemia of less than 3 months and no history of taking a medication that might affect glucose metabolism. 2.2. Methods The medical histories of the study subjects were reviewed to ensure that they fulfilled the enrollment criteria. Height, weight, body mass index (BMI), abdominal circumference, resting blood pressure, and other anthropometric data were also recorded. To diagnose type 2 DM, we used oral glucose tolerance test (OGTT). Total cholesterol, HDL-cholesterol, LDL-cholesterol, triglyceride, and HbA1c were measured before carrying out OGTT. Before OGTT, basal plasma glucose (Glc0), insulin (Ins0), and C-peptide (Cpep0) levels were measured after an 8 h fast. After a 75 g of glucose loading, plasma glucose concentrations at 30, 60, 90, and 120 min (Glc30, Glc60, Glc90, and Glc120) and the insulin (Ins30) and C-peptide (Cpep30) concentrations at 30 min were measured. According to OGTT results, subject were divided into three groups; a normal glucose tolerance (NGT) group, a prediabetes (preDM) group, comprised of an impaired fasting glucose (IFG) group and/or an impaired glucose tolerance (IGT) group, and a type 2 diabetes mellitus (T2DM) group. Study subjects were diagnosed according to the American Diabetes Association 2004 [14]. And, HOMA-IR (the insulin resistance index) and IGI (Insulinogenic index, which means the insulin secretion ability index) were calculated for all subjects who underwent OGTT [15]. HOMA-IR ¼ IGI ¼
Ins0 Glc0 22:5
Ins30 Ins0 18 ðGlc30 Glc0 Þ
where Ins0 is the fasting plasma insulin (mIU/L), Ins30 the insulin 30 min after glucose intake (mIU/L), Glc0 the fasting plasma glucose (mmol/L), and Glc30 is the plasma glucose 30 min after glucose intake (mmol/L).
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Table 1 Modified ATP III diagnostic criteria of metabolic syndrome incorporating the Asia-Pacific abdominal obesity guideline Abdominal obesity Men Women
Waist circumference (by Asia-Pacific guideline) >90 cm >80 cm
Triglyceride
150 mg/dL (1.7 mmol/L)
HDL cholesterol Men Women
<40 mg/dL (1.03 mmol/L) <50 mg/dL (1.3 mmol/L)
Blood pressure Fasting plasma glucose
130 mmHg/85 mmHg or anti-hypertensive agent 110 mg/dL or diabetes
Study subjects were stratified according to the presence of MS, and were diagnosed according to adult treatment panel (ATP) III diagnostic criteria of MS of the National Cholesterol Education Program (NCEP) by using basic anthropometric data, OGTT results, and lipid profiles [11]. However, for MS diagnosis, abdominal circumference thresholds were taken as 90 cm for men and 80 cm for women, according to the AsianPacific abdominal obesity guidelines [16] (Table 1). By using the indices mentioned above, the three subject groups were subdivided into six subgroups, i.e., NGT, preDM, and T2DM each with/without MS. The clinical characteristics, insulin secretory functions, and insulin resistances of these subgroups were compared. For raising a reliability of subject’s selection, we also investigated the possibility of including inappropriate subjects with genetic defects (i.e., MODY) or immune mediated diabetes (i.e., type 1DM or SPIDDM) that might fall into the error of interpreting study results. To exclude this possibility, we reviewed all pedigree of study subjects and exclude subjects whose first-degree relatives had diabetes less than 25 years old or a tendency of autosomal dominant hereditary pattern. We also measured islet autoantibody (GAD Ab and IA-2 Ab) of all preDM and T2DM subjects by radioimmunoassay (Linco Research, MO, USA) and exclude autoantibody positive subjects. 2.3. Data analysis Statistical analysis and data management were carried using the Statistical Package for the Social Sciences (SPSS, Version 12.0; SPSS Inc., Chicago, Illinois). In order to confirm statistical significances between subgroups, the Student’s t-test, one-way ANOVA, and the Chi-square test were used.
3. Results 3.1. Clinical characteristics of the study subjects According to OGTT results, 63 subjects were diagnosed with normal glucose tolerance, 81 subjects
Fig. 1. Prevalence of metabolic syndrome among study subjects.
with impaired fasting blood glucose and/or impaired glucose tolerance, and 178 with type 2 DM. According to ATP III criteria modified in-line with the AsianPacific guidelines, 218 subjects (67.7% of total) were diagnosed with MS. When subjects in the three main groups were compared, 34.9% of the NGT group had MS, whereas 60.5% of the prediabetes group, and 82.6% of the type 2 DM group had MS (Fig. 1). By gender, 41.3% of men and 29.4% of women in the NGT group, 56.5% of men and 65.7% of women in the prediabetes group, and 75.7% of men and 90.3% of women in the type 2 DM group had MS. When the three groups were compared according to the presence or not of MS, and excluding the factors that were used to diagnose the MS, most variables such as age, fasting blood glucose, blood glucose 2 h after glucose load, HbA1c, total cholesterol, and LDL were not statistically significant in the individual groups (Table 2). But in the type 2 DM group, the prevalence of women was significantly high, and in the prediabetes and type 2 DM groups, the concentrations of insulin and C-peptide at the time of glucose loading (Ins0, Cpep0) and 30 min (Ins30, Cpep30) after loading were significantly higher for MS subgroups.
3.2. Comparisons of HOMA-IR and IGI according to glucose tolerance and metabolic syndrome The three groups (NGT, preDM, and type 2 DM) were stratified by the number of MS components and HOMA-IR and IGI were compared (Table 3). HOMAIR increased significantly as the number of MS components increased in the preDM and type 2 DM groups. However, IGI significantly increased as the number of MS components increased only in the preDM group, whereas in the type 2 DM group, IGI showed no
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Table 2 Clinical characteristics of the study subjects NGT
Subjects (M/F) Age (years) BMI (kg/m2) AC (cm) SBP (mmHg) DBP (mmHg) HTN med Smoker FPG (mmol/L) pp2 H (mmol/L) Ins0 (mIU/L) Ins30 (mIU/L) C-pep0 (nmol/L) C-pep30 (nmol/L) HbA1c (%) T-chol (mmol/L) TG (mmol/L) HDL (mmol/L) LDL (mmol/L) IGI HOMA-IR
Prediabetes
New T2DM
MS
No MS
p
MS
No MS
p
MS
No MS
p
22 (12/10) 48.7 13.3 26.5 3.4 91.5 5.1 138.8 20.2 89.1 12.4 9 (40.91%) 6 (27.27%) 5.01 0.58 6.39 1.14 8.3 5.4 70.6 46.4 0.67 0.23 2.33 0.90 5.00 0.76 5.00 1.01 2.13 1.39 1.07 0.20 2.93 1.00 1.25 0.97 1.83 1.12
41 (17/24) 44.9 12.4 24.3 5.0 85.5 11.1 120.9 14.8 78.1 9.4 4 (9.76%) 12 (29.27%) 5.20 0.47 5.93 1.18 7.7 6.0 55.2 39.8 0.53 0.30 1.86 0.73 5.03 0.54 5.05 1.06 1.31 0.77 1.33 0.28 3.03 0.94 0.91 0.74 1.80 1.42
0.321 0.259 0.075 0.001 <0.001 <0.001 0.004 0.867 0.164 0.143 0.698 0.174 0.119 0.031 0.886 0.858 0.016 <0.001 0.799 0.124 0.919
49 (26/23) 51.4 10.5 27.1 3.3 93.0 7.8 132.3 20.7 84.7 13.2 15 (30.61%) 10 (20.41%) 5.68 0.68 8.92 1.26 10.5 5.2 62.2 48.9 0.77 0.43 1.96 0.83 5.47 0.77 5.40 1.39 2.70 2.91 0.98 0.19 3.00 0.80 0.91 0.77 2.68 1.39
32 (20/12) 51.6 10.4 25.0 2.6 86.5 6.4 123.7 17.4 77.9 11.4 9 (28.13%) 10 (31.25%) 5.59 0.69 8.98 1.20 7.2 3.8 38.3 24.3 0.53 0.23 1.50 0.67 5.70 0.81 5.23 1.33 1.34 0.66 1.26 0.35 3.30 1.18 0.55 0.63 1.79 0.91
0.402 0.924 0.004 0.002 0.054 0.019 0.811 0.269 0.529 0.835 0.003 0.004 0.010 0.004 0.250 0.564 0.003 <0.001 0.296 0.031 0.001
147 (72/75) 52.9 11.7 26.6 3.3 92.1 8.7 131.1 18.6 84.3 12.8 67 (45.58%) 38 (25.85%) 8.40 3.50 16.49 5.12 9.6 6.5 24.5 24.5 0.73 0.40 1.10 0.70 7.87 2.01 5.46 1.13 2.39 1.58 1.05 0.24 3.15 0.97 0.24 0.40 3.45 2.49
31 (23/8) 49.7 12.5 23.3 2.5 85.0 6.4 119.1 14.6 77.7 11.7 2 (34.2%) 14 (45.16%) 8.37 2.78 16.29 3.98 5.5 3.0 13.5 9.1 0.50 0.30 0.80 0.47 7.56 2.09 5.27 0.73 1.52 1.18 1.21 0.23 3.08 0.62 0.10 0.01 2.37 1.37
0.011 0.171 <0.001 <0.001 0.001 0.010 <0.001 0.032 0.979 0.838 <0.001 <0.001 0.005 0.002 0.447 0.246 0.004 <0.001 0.800 0.001 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 IGI showed no significant differences. On comparing the three groups stratified by the presence of MS, mean HOMA-IR and IGI were higher in those with MS (Fig. 2). However, in the case of the prediabetes and type 2 DM groups those with MS, showed significantly higher HOMA-IR and IGI values than those without, whereas in the NGT subgroup, HOMA-IR and IGI levels were not dependent on the presence of MS. When the three groups were subdivided according to the presence of MS and examined with respect to glucose tolerance, the NGT, preDM, and type 2 DM subgroups in MS group showed significant higher
HOMA-IR and lower IGI according to glucose tolerance (Fig. 3). On the other hand, the NGT, preDM, and type 2 DM subgroups in non-MS group showed a significant decrease in IGI but no significant difference in HOMA-IR as glucose tolerance worsened. 4. Discussion Like other studies, this study shows that MS and type 2 DM have much in common. Unlike the majority of studies carried out in the West, which found higher prevalences for MS in men than in women, this study shows that women had the higher prevalence [12,13]. 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
1.10 0.57, n = 4 0.91 0.59, n = 14 0.31 0.56, n = 56
1.12 1.28, n = 7 0.22 0.26, n = 43
0.448 0.019 0.051
1.03 0.83, n = 63 0.77 0.73, n = 81 0.21 0.26, n = 178
component number of MS 1.75 0.88, n = 18 2.19 2.04, n = 4 2.32 1.06, n = 28 3.06 1.71, n = 14 2.75 1.94, n = 48 3.16 2.31, n = 56
3.35 1.57, n = 7 4.59 2.90, n = 43
0.641 0.005 <0.001
1.81 1.32, n = 63 2.33 1.29, n = 81 3.20 2.40, n = 178
Change of IGI according to the component number of MS NGT 0.91 0.74, n = 41 1.28 1.05, n = 18 Prediabetes 0.55 0.63, n = 32 0.86 0.71, n = 28 T2DM 0.10 0.10, n = 31 0.16 0.24, n = 48 Change of HOMA-IR according to the NGT 1.80 1.42, n = 41 Prediabetes 1.79 0.91, n = 32 T2DM 2.06 1.48, n = 31
Values are mean S.D. Bold values means statistically significant ( p < 0.05).
S.Y. Rhee et al. / Diabetes Research and Clinical Practice 76 (2007) 397–403
Fig. 2. IGI and HOMA-IR differences according to the presence of MS in the three glucose tolerance subgroups. Both IGI and HOMA-IR were significantly elevated in MS subgroups.
ethnic differences and the different diagnostic criteria used. According to a study carried out on normal subjects presenting for a health examination, the prevalence of MS in Korea is 6.8% (5.2% for men and 9.0% for women) according to the ATP III criteria, and 10.9% (9.8% for men and 12.4% for women) according to the modified Asian-Pacific criteria. Here again women showed somewhat higher prevalence [17]. However, we also believe there are other external factors that may have contributed to this female predominance, especially since Korean men of 40–50 years old have two to three times the mortality rate of women, as this increased survival of women per se probably affected the higher prevalence observed in women [17]. On comparing the three study groups, i.e., NGT, preDM, and type 2 DM, according to the presence or absence of MS, variables such as fasting blood glucose, plasma glucose 2 h after glucose loading, and HbA1c show no statistical significance. However, MS subgroups in the prediabetes and type 2 DM groups showed significantly higher Ins0, Ins30, Cpep0, Cpep30, IGI, and
401
Fig. 3. Differences in IGI and HOMA-IR according to glucose tolerance in patients with/without MS. In MS subjects, IGI values progressively decreased and HOMA-IR values progressively increased with increased glucose tolerance aggravation. However, though IGI values progressively decreased in patients without MS with increasing glucose tolerance aggravation, HOMA-IR values were unaffected.
HOMA-IR levels than the corresponding non-MS subgroups, which mean that a change in insulin secretion (IGI) occurred as insulin resistance (HOMA-IR) was aggravated by the presence of MS within each group. However, this tendency was not clear in NGT subjects, but as the difference in insulin resistance shows no statistical significance, neither does the secretion of insulin show any significant difference. However, when comparing the prediabetes and type 2 DM groups in terms of number of MS diagnostic components, IGI showed no significant changes in the type 2 DM group. HOMA-IR levels in both groups increased as the number of diagnostic components increased. But IGI showed a significant decrease with increased number of components only in the prediabetes group. This means that in the prediabetes group, insulin secretion increases compensatory to an aggravation of insulin resistance, whereas in the type 2 DM group, this compensatory insulin secretion is insufficient. Therefore,
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Fig. 4. Hypothesis concerning primary metabolic changes during the development of type 2 DM. In patients with MS, IGI (compensatory insulin secretion) deterioration and HOMA-IR (insulin resistance) aggravation are both important in the primary pathogenesis of diabetes. However, HOMA-IR aggravation may not be an important factor in the pathogenesis of diabetes in those without MS.
our results imply that a deterioration in insulin secretory function may be more important than an aggravated insulin resistance in early stage type 2 DM. The most noticeable result of our study is that even though decreasing IGI was statistically significant in non-MS subjects, HOMA-IR did not change significantly as glucose tolerance worsened (Fig. 3). Type 2 DM subjects with accompanying MS showed the same significant effect as insulin resistance was aggravated and insulin secretory function deteriorated. However, in type 2 DM subjects without MS, only insulin secretory function significantly decreased; insulin resistance showed no significant rise. These findings suggest that, even though their proportions are relatively small, there exist type 2 DM patients whose disease cannot be explained by the current pathogenic theory—compensatory insulin deterioration against a background of insulin resistance aggravation (Fig. 4). Yeckel et al. showed that specific impairment of b-cell responsiveness in young obese patients was quite distinct from insulin sensitivity deterioration [18]. This finding supports the results of the present study, because it shows that even though there are some differences in study subjects, increased insulin resistance and decreased glucose tolerance do not always occur simultaneously in diabetes patients. In the present study we compared cross sectional insulin resistance and insulin secretory function subject data. Therefore, we were unable to observe continuing changes in subjects. Moreover, because of the multiple sub-groupings involved, subject numbers per subgroup were relatively small. It is also difficult to compare the results of our study with those of western studies, because we used ATP III diagnostic criteria modified
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, importantly the study demonstrates the existence of early stage type 2 DM patients that show no close relation between insulin secretion deterioration and insulin resistance aggravation. Prospective studies that overcome the present study’s limitations, comparative studies between races, and work at the molecular level would empower us to present a clearer view of the comparative characteristics, relationships, and pathophysiologies of MS and early stage type 2 DM. Acknowledgement This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health &Welfare, Republic of Korea (Grant No. A050463). The authors appreciate the efforts of Young Ji Yoon in preparation of the manuscript. References [1] R.A. DeFronzo, Pathogenesis of type 2 diabetes mellitus, Med. Clin. North. Am. 88 (2004) 787–835, IX. [2] S.E. Kahn, Clinical review 135: the importance of beta-cell failure in the development and progression of type 2 diabetes, J. Clin. Endocrinol. Metab. 86 (2001) 4047–4058. [3] J.L. Leahy, Natural history of beta-cell dysfunction in NIDDM, Diabetes Care 13 (1990) 992–1010. [4] C. Weyer, C. Bogardus, D.M. Mott, R.E. Pratley, The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus, J. Clin. Invest. 104 (1999) 787–794. [5] M. Hawkins, L. Rossetti, Insulin Resistance and Its Role in the Pathogenesis of Type 2 Diabetes, Lippincott Willians & Wilkins, 2005. [6] A.R. Folsom, L.H. Kushi, K.E. Anderson, P.J. Mink, J.E. Olson, D.P. Hong, et al., Associations of general and abdominal obesity with multiple health outcomes in older women: the Iowa Women’s Health Study, Arch. Intern. Med. 160 (2000) 2117– 2128. [7] E.E. Calle, M.J. Thun, J.M. Petrelli, C. Rodriguez, C.W. Heath Jr., Body-mass index and mortality in a prospective cohort of U.S. adults, N. Engl. J. Med. 341 (1999) 1097–1105. [8] S. Lillioja, D.M. Mott, M. Spraul, R. Ferraro, J.E. Foley, E. Ravussin, et al., Insulin resistance and insulin secretory dysfunc-
S.Y. Rhee et al. / Diabetes Research and Clinical Practice 76 (2007) 397–403
[9]
[10]
[11]
[12]
[13]
tion as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians, N. Engl. J. Med. 329 (1993) 1988–1992. B.C. Martin, J.H. Warram, A.S. Krolewski, R.N. Bergman, J.S. Soeldner, C.R. Kahn, Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study, Lancet 340 (1992) 925–929. J.B. Meigs, Invited commentary: insulin resistance syndrome? Syndrome X? Multiple metabolic syndrome? A syndrome at all? Factor analysis reveals patterns in the fabric of correlated metabolic risk factors, Am. J. Epidemiol. 152 (2000) 908–911. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III), JAMA 285 (2001) 2486–2497. E.S. Ford, W.H. Giles, W.H. Dietz, Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey, JAMA 287 (2002) 356–359. D. Tripathy, N. Carlsson, P. Almgren, B. Isomaa, M.R. Taskinen, T. Tuomi, et al., Insulin secretion and insulin sensitivity in
[14] [15]
[16]
[17]
[18]
403
relation to glucose tolerance: lessons from the Botnia Study, Diabetes 49 (2000) 975–980. Diagnosis and classification of diabetes mellitus, Diabetes Care 27 (Suppl. 1) (2004) S5–S10. D.R. Matthews, J.P. Hosker, A.S. Rudenski, B.A. Naylor, D.F. Treacher, R.C. Turner, Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man, Diabetologia 28 (1985) 412– 419. The IDF consensus worldwide definition of the metabolic syndrome [article online], 2005, Available from http://www.idf.org/ webdata/docs/IDF_Metasyndrome_definition.pdf W.Y. Lee, J.S. Park, S.Y. Noh, E.J. Rhee, S.W. Kim, P.Z. Zimmet, Prevalence of the metabolic syndrome among 40,698 Korean metropolitan subjects, Diab. Res. Clin. Pract. 65 (2004) 143– 149. C.W. Yeckel, S.E. Taksali, J. Dziura, R. Weiss, T.S. Burgert, R.S. Sherwin, et al., The normal glucose tolerance continuum in obese youth: evidence for impairment in beta-cell function independent of insulin resistance, J. Clin. Endocrinol. Metab. 90 (2005) 747–754.
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 The pathogenesis of diabetes is complicated by several metabolism-related problems. In particular, a
* Corresponding author at: Department of Endocrinology and Metabolism, College of Medicine, Kyung Hee University, #1 Hoegi-dong, Dongdaemoon-ku, Seoul, Republic of Korea. Tel.: +82 2 958 8199/8200/8128; fax: +82 2 968 1848. E-mail addresses: [email protected], [email protected] (J.-t. Woo).
deterioration in insulin secretion and an aggravation of insulin resistance are known to be essentials in the primary pathogenesis of type 2 diabetes mellitus (DM) [1]. A deterioration in insulin secretion is caused by glucose toxicity, b-cell dysfunction, an impaired proinsulin biosynthesis, and lipotoxicity [2]. Of these, bcells dysfunction is considered common trait in type 2 DM [3,4]. Absolute b-cell function decline due to disease aggravation leads to a deterioration of insulin 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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Insulin resistance can be defined as resistance to the metabolic effects of endogenous insulin secretion. Physiologically, endogenous insulin secretion allows the body’s glucose metabolism to maintain an equilibrium [5]. However, aggravation of insulin resistance interrupts normal physiologic actions of insulin and causes hyperinsulinemia, which is not only important in progression of type 2 DM but is also important in other diseases such as hypertension, dyslipidemia, atherosclerosis, and malignancy [6,7]. Several cross-sectional and longitudinal studies have showed that a deterioration in insulin secretion and an aggravation of insulin resistance occur simultaneously before clinically overt hyperglycemia appears [8,9]. This means that during the onset of type 2 DM, increases in insulin secretion occurs complementary to rising insulin resistance, and that as a result patients show normal glucose tolerance. However, as endogenous insulin production falls, there is not enough insulin to compensate for the increasing insulin resistance. This process explains the primary pathogenesis of type 2 DM [1,2]. The aggravation of insulin resistance is also known to be closely related to metabolic syndrome (MS) [10]. MS is not a definitive disease entity but rather a cluster of diseases, which include obesity, hyperglycemia, and disorders of glucose tolerance and dyslipidemia [11]. According to NHANES III, the prevalence of MS among American adults of over 20 years old is 20%, while among for those over 60 years old its prevalence is as high as 40% [12]. In terms of insulin resistance, type 2 DM and MS are closely related. The Botnia study showed that 84% of men and 78% of women with type 2 DM had accompanying MS. For patients with prediabetes, 64% of men and 42% of women had MS, and for NGT groups, only 15% of men and 10% of women had MS [13]. Not all type 2 DM patients have MS and neither do all MS patients have accompanying type 2 DM. This signifies that even though these two diseases have much in common, that they differ pathophysiologically. For these reasons, we undertook this study to compare differences in type 2 DM according to the coexistence of MS with respect to insulin secretion and insulin resistance. To exclude the effect of artificial intervention or severe b-cell dysfunction, the subjects enrolled in this study were confined to newly diagnosed and drug naive. Thus, the 322 study subjects had no drug history that may have affected glucose metabolism and had a relatively short medical history of hyperglycemia. Insulin resistance and insulin secretory indexes
in these subjects were determine using specific equations and the study subjects were divided into three groups, which were additionally subdivided based on the presence or absence of MS, and differences between these subgroups were analyzed. 2. Subjects and methods 2.1. Subjects This study was carried out from January 2002 to November 2004 inclusive on 322 subjects suspected of having type 2 DM at the Department of Endocrinology and Metabolism, Kyung Hee University Hospital. In order to avoid severe b-cell dysfunction and to exclude any change in insulin secretory function or insulin resistance due to artificial intervention, study subjects were confined to have a history of hyperglycemia of less than 3 months and no history of taking a medication that might affect glucose metabolism. 2.2. Methods The medical histories of the study subjects were reviewed to ensure that they fulfilled the enrollment criteria. Height, weight, body mass index (BMI), abdominal circumference, resting blood pressure, and other anthropometric data were also recorded. To diagnose type 2 DM, we used oral glucose tolerance test (OGTT). Total cholesterol, HDL-cholesterol, LDL-cholesterol, triglyceride, and HbA1c were measured before carrying out OGTT. Before OGTT, basal plasma glucose (Glc0), insulin (Ins0), and C-peptide (Cpep0) levels were measured after an 8 h fast. After a 75 g of glucose loading, plasma glucose concentrations at 30, 60, 90, and 120 min (Glc30, Glc60, Glc90, and Glc120) and the insulin (Ins30) and C-peptide (Cpep30) concentrations at 30 min were measured. According to OGTT results, subject were divided into three groups; a normal glucose tolerance (NGT) group, a prediabetes (preDM) group, comprised of an impaired fasting glucose (IFG) group and/or an impaired glucose tolerance (IGT) group, and a type 2 diabetes mellitus (T2DM) group. Study subjects were diagnosed according to the American Diabetes Association 2004 [14]. And, HOMA-IR (the insulin resistance index) and IGI (Insulinogenic index, which means the insulin secretion ability index) were calculated for all subjects who underwent OGTT [15]. HOMA-IR ¼ IGI ¼
Ins0 Glc0 22:5
Ins30 Ins0 18 ðGlc30 Glc0 Þ
where Ins0 is the fasting plasma insulin (mIU/L), Ins30 the insulin 30 min after glucose intake (mIU/L), Glc0 the fasting plasma glucose (mmol/L), and Glc30 is the plasma glucose 30 min after glucose intake (mmol/L).
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399
Table 1 Modified ATP III diagnostic criteria of metabolic syndrome incorporating the Asia-Pacific abdominal obesity guideline Abdominal obesity Men Women
Waist circumference (by Asia-Pacific guideline) >90 cm >80 cm
Triglyceride
150 mg/dL (1.7 mmol/L)
HDL cholesterol Men Women
<40 mg/dL (1.03 mmol/L) <50 mg/dL (1.3 mmol/L)
Blood pressure Fasting plasma glucose
130 mmHg/85 mmHg or anti-hypertensive agent 110 mg/dL or diabetes
Study subjects were stratified according to the presence of MS, and were diagnosed according to adult treatment panel (ATP) III diagnostic criteria of MS of the National Cholesterol Education Program (NCEP) by using basic anthropometric data, OGTT results, and lipid profiles [11]. However, for MS diagnosis, abdominal circumference thresholds were taken as 90 cm for men and 80 cm for women, according to the AsianPacific abdominal obesity guidelines [16] (Table 1). By using the indices mentioned above, the three subject groups were subdivided into six subgroups, i.e., NGT, preDM, and T2DM each with/without MS. The clinical characteristics, insulin secretory functions, and insulin resistances of these subgroups were compared. For raising a reliability of subject’s selection, we also investigated the possibility of including inappropriate subjects with genetic defects (i.e., MODY) or immune mediated diabetes (i.e., type 1DM or SPIDDM) that might fall into the error of interpreting study results. To exclude this possibility, we reviewed all pedigree of study subjects and exclude subjects whose first-degree relatives had diabetes less than 25 years old or a tendency of autosomal dominant hereditary pattern. We also measured islet autoantibody (GAD Ab and IA-2 Ab) of all preDM and T2DM subjects by radioimmunoassay (Linco Research, MO, USA) and exclude autoantibody positive subjects. 2.3. Data analysis Statistical analysis and data management were carried using the Statistical Package for the Social Sciences (SPSS, Version 12.0; SPSS Inc., Chicago, Illinois). In order to confirm statistical significances between subgroups, the Student’s t-test, one-way ANOVA, and the Chi-square test were used.
3. Results 3.1. Clinical characteristics of the study subjects According to OGTT results, 63 subjects were diagnosed with normal glucose tolerance, 81 subjects
Fig. 1. Prevalence of metabolic syndrome among study subjects.
with impaired fasting blood glucose and/or impaired glucose tolerance, and 178 with type 2 DM. According to ATP III criteria modified in-line with the AsianPacific guidelines, 218 subjects (67.7% of total) were diagnosed with MS. When subjects in the three main groups were compared, 34.9% of the NGT group had MS, whereas 60.5% of the prediabetes group, and 82.6% of the type 2 DM group had MS (Fig. 1). By gender, 41.3% of men and 29.4% of women in the NGT group, 56.5% of men and 65.7% of women in the prediabetes group, and 75.7% of men and 90.3% of women in the type 2 DM group had MS. When the three groups were compared according to the presence or not of MS, and excluding the factors that were used to diagnose the MS, most variables such as age, fasting blood glucose, blood glucose 2 h after glucose load, HbA1c, total cholesterol, and LDL were not statistically significant in the individual groups (Table 2). But in the type 2 DM group, the prevalence of women was significantly high, and in the prediabetes and type 2 DM groups, the concentrations of insulin and C-peptide at the time of glucose loading (Ins0, Cpep0) and 30 min (Ins30, Cpep30) after loading were significantly higher for MS subgroups.
3.2. Comparisons of HOMA-IR and IGI according to glucose tolerance and metabolic syndrome The three groups (NGT, preDM, and type 2 DM) were stratified by the number of MS components and HOMA-IR and IGI were compared (Table 3). HOMAIR increased significantly as the number of MS components increased in the preDM and type 2 DM groups. However, IGI significantly increased as the number of MS components increased only in the preDM group, whereas in the type 2 DM group, IGI showed no
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Table 2 Clinical characteristics of the study subjects NGT
Subjects (M/F) Age (years) BMI (kg/m2) AC (cm) SBP (mmHg) DBP (mmHg) HTN med Smoker FPG (mmol/L) pp2 H (mmol/L) Ins0 (mIU/L) Ins30 (mIU/L) C-pep0 (nmol/L) C-pep30 (nmol/L) HbA1c (%) T-chol (mmol/L) TG (mmol/L) HDL (mmol/L) LDL (mmol/L) IGI HOMA-IR
Prediabetes
New T2DM
MS
No MS
p
MS
No MS
p
MS
No MS
p
22 (12/10) 48.7 13.3 26.5 3.4 91.5 5.1 138.8 20.2 89.1 12.4 9 (40.91%) 6 (27.27%) 5.01 0.58 6.39 1.14 8.3 5.4 70.6 46.4 0.67 0.23 2.33 0.90 5.00 0.76 5.00 1.01 2.13 1.39 1.07 0.20 2.93 1.00 1.25 0.97 1.83 1.12
41 (17/24) 44.9 12.4 24.3 5.0 85.5 11.1 120.9 14.8 78.1 9.4 4 (9.76%) 12 (29.27%) 5.20 0.47 5.93 1.18 7.7 6.0 55.2 39.8 0.53 0.30 1.86 0.73 5.03 0.54 5.05 1.06 1.31 0.77 1.33 0.28 3.03 0.94 0.91 0.74 1.80 1.42
0.321 0.259 0.075 0.001 <0.001 <0.001 0.004 0.867 0.164 0.143 0.698 0.174 0.119 0.031 0.886 0.858 0.016 <0.001 0.799 0.124 0.919
49 (26/23) 51.4 10.5 27.1 3.3 93.0 7.8 132.3 20.7 84.7 13.2 15 (30.61%) 10 (20.41%) 5.68 0.68 8.92 1.26 10.5 5.2 62.2 48.9 0.77 0.43 1.96 0.83 5.47 0.77 5.40 1.39 2.70 2.91 0.98 0.19 3.00 0.80 0.91 0.77 2.68 1.39
32 (20/12) 51.6 10.4 25.0 2.6 86.5 6.4 123.7 17.4 77.9 11.4 9 (28.13%) 10 (31.25%) 5.59 0.69 8.98 1.20 7.2 3.8 38.3 24.3 0.53 0.23 1.50 0.67 5.70 0.81 5.23 1.33 1.34 0.66 1.26 0.35 3.30 1.18 0.55 0.63 1.79 0.91
0.402 0.924 0.004 0.002 0.054 0.019 0.811 0.269 0.529 0.835 0.003 0.004 0.010 0.004 0.250 0.564 0.003 <0.001 0.296 0.031 0.001
147 (72/75) 52.9 11.7 26.6 3.3 92.1 8.7 131.1 18.6 84.3 12.8 67 (45.58%) 38 (25.85%) 8.40 3.50 16.49 5.12 9.6 6.5 24.5 24.5 0.73 0.40 1.10 0.70 7.87 2.01 5.46 1.13 2.39 1.58 1.05 0.24 3.15 0.97 0.24 0.40 3.45 2.49
31 (23/8) 49.7 12.5 23.3 2.5 85.0 6.4 119.1 14.6 77.7 11.7 2 (34.2%) 14 (45.16%) 8.37 2.78 16.29 3.98 5.5 3.0 13.5 9.1 0.50 0.30 0.80 0.47 7.56 2.09 5.27 0.73 1.52 1.18 1.21 0.23 3.08 0.62 0.10 0.01 2.37 1.37
0.011 0.171 <0.001 <0.001 0.001 0.010 <0.001 0.032 0.979 0.838 <0.001 <0.001 0.005 0.002 0.447 0.246 0.004 <0.001 0.800 0.001 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 IGI showed no significant differences. On comparing the three groups stratified by the presence of MS, mean HOMA-IR and IGI were higher in those with MS (Fig. 2). However, in the case of the prediabetes and type 2 DM groups those with MS, showed significantly higher HOMA-IR and IGI values than those without, whereas in the NGT subgroup, HOMA-IR and IGI levels were not dependent on the presence of MS. When the three groups were subdivided according to the presence of MS and examined with respect to glucose tolerance, the NGT, preDM, and type 2 DM subgroups in MS group showed significant higher
HOMA-IR and lower IGI according to glucose tolerance (Fig. 3). On the other hand, the NGT, preDM, and type 2 DM subgroups in non-MS group showed a significant decrease in IGI but no significant difference in HOMA-IR as glucose tolerance worsened. 4. Discussion Like other studies, this study shows that MS and type 2 DM have much in common. Unlike the majority of studies carried out in the West, which found higher prevalences for MS in men than in women, this study shows that women had the higher prevalence [12,13]. 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
1.10 0.57, n = 4 0.91 0.59, n = 14 0.31 0.56, n = 56
1.12 1.28, n = 7 0.22 0.26, n = 43
0.448 0.019 0.051
1.03 0.83, n = 63 0.77 0.73, n = 81 0.21 0.26, n = 178
component number of MS 1.75 0.88, n = 18 2.19 2.04, n = 4 2.32 1.06, n = 28 3.06 1.71, n = 14 2.75 1.94, n = 48 3.16 2.31, n = 56
3.35 1.57, n = 7 4.59 2.90, n = 43
0.641 0.005 <0.001
1.81 1.32, n = 63 2.33 1.29, n = 81 3.20 2.40, n = 178
Change of IGI according to the component number of MS NGT 0.91 0.74, n = 41 1.28 1.05, n = 18 Prediabetes 0.55 0.63, n = 32 0.86 0.71, n = 28 T2DM 0.10 0.10, n = 31 0.16 0.24, n = 48 Change of HOMA-IR according to the NGT 1.80 1.42, n = 41 Prediabetes 1.79 0.91, n = 32 T2DM 2.06 1.48, n = 31
Values are mean S.D. Bold values means statistically significant ( p < 0.05).
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Fig. 2. IGI and HOMA-IR differences according to the presence of MS in the three glucose tolerance subgroups. Both IGI and HOMA-IR were significantly elevated in MS subgroups.
ethnic differences and the different diagnostic criteria used. According to a study carried out on normal subjects presenting for a health examination, the prevalence of MS in Korea is 6.8% (5.2% for men and 9.0% for women) according to the ATP III criteria, and 10.9% (9.8% for men and 12.4% for women) according to the modified Asian-Pacific criteria. Here again women showed somewhat higher prevalence [17]. However, we also believe there are other external factors that may have contributed to this female predominance, especially since Korean men of 40–50 years old have two to three times the mortality rate of women, as this increased survival of women per se probably affected the higher prevalence observed in women [17]. On comparing the three study groups, i.e., NGT, preDM, and type 2 DM, according to the presence or absence of MS, variables such as fasting blood glucose, plasma glucose 2 h after glucose loading, and HbA1c show no statistical significance. However, MS subgroups in the prediabetes and type 2 DM groups showed significantly higher Ins0, Ins30, Cpep0, Cpep30, IGI, and
401
Fig. 3. Differences in IGI and HOMA-IR according to glucose tolerance in patients with/without MS. In MS subjects, IGI values progressively decreased and HOMA-IR values progressively increased with increased glucose tolerance aggravation. However, though IGI values progressively decreased in patients without MS with increasing glucose tolerance aggravation, HOMA-IR values were unaffected.
HOMA-IR levels than the corresponding non-MS subgroups, which mean that a change in insulin secretion (IGI) occurred as insulin resistance (HOMA-IR) was aggravated by the presence of MS within each group. However, this tendency was not clear in NGT subjects, but as the difference in insulin resistance shows no statistical significance, neither does the secretion of insulin show any significant difference. However, when comparing the prediabetes and type 2 DM groups in terms of number of MS diagnostic components, IGI showed no significant changes in the type 2 DM group. HOMA-IR levels in both groups increased as the number of diagnostic components increased. But IGI showed a significant decrease with increased number of components only in the prediabetes group. This means that in the prediabetes group, insulin secretion increases compensatory to an aggravation of insulin resistance, whereas in the type 2 DM group, this compensatory insulin secretion is insufficient. Therefore,
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Fig. 4. Hypothesis concerning primary metabolic changes during the development of type 2 DM. In patients with MS, IGI (compensatory insulin secretion) deterioration and HOMA-IR (insulin resistance) aggravation are both important in the primary pathogenesis of diabetes. However, HOMA-IR aggravation may not be an important factor in the pathogenesis of diabetes in those without MS.
our results imply that a deterioration in insulin secretory function may be more important than an aggravated insulin resistance in early stage type 2 DM. The most noticeable result of our study is that even though decreasing IGI was statistically significant in non-MS subjects, HOMA-IR did not change significantly as glucose tolerance worsened (Fig. 3). Type 2 DM subjects with accompanying MS showed the same significant effect as insulin resistance was aggravated and insulin secretory function deteriorated. However, in type 2 DM subjects without MS, only insulin secretory function significantly decreased; insulin resistance showed no significant rise. These findings suggest that, even though their proportions are relatively small, there exist type 2 DM patients whose disease cannot be explained by the current pathogenic theory—compensatory insulin deterioration against a background of insulin resistance aggravation (Fig. 4). Yeckel et al. showed that specific impairment of b-cell responsiveness in young obese patients was quite distinct from insulin sensitivity deterioration [18]. This finding supports the results of the present study, because it shows that even though there are some differences in study subjects, increased insulin resistance and decreased glucose tolerance do not always occur simultaneously in diabetes patients. In the present study we compared cross sectional insulin resistance and insulin secretory function subject data. Therefore, we were unable to observe continuing changes in subjects. Moreover, because of the multiple sub-groupings involved, subject numbers per subgroup were relatively small. It is also difficult to compare the results of our study with those of western studies, because we used ATP III diagnostic criteria modified
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, importantly the study demonstrates the existence of early stage type 2 DM patients that show no close relation between insulin secretion deterioration and insulin resistance aggravation. Prospective studies that overcome the present study’s limitations, comparative studies between races, and work at the molecular level would empower us to present a clearer view of the comparative characteristics, relationships, and pathophysiologies of MS and early stage type 2 DM. Acknowledgement This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health &Welfare, Republic of Korea (Grant No. A050463). The authors appreciate the efforts of Young Ji Yoon in preparation of the manuscript. References [1] R.A. DeFronzo, Pathogenesis of type 2 diabetes mellitus, Med. Clin. North. Am. 88 (2004) 787–835, IX. [2] S.E. Kahn, Clinical review 135: the importance of beta-cell failure in the development and progression of type 2 diabetes, J. Clin. Endocrinol. Metab. 86 (2001) 4047–4058. [3] J.L. Leahy, Natural history of beta-cell dysfunction in NIDDM, Diabetes Care 13 (1990) 992–1010. [4] C. Weyer, C. Bogardus, D.M. Mott, R.E. Pratley, The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus, J. Clin. Invest. 104 (1999) 787–794. [5] M. Hawkins, L. Rossetti, Insulin Resistance and Its Role in the Pathogenesis of Type 2 Diabetes, Lippincott Willians & Wilkins, 2005. [6] A.R. Folsom, L.H. Kushi, K.E. Anderson, P.J. Mink, J.E. Olson, D.P. Hong, et al., Associations of general and abdominal obesity with multiple health outcomes in older women: the Iowa Women’s Health Study, Arch. Intern. Med. 160 (2000) 2117– 2128. [7] E.E. Calle, M.J. Thun, J.M. Petrelli, C. Rodriguez, C.W. Heath Jr., Body-mass index and mortality in a prospective cohort of U.S. adults, N. Engl. J. Med. 341 (1999) 1097–1105. [8] S. Lillioja, D.M. Mott, M. Spraul, R. Ferraro, J.E. Foley, E. Ravussin, et al., Insulin resistance and insulin secretory dysfunc-
S.Y. Rhee et al. / Diabetes Research and Clinical Practice 76 (2007) 397–403
[9]
[10]
[11]
[12]
[13]
tion as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians, N. Engl. J. Med. 329 (1993) 1988–1992. B.C. Martin, J.H. Warram, A.S. Krolewski, R.N. Bergman, J.S. Soeldner, C.R. Kahn, Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study, Lancet 340 (1992) 925–929. J.B. Meigs, Invited commentary: insulin resistance syndrome? Syndrome X? Multiple metabolic syndrome? A syndrome at all? Factor analysis reveals patterns in the fabric of correlated metabolic risk factors, Am. J. Epidemiol. 152 (2000) 908–911. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III), JAMA 285 (2001) 2486–2497. E.S. Ford, W.H. Giles, W.H. Dietz, Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey, JAMA 287 (2002) 356–359. D. Tripathy, N. Carlsson, P. Almgren, B. Isomaa, M.R. Taskinen, T. Tuomi, et al., Insulin secretion and insulin sensitivity in
[14] [15]
[16]
[17]
[18]
403
relation to glucose tolerance: lessons from the Botnia Study, Diabetes 49 (2000) 975–980. Diagnosis and classification of diabetes mellitus, Diabetes Care 27 (Suppl. 1) (2004) S5–S10. D.R. Matthews, J.P. Hosker, A.S. Rudenski, B.A. Naylor, D.F. Treacher, R.C. Turner, Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man, Diabetologia 28 (1985) 412– 419. The IDF consensus worldwide definition of the metabolic syndrome [article online], 2005, Available from http://www.idf.org/ webdata/docs/IDF_Metasyndrome_definition.pdf W.Y. Lee, J.S. Park, S.Y. Noh, E.J. Rhee, S.W. Kim, P.Z. Zimmet, Prevalence of the metabolic syndrome among 40,698 Korean metropolitan subjects, Diab. Res. Clin. Pract. 65 (2004) 143– 149. C.W. Yeckel, S.E. Taksali, J. Dziura, R. Weiss, T.S. Burgert, R.S. Sherwin, et al., The normal glucose tolerance continuum in obese youth: evidence for impairment in beta-cell function independent of insulin resistance, J. Clin. Endocrinol. Metab. 90 (2005) 747–754.