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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 3 1483-1488
Copyright © 2005 by The Endocrine Society

Insulin-Like Growth Factor Binding Protein-1 Is Independently Affected by Ethnicity, Insulin Sensitivity, and Leptin in Healthy, Glucose-Tolerant Young Men

Choon F. Liew, Stephen D. Wise, Kwee P. Yeo and Kok O. Lee

Department of Medicine (C.F.L., K.O.L.), National University Hospital, Singapore 119074; and Lilly-NUS Centre for Clinical Pharmacology (S.D.W., K.P.Y.), National University of Singapore, Singapore 117597

Address all correspondence and requests for reprints to: Professor K. O. Lee, Department of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074. E-mail: mdcleeko{at}nus.edu.sg.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We examined the relationships among IGF binding protein (IGFBP)-1, insulin sensitivity, and leptin in different ethnic groups (Asian Indians, Chinese, and Caucasians) using the euglycemic hyperinsulinemic clamp. Ten healthy, young and nondiabetic subjects of each ethnic group, matched for body mass index, age, and physical activity were studied. A euglycemic clamp was performed on all subjects. IGFBP-1, insulin, and leptin were measured after fasting and during the clamp. Fasting IGFBP-1 concentration was highest in Chinese (P = 0.027). Asian Indians had the lowest insulin sensitivity index (P = 0.006). The ratio of insulin to IGFBP-1 at fasting and throughout the euglycemic clamp was higher in Asian Indians. Fasting IGFBP-1 had a strong negative correlation with fasting leptin levels (r = –0.715, P = 0.001). Multiple linear regression demonstrated that fasting insulin, leptin, ethnicity, and insulin sensitivity were significant predictors for fasting IGFBP-1. IGFBP-1 is independently determined by ethnicity, insulin sensitivity, and leptin in glucose-tolerant men. The presence of relative insulin resistance and low fasting IGFBP-1 levels in Asian Indians may contribute to their higher risk of developing diabetes and cardiovascular disease.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ETHNIC DIFFERENCES HAVE been described and well-recognized in the prevalence and complications of type 2 diabetes mellitus (DM). Compared with Caucasians, Asian Indians have a higher prevalence of type 2 DM and coronary heart disease (1, 2, 3), which cannot be accounted for by conventional risk factors, such as smoking, hypertension, hypercholesterolemia, and obesity (4, 5). It has been postulated that insulin resistance predisposes to cardiovascular disease as well as type 2 DM (6).

IGF-I circulates bound to specific high-affinity IGF binding protein (IGFBPs). To date, six distinct IGFBPs have been described (7, 8, 9, 10, 11, 12). IGFBP-1 has been shown to modify the short-term effects of IGFs. Acute and chronic elevations in plasma insulin suppress the hepatic production and the circulating level of IGFBP-1, which, in turn, serve to increase the bioavailability of free IGF-I (13). There is growing evidence that IGFBP-1 and the IGF/IGFBP system may form an important link between the development of hyperinsulinemia/insulin resistance and the development of cardiovascular disease (14, 15). In the circulation, IGFBP-1 may prevent the adverse IGF-mediated remodeling effect on the vasculature. Leptin is associated with the insulin resistance syndrome (16) and has an inverse relationship with insulin sensitivity (17, 18) and IGFBP-1 (19).

We have recently demonstrated that insulin resistance was higher even in healthy, young, and nondiabetic Asian Indians compared with Chinese and Caucasians (20). This may explain the epidemiological observation that Asian Indians have a significantly higher prevalence of type 2 DM and a much higher incidence of myocardial infarction compared with other ethnic groups living in Singapore (21). In the present study, we examined the IGFBP-1 concentrations in the same cohort of subjects and described the dynamic interactions between IGFBP-1 and insulin during the euglycemic hyperinsulinemic clamp and the relationships of IGFBP-1 with fasting insulin, fasting leptin, and insulin sensitivity.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Thirty lean, healthy, glucose-tolerant men (10 of each ethnic group) were included in this study. Exclusion criteria were first-degree family history of diabetes, current use of prescription medication, smoking, and significant systemic disease. Each subject underwent a medical examination, laboratory tests, and an oral glucose tolerance test at screening visit to confirm their healthy and normal glucose tolerance status. Subjects of each ethnic group were closely matched for their body mass index (BMI), age, and physical activity. Their characteristics have been previously described (20).

Anthropometric measurements

Waist to hip ratio (WHR) was calculated as the circumference of the narrowest part of the waist divided by the broadest part of the hip, and BMI was defined as the total body weight in kilograms divided by the square of height in meters. Measurements of waist and hip were taken using the same nonelastic tape measure with the subject standing upright. Body composition was analyzed by determination of percentage of body fat and fat-free (lean body) mass using tetrapolar bioelectric impedance analysis (Tanita Body Composition Scale, model TBF-300, Tanita Corp., Tokyo, Japan; measurement frequency, 50 kHz).

Euglycemic, hyperinsulinemic clamp

The euglycemic, hyperinsulinemic clamp technique was used for the determination of insulin sensitivity (22). Insulin was infused at a constant infusion rate of 40 mU/m2 body surface area per minute for the duration of the clamp of 120 min. The infusion rate of the 20% dextrose was adjusted manually to maintain a constant blood glucose concentration at basal level. The average value of the glucose infusion rate during the final 40 min of the clamp was defined as whole-body insulin-mediated glucose uptake (molar). The insulin sensitivity index was expressed as whole-body glucose uptake (molar) divided by steady-state serum insulin concentration during the final 40 min of the clamp. Metabolic clearance rate of insulin was derived using the formula: insulin infusion rate (40 mU/m2) divided by steady-state serum insulin minus fasting insulin.

Serum IGFBP-1 concentrations were measured at baseline; 30, 60, 90, and 120 min during the clamp; and 120 min after termination of clamp. Serum leptin concentrations were determined at baseline; 60, 90, and 120 min during the clamp; and 120 min after the clamp. Informed consent was obtained from all subjects, and the study was approved by the research ethics committee of National University Hospital, Singapore.

Laboratory analyses

Blood glucose concentration was determined by a glucose analyzer (based on a glucose oxidase technique; YSI Inc., Yellow Springs, OH). Serum IGFBP-1 (23) and leptin (24) were measured by validated, specific RIAs (Lilly Research Laboratories, Giessen, Germany) as described previously. Serum insulin was measured at Quintiles Laboratories (Singapore) using a Microparticle Enzyme Immunoassay (Abbott IMx Insulin assay; Abbott Laboratories, Abbott Park, IL) with intra- and interassay coefficient of variation of 4.0 and 4.5%, respectively. Fasting serum total cholesterol, triglyceride, and high-density lipoprotein-cholesterol levels were assayed in the Department of Laboratory Medicine of the National University Hospital of Singapore.

Statistical analysis

Statistical analysis was performed using the SPSS software version 10.0. Univariate ANOVA (general linear model) was used for comparison of means of the three ethnic groups. IGFBP-1, leptin, insulin, triglyceride, and insulin sensitivity index were log-transformed before statistical analyses to account for deviation from normal distribution. The correlation analysis was performed using Pearson’s correlation. Multiple linear regression analysis was performed with a step-wise method. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
We have studied the IGFBP-1 concentrations in three different ethnic groups (Asian Indians, Chinese, and Caucasians); the relationships of IGFBP-1 with insulin, leptin and insulin sensitivity at fasting state; and the dynamic interactions between IGFBP-1 and insulin levels during hyperinsulinemia.

Baseline characteristics of the subjects are shown in Table 1Go. There was no statistical difference in age, BMI, and WHR among the three ethnic groups. Asian Indian subjects had a higher percentage of body fat compared with Chinese and Caucasians (P = 0.001).


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  		TABLE 1. Clinical characteristics of subjects from three ethnic groups

 
The metabolic characteristics are presented in Table 2Go. Fasting insulin, fasting triglyceride, and fasting leptin concentrations were significantly higher in Asian Indians than the other two ethnic groups. Fasting IGFBP-1 concentration was highest in Chinese (P = 0.027). Asian Indians had the lowest insulin sensitivity index and insulin clearance rate compared with both Chinese and Caucasians (P = 0.006 and P < 0.001, respectively).


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  		TABLE 2. Metabolic characteristics of subjects from three ethnic groups

 
Fasting IGFBP-1 concentration was inversely correlated with fasting insulin concentration (r = –0.692, P = 0.001) (Fig. 1Go). The changes of both IGFBP-1 and insulin concentrations during the euglycemic hyperinsulinemic clamp are shown in Fig. 2Go. The ratio of insulin to IGFBP-1 at fasting and at all the time points during euglycemic clamp was consistently higher in Asian Indians compared with Caucasians and Chinese (Table 3Go). Similarly, the ratio of area under the curve (AUC) of insulin to IGFBP-1 for 0–120 and 0–240 min was greatest in Asian Indians (P = 0.002).



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  		FIG. 1. Relationship between log10 fasting IGFBP-1 and log10 fasting insulin.

 


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  		FIG. 2. Relationship between IGFBP-1 and insulin of different ethnic groups during the euglycemic clamp.

 

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  		TABLE 3. Comparison of ratio of insulin to IGFBP-1 during euglycemic clamps

 
There was a significant inverse relationship between fasting IGFBP-1 and fasting leptin levels (r = –0.715, P = 0.001) as shown in Fig. 3Go. Fasting IGFBP-1 concentration was positively correlated with insulin sensitivity index (r = 0.546, P = 0.002) (Fig. 4Go).



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  		FIG. 3. Relationship between log10 fasting IGFBP-1 and log10 fasting leptin.

 


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  		FIG. 4. Relationship between fasting IGFBP-1 and insulin sensitivity index.

 
Step-wise linear regression analysis with IGFBP-1 levels as the dependent variable was performed (Table 4Go). The multiple regression model showed that fasting insulin, ethnicity, fasting leptin, and insulin sensitivity index were significant predictors for fasting IGFBP-1 (P < 0.001, P < 0.001, P < 0.001, and P = 0.042, respectively). The significant variables explained 81% of the IGFBP-1 variation. There was no significant relationship between IGFBP-1 and total body fat, BMI, and WHR in this model. A separate linear regression analysis in a model, which included insulin sensitivity index, insulin clearance rate, fasting IGFBP-1, ethnicity, fasting leptin, percentage of body fat, fasting insulin, BMI, and WHR, demonstrated that insulin clearance rate (P = 0.003) and fasting IGFBP-1 levels (P = 0.034) are significant independent predictors of insulin sensitivity index. These factors accounted for 50% of the variation in insulin sensitivity index (Table 5Go).


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  		TABLE 4. Step-wise multiple regression analyses of the variables associated with fasting IGFBP-1

 

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  		TABLE 5. Step-wise multiple regression analyses of the variables associated with insulin sensitivity index

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our study demonstrates a new finding of interethnic difference in fasting IGFBP-1 levels in healthy, nonobese, normal glucose tolerance subjects. Fasting insulin, fasting leptin, ethnicity, and insulin sensitivity index are shown to be independent predictors of fasting IGFBP-1 levels. Previous studies have shown that insulin is inversely associated with IGFBP-1 levels (25). This study confirms this relationship and the dynamic suppression of IGFBP-1 during the hyperinsulinemic state.

The effect of ethnicity on IGFBP-1 has not been thoroughly investigated. In fact, there are no data on IGFBP-1 in Chinese compared with other ethnic groups. The finding of Chinese having higher fasting IGFBP-1 levels in relation to Asian Indians and Caucasians is unexpected. The implications of this observation remain to be elucidated. IGFBP-1 concentrations are lower in Asian Indians compared with Chinese due to higher insulin levels but are not lower than in Caucasians. IGFBP-1 levels in Asian Indians are not as low as expected for the degree of hyperinsulinemia, possibly due to hepatic insulin resistance.

In the fasting state, the insulin level was highest in Asian Indians. Despite the higher fasting insulin in Asian Indians, fasting IGFBP-1 was not lower in Asian Indians compared with Caucasians. The ratio of fasting insulin to fasting IGFBP-1 concentrations was significantly higher in Asian Indians compared with Caucasians and Chinese and remained so throughout the euglycemic hyperinsulinemic clamp (Table 3Go). These findings suggest that there may be a relative lack of hepatic sensitivity in IGFBP-1 suppression by insulin in Asian Indians at fasting and during hyperinsulinemic states.

The regulation of IGFBP-1 synthesis and secretion by insulin is via the effect of insulin on the liver, which is the main source of circulating IGFBP-1 (26). Therefore, this differential IGFBP-1 regulation by insulin may be a reflection of the underlying hepatic insulin resistance in Asian Indians. Our hypothesis is that Asian Indians seem to have a different physiology compared with Caucasians and Chinese, specifically involving altered hepatic insulin sensitivity leading to the loss of the tight relationship among insulin sensitivity-regulating insulin levels, which in turn regulate IGFBP-1. Hence, Asian Indians appear to have the presence of both hepatic and peripheral insulin resistance in view of their lack of hepatic sensitivity in IGFBP-1 suppression by insulin and their lower insulin sensitivity index, a measure of peripheral insulin sensitivity.

A population-based study of three ethnic groups (namely European, Asian Indian, and African Caribbean) showed that IGFBP-1 was independently and inversely related to fasting insulin, BMI, and African Caribbean compared with European ethnicity (27). Similar to our findings, they observed that, in normal glucose-tolerant subjects, IGFBP-1 levels were not significantly different between Europeans and Asian Indians.

The finding of insulin sensitivity as a significant determinant of IGFBP-1 is consistent with previous studies (28, 29, 30). Heald et al. (28) demonstrated the positive association between IGFBP-1 and insulin sensitivity in a population-based study of European and Pakistani subjects. The subjects studied included those who were normal, those who exhibited impaired glucose tolerance, and those who were diabetic. Similarly, Mohamed-Ali et al. (29) showed that IGFBP-1 correlated with insulin sensitivity as well as high-density lipoprotein-cholesterol, triglycerides, and insulin in a clinic-based cross-sectional study of patients with type 2 DM. In these studies, insulin sensitivity was derived using homeostasis model assessment. Our study is different in that the subjects were young, nonobese, and nondiabetic men, and the euglycemic clamp was used.

In view of the consistent findings of an association between fasting IGFBP-1 and insulin sensitivity, IGFBP-1 may potentially be a useful a marker of insulin resistance. In fact, our study demonstrated that fasting IGFBP-1 is a significant predictor of insulin sensitivity index in the step-wise regression analysis. This has clinical implications because fasting IGFBP-1, as a surrogate marker of insulin sensitivity, can be easily measured as opposed to the assessment of insulin sensitivity by the laborious methodology of euglycemic hyperinsulinemic clamp.

In addition, IGFBP-1 has been found to be associated with risk factors for cardiovascular disease (15, 28, 29, 31, 32, 33). The epidemiological findings of relatively higher prevalence of diabetes and cardiovascular disease in Asian Indians (1, 2, 3, 6) may be related to a low fasting IGFBP-1. There is emerging evidence that IGFBP-1 or the IGF/IGFBP system may be a vital link between the development of hyperinsulinemia/insulin resistance and the development of cardiovascular disease (14, 15, 28). These observational studies demonstrated compelling relationships between IGFBP-1 and insulin resistance/diabetes and cardiovascular disease or its risk factors, but they do not prove a cause and effect. Alternatively, IGFBP-1, per se, could just be a marker of the insulin resistance syndrome and may not be instrumental in the pathogenesis of insulin resistance and cardiovascular disease.

In the prediabetic insulin-resistant state, hyperinsulinemia, with the consequent low circulating IGFBP-1 levels, may play a significant role in the development of cardiovascular disease. IGFBP-1 plays a vital role in the short-term modulation of IGF bioavailability. Free IGF-I levels have been demonstrated to be inversely related to IGFBP-1 levels (34). In vitro, IGF-I is a potent survival factor preventing apoptosis of vascular smooth muscle cells (35). In transgenic mice models, overexpression of IGFBP-1 modulates the insulin/IGF-I axis and may have favorable effects on vascular endothelial function and blood pressure homeostasis by increased nitric oxide bioavailability (36). It was found in the present study that Asian Indians have a combination of relative insulin resistance (6) and low IGFBP-1 (15, 31), which have both been shown to be associated with cardiovascular risk factors. This combination of insulin resistance and lack of protection of circulating levels of IGFBP-1 may, in part, account for the higher prevalence of type 2 DM and cardiovascular disease in Asian Indians, which cannot be explained by conventional risk factors. The role of IGFBP-1 in the development of diabetic complications remains speculative (37), although studies have demonstrated that low levels of IGFBP-1 are associated with the presence of macrovascular disease in subjects with type 2 DM (15, 38).

The body composition among the different ethnic groups was different in that Asian Indians had the highest percentage of body fat. Therefore, it was not unexpected that fasting leptin was also highest in Asian Indians, because studies have shown close correlations between leptin concentrations and body fat mass (39, 40). Additionally, we have demonstrated that there is an inverse relationship between leptin and IGFBP-1, and using multiple regression analysis, leptin was an independent predictor of IGFBP-1 level. Our results further strengthen the observations of previous reports on the inverse association between leptin and IGFBP-1 in older, postmenopausal subjects (19, 41).

Both leptin and IGFBP-1 have been reputed to be associated with insulin resistance and with increased risk of cardiovascular disease. The possible biological explanations of the relationship between leptin and IGFBP-1 are not well understood, although it is probable that they could interact centrally, through the hypothalamic regulation by leptin on GH secretion (42), and peripherally via the direct interaction between leptin and IGFBP-1. Another possible hypothesis is that altered body composition or higher percentage of body fat would lead to both elevated leptin and insulin resistance with compensatory hyperinsulinemia, which may result in lower IGFBP-1 levels due to the inhibitory effect of insulin on hepatic IGFBP-1 release.

In summary, we have demonstrated that ethnicity, fasting insulin, fasting leptin, and insulin sensitivity can independently affect fasting IGFBP-1 level. Healthy, glucose-tolerant Asian Indian subjects have an adverse combination of relative insulin resistance and low fasting IGFBP-1 levels, which may account for their higher risk of developing diabetes and cardiovascular disease. The complex interactions of the insulin, the IGF/IGFBP system, and leptin require additional investigation, which may provide us with a better understanding of the pathogenesis of insulin resistance and its associated disorders and the susceptibility of certain ethnic groups to these conditions.


   Footnotes
 
First Published Online December 14, 2004

Abbreviations: AUC, Area under the curve; BMI, body mass index; DM, diabetes mellitus; IGFBP, IGF binding protein; WHR, waist to hip ratio.

Received July 29, 2004.

Accepted December 2, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals