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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0919
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 12 4656-4663
Copyright © 2007 by The Endocrine Society

Impact of Family History of Diabetes and Ethnicity on β-Cell Function in Obese, Glucose-Tolerant Individuals

Neda Rasouli, Horace J. Spencer, Amir Adel Rashidi and Steven C. Elbein

Research and Medical Services (N.R., S.C.E.), Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205; and Division of Endocrinology, Department of Internal Medicine (N.R., A.A.R., S.C.E.) and Department of Biostatistics (H.J.S.), University of Arkansas for Medical Sciences, College of Medicine, Little Rock, Arkansas 72205

Address all correspondence and requests for reprints to: Neda Rasouli, M.D., Central Arkansas Veterans Healthcare System, 111J LR, 4300 West 7th Street, Little Rock, Arkansas 72205. E-mail: rasoulineda{at}uams.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The increased insulin secretion in response to reduced insulin sensitivity (SI) is heritable, but whether the genetic predisposition is restricted to members of high-risk Caucasian families is unknown. Furthermore, the relative importance of insulin resistance and defective β-cell compensation in the increased prevalence of type 2 diabetes (T2DM) in African-American compared with Caucasian individuals is uncertain.

Objectives: We tested whether obese individuals with a family history of T2DM have decreased β-cell compensation compared with obese controls without a family history of T2DM. In addition, we compared SI and insulin secretion measures in African-American and Caucasian individuals.

Design: SI, acute insulin response to iv glucose (AIRg), maximally potentiated insulin response to arginine (AIRmax), and disposition indexes (DIs) (DI = SI * AIRg; DImax = SI * AIRmax) were compared among nondiabetic Caucasian and African-American individuals with and without a family history of diabetes.

Setting: This study was performed in an Ambulatory General Clinical Research Center.

Subjects: Subjects were healthy, nondiabetic individuals with or without a family history of T2DM.

Interventions: There were no interventions.

Main Outcome Measures: Comparison of SI, AIRg, AIRmax, DI, and DImax between Caucasians and African-Americans with or without a strong family history of T2DM were made.

Results: Obese subjects did not differ in SI, AIRg, or DI by family history of diabetes. African-Americans had 8% lower SI (P < 0.001), but 68% higher AIRg (P < 0.001) and 46% higher DI (P = 0.001) than age, gender, body mass index-matched Caucasian individuals. However, African-Americans had lower DImax compared with Caucasians.

Conclusions: We found no reduction in insulin secretion in obese subjects with a family history of T2DM compared with controls, but in general, African-Americans were more insulin resistant and had lower maximal β-cell response (DImax). The paradoxical increased DI could be explained by the reduced hepatic insulin extraction.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE INCREASING PREVALENCE of diabetes has paralleled that of obesity. Obesity offers a natural state of reduced insulin sensitivity (SI) and provides a common physiological β-cell challenge. Type 2 diabetes (T2DM) is characterized by diminished insulin secretion in the milieu of peripheral insulin resistance and increased hepatic glucose production (1). A genetic component to T2DM is unquestionable (2), given the increased risk seen in relatives of T2DM (3), as well as the high prevalence for the disease in particular ethnic groups (4, 5, 6, 7, 8) and the results of numerous linkage and more recently, genome-wide association studies (9, 10, 11, 12).

We have shown previously that the expected compensatory insulin hypersecretion of obesity was incomplete in nondiabetic obese Caucasian individuals with a strong family history of T2DM, when compared with a similar but separately ascertained and tested control population (13). However, whether this finding is restricted to nondiabetic members of families with multiple diabetic members is unknown. Lean nondiabetic individuals in whom short-term insulin resistance was induced by nicotinic acid treatment did not show differences in β-cell compensation by family history (14). Because β-cell compensation for this short-term experimental insulin resistance was incomplete in both the study and control groups, we hypothesized that the compensatory response to the long-term insulin resistance associated with obesity would expose a genetic predisposition to β-cell failure in nondiabetic individuals with a family history of T2DM.

African-Americans have a higher prevalence of T2DM compared with Caucasians (4, 7, 8), yet the exact mechanism underlying this increased risk is not known. In a cross-sectional study, Haffner et al. (15) reported that nondiabetic African-American individuals were more obese, more insulin resistant, and had higher insulin secretion compared with non-Hispanic white individuals. However, differences in obesity did not fully explain the excess insulin resistance and hyperinsulinemia (15). Other investigators found decreased SI and higher insulin secretion in African-American women and children compared with their non-Hispanic white counterparts (8, 16).

To address the roles of family history and ethnicity in SI and β-cell compensation over a broad range of obesity, we tested healthy nondiabetic obese individuals of European or African ancestry who were matched for age, gender, and body mass index (BMI). Both ethnic groups were ascertained for either a history of two or more first-degree relatives with T2DM or no family history of diabetes. We hypothesized that a genetic predisposition to T2DM would reduce the β-cell compensation to the chronic insulin resistance of obesity. To examine further the role of ethnicity, we examined African-American and Caucasian individuals who were similarly studied but ascertained without regard to family history.


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

All subjects provided written, informed consent under a protocol that was approved by the institutional review board of the University of Arkansas for Medical Sciences. Subjects in good health, between 18 and 45 yr of age, and with a BMI between 18 and 48 kg/m2 were recruited by local advertisement. A subgroup of subjects was recruited for a BMI between 30 and 40 kg/m2, and based on a strong family history of T2DM or no history of T2DM using a matched-pair design. Caucasian and African-American subjects were recruited and matched separately. Subjects with a family history of T2DM were defined as having at least one diabetic first-degree relative and one additional first or second-degree relative with T2DM. Control subjects were ascertained for no reported history of T2DM in a first or second-degree relative. Subjects with a history of coronary artery disease or any other major health problem were excluded. A total of 333 subjects were recruited, of whom 141 individuals met the more restrictive criteria for family history and BMI, and were included in an obesity and family history substudy.

Study design

All studies were performed in the General Clinical Research Center of the University of Arkansas for Medical Sciences. Body composition (percent body fat) was measured by dual x-ray absorptiometry. A standard 75-g oral glucose tolerance test (OGTT) was performed with sampling for glucose and insulin at baseline, 30, 60, 90, and 120 min. Individuals with a normal fasting and 2-h post-challenge glucose and normal laboratory values were invited to return for a frequently sampled iv glucose tolerance test (FSIGT), as described previously (17). The tolbutamide-modified test was changed to the insulin-modified FSIGT (0.04 U/kg) during the study because tolbutamide became unexpectedly unavailable. Visits for menstruating women were timed such that the FSIGT visit coincided with the follicular phase of the menstrual cycle. FSIGT was performed by placing catheters in each arm. After 20 min, three baseline samples (–10, –5, and –1 min) were obtained. An iv glucose bolus of 11.4 g/m2 was given over 1 min, and sampling continued at 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 19 min. At 20 min, either 125 mg/m2 iv tolbutamide or 0.04 U/kg insulin was given over 30 sec, and sampling continued at 22, 23, 24, 25, 27, 30, 40, 50, 70, 90, 100, 120, 150, and 180 min. If the glucose between 120 and 180 min differed by more than 0.3 mmol/liter or showed an upward or downward trend, we continued sampling until the glucose no longer varied from the previous sample by over 0.3 mmol/liter, up to 240 min. In a subgroup of 153 subjects, an arginine stimulation test was performed to study maximal insulin response. At the conclusion of the FSIGT, a second glucose bolus of D20 (50 g) was given, followed by a variable glucose infusion to maintain a glucose level between 25 and 28 mmol/liter (450–500 mg/dl) for at least 30 min, at which time baseline samples for insulin were obtained, and 5 g arginine was administered iv over 30 sec. Samples for insulin measurement were taken at 2, 3, 4, 6, 8, and 10 min after arginine injection.

SI and glucose effectiveness (SG) (the capacity of glucose to mediate its own disposal) were calculated from the insulin and glucose data using the MinMod Millennium program (18, 19). Acute insulin response to glucose (AIRg), an index of first-phase insulin secretion, was calculated from the incremental insulin area above baseline during the first 10 min after iv glucose administration. The maximal insulin response [maximally potentiated insulin response to arginine (AIRmax)], which is a measure of maximal β-cell secretory capacity or β-cell mass (20), was determined as the mean excursion over the hyperglycemic baseline after an iv arginine bolus, as described previously (21). To correct for the well-described effects of the prevailing SI on insulin secretion, we also determined the disposition index (DI) (SI x AIRg) based on the previously described hyperbolic relationship (22, 23). Analogously, we calculated DImax as SI x AIRmax (24).

Laboratory procedures

Insulin levels were measured using an immuno-chemiluminometric assay (MLT Assay, Cardiff, Wales, UK). The insulin assay has a sensitivity of 0.25 mU/liter for insulin, with 1% cross-reactivity with proinsulin and 4–8% coefficient of variation. Plasma glucose was measured by a glucose oxidase assay, and blood lipids were measured using standard clinical assays by LabCorp, Inc. (Burlington, NC).

Statistical methods

Continuous data are reported using means and 95% confidence intervals, whereas categorical variables are summarized using counts and percentages. Continuous variables that were not normally distributed, including BMI, SI, AIRg, AIRmax, DI, and DImax, were natural log transformed before analyses. Initially, Student’s two-sample t tests were performed first to compare demographic and clinical characteristics between family history and control groups within the obese subgroup, then between ethnic groups using all subjects. Whenever assuming equality of variances was not reasonable, the Satterthwaite method (25) was used to estimate the SE of differences between groups. For metabolic data, analysis of covariance models (SAS version 9.1 and R version 2.4.1; SAS Institute Inc., Cary, NC) were used to estimate the effect of family history and ethnicity while accounting for the covariates age, gender, BMI, and protocol type (tolbutamide or insulin). To account for the possibility that the effects of age or BMI may not be linear, restricted cubic splines were used to model potential nonlinearities in these covariates. Initially, all covariates and all two-way interactions with family history were included in the model. Interaction terms with P values greater than 0.10 were removed from the model; however, all other covariates, including nonlinear effect terms, were kept. The same modeling strategy was used to evaluate the effect of ethnicity in the larger set of data.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Does a family history of diabetes diminish β-cell compensation for chronic insulin resistance in obese nondiabetic individuals?

To investigate the role of genetic predisposition to T2DM in a setting of chronic insulin resistance, we studied β-cell function in 141 nondiabetic obese subjects with or without a family history of T2DM. Baseline characteristics of subjects are summarized in Table 1Go. The groups did not differ in age, BMI, body fat, blood pressure, lipid profile, or glucose tolerance. African-American individuals comprised 35% of family history group and 43% of control group; however, the difference was not significant. SI and SG in subjects with a family history of diabetes were similar to the control group: SI, 2.46 (2.09–2.84) vs. 2.63 (2.22–3.03) x 10–4 min–1/(µU/ml) (P = 0.42). Subjects with or without family history had comparable insulin secretion, measured either as AIRg [724.3 (617.6–831.1) vs. 786.7 (643.3–930.1) (µU/ml); P = 0.78] or AIRmax [288.4 (235.4–341.5) vs. 306.3 (260.5–352.0) (µU/ml); P = 0.47)] (Table 1Go). Finally, β-cell compensation determined as DI did not differ by family history of T2DM [1655 (1392–1918) vs. 1804 (1413–2195); P = 0.96] in family history and controls, respectively, after correcting for age, gender, and ethnicity. Figure 1Go summarizes the findings separated by ethnicity.


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  		TABLE 1. Baseline characteristics of obese subjects

 

Figure 1
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  		FIG. 1. Comparison of SI (A), AIRg (B), and DI (C) by ethnicity and family history (FamHx) of T2DM. There were no significant differences in SI, AIRg, or DI between obese subjects with or without family history of diabetes.

 
We anticipated that obesity-related chronic insulin resistance would expose a genetic defect in β-cell compensation. Alternatively, obesity may have instead obscured the role of genetic predisposition on β-cell function by reducing compensation, regardless of predisposition. To test these hypotheses, we examined the effect of family history on β-cell function over a wide range of BMI (18–48 kg/m2, n = 333). Again, SI, AIRg, and DI did not differ by family history of T2DM.

Do African-Americans have decreased β-cell compensation for insulin resistance compared with Caucasians?

To investigate the etiology of the increased prevalence of diabetes in African-American compared with Caucasian individuals, we compared 121 African-American and 212 Caucasian nondiabetic individuals for SI, AIRg, and DI, and 105 Caucasian and 48 African-American individuals for AIRmax. Baseline characteristics of subjects are summarized in Table 2Go. The groups did not differ by age, BMI, waist circumference, or waist-to-hip ratio. However, African-Americans had lower percent body fat, lower blood pressure, and a more favorable lipid profile compared with Caucasians (Table 2Go). Furthermore, despite a trend toward a higher fasting glucose (P = 0.09), African-American subjects had a lower 2-h post-challenge glucose (P = 0.05) and a trend toward lower glucose area under curve during the OGTT (P = 0.06) than Caucasians. Nonetheless, neither fasting nor 2-h post-challenge insulin levels differed between groups. African-Americans were significantly more insulin resistant than Caucasians, as shown by both a higher post-challenge insulin area under curve during the OGTT, and by significantly lower SI: 3.85 (3.16–4.55) vs. 4.22 (3.78–4.67) x 10–4 min–1/(µU/ml) (P < 0.0001; Table 2Go). Furthermore, both AIRg and DI were significantly higher in African-American subjects: AIRg, 806.5 (693.7–919.3) vs. 478.7 (429.8–527.6) (µU/ml) (P < 0.01); DI, 2331.8 (1977–2686) vs. 1597.9 (1433–1763) (P = 0.01). In contrast, maximal secretory capacity (AIRmax) did not differ between groups: 233.6 (192.0–275.1) in African-Americans vs. 256.9 (228.3–285.5) in Caucasians (P = 0.56; Table 2Go). Accordingly, considering the lower SI, African-American subjects had a significantly lower DImax than Caucasian subjects: 550.3 (439.6–661.0) vs. 625.3 (559.8–690.9) (P = 0.003).


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  		TABLE 2. Baseline characteristics of all subjects

 
Does β-cell compensation for insulin resistance deteriorate with obesity?

When SI is graphed on the abscissa and insulin secretion (AIRg) on the ordinate, cross-sectional studies have shown a hyperbolic relationship (23). Therefore, an appropriate compensation of AIRg for obesity-induced reductions in SI should remain on the same hyperbolic curve, such that DI (SI * AIRg) remains constant. As expected, SI decreased with increasing BMI (P < 0.01) (Figs. 2Go and 3Go). However, in subjects both with and without a family history of T2DM, DI also decreased, suggesting inadequate compensation for obesity, regardless of genetic predisposition. The association between BMI and DI was significant (P < 0.01), as shown in Fig. 2Go. Furthermore, DI decreased with increasing BMI in both ethnic groups. The association between BMI and DI was significant, independent of ethnicity (P = 0.02; Fig. 3Go).


Figure 2
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  		FIG. 2. SI, insulin secretion, and β-cell compensation over the range of BMI in individuals with and without a family history (FamHx) of T2DM. A, SI by BMI. B, AIRg by BMI. C, β-cell compensation (DI) by BMI.

 

Figure 3
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  		FIG. 3. Comparison of SI, insulin secretion, and β-cell compensation by ethnicity over the range of BMI. Panels A–C are as in Fig. 2Go.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Obesity and family history of T2DM confer approximately equal and synergistic risks for the prevalence of T2DM in previous National Health and Nutritional Examination Survey studies (26). Furthermore, diabetes prevalence is doubled in African-American individuals. Previous work from our laboratory showed that the ability of the β-cell to compensate for insulin resistance, such as occurs with obesity, is heritable (13), a finding that is well replicated (27, 28) in Caucasians and African-Americans. Finally, in previous studies from our laboratory (29), β-cell compensation (DI) decreased with increasing obesity in the setting of a strong family history of diabetes, suggesting that obesity might be exposing or inducing a defect in insulin secretion in predisposed individuals. We undertook the current study to explore the question of whether obesity alone caused a failure of the β-cell to compensate for insulin resistance, or whether a family history of T2DM conferred an additional risk. Furthermore, we asked whether the risk conferred might differ between Caucasian and African-American subjects, thus explaining part of the higher prevalence of diabetes among African-American subjects.

In examining the role of insulin secretion in compensating for reduced SI, we and others (22, 23) have relied on the concept of the DI (SI x insulin secretion). If SI and AIRg are related by a hyperbolic curve, reductions in SI such as occur with obesity would be compensated by increased AIRg, thus maintaining a constant DI. In an earlier study, we sought to identify a fixed defect in β-cell mass or function by inducing insulin resistance in relatively lean individuals with and without a history of T2DM (14). In that study all subjects failed to compensate completely for the short-term induction of insulin resistance by appropriately increasing insulin secretion, but glucose-tolerant members of high-risk families did not show a greater decrease in DI than individuals with no known genetic predisposition. In the current study, we asked whether the failure to see a role of genetic predisposition was because β-cell compensation takes more than a few weeks. Thus, we examined comparably obese individuals with and without a family history of T2DM. However, once again we failed to find any significant influence of family history of T2DM on insulin secretion. Furthermore, both individuals with a family history and individuals without a family history of T2DM showed a decrease in DI over the weight range from lean to obese. These findings appear to contradict the well-established heritability of insulin secretion and DI, and our own earlier publication using very high-risk families from Utah (29).

Unlike our previous studies in Utah, we restricted the current studies to glucose-tolerant individuals. We did so because β-cell dysfunction in individuals with impaired glucose tolerance is now well demonstrated by our laboratory (26). Individuals with increased fasting plasma glucose likewise show a decreased DI (30). In contrast, whether glucose-tolerant individuals with normal fasting plasma glucose levels have detectable defects in β-cell function is controversial. Previous studies addressing this question have been both cross-sectional as in our study, and prospective covering a range of ages and glucose tolerance stages. In a small cross-sectional study of individuals at various stages ranging from glucose tolerant to diabetic, Byrne et al. (31) failed to find a difference in insulin secretion rate corrected for BMI in glucose-tolerant control individuals and first-degree relatives of diabetic individuals. Vaag et al. (32) reported in a cross-sectional study that nondiabetic, monozygotic twins of T2DM subjects were both more insulin resistant and had reduced insulin secretion compared with controls, but these individuals were also more obese and had a high prevalence of impaired glucose tolerance. Pimenta et al. (33) reported reduced first and second-phase insulin secretion in a cross-sectional study of 50 Caucasian individuals with a family history of diabetes compared with 50 controls but surprisingly found no difference in SI. In contrast, using an insulin response to oral glucose and clamp-derived measures of SI, Ferrannini et al. (34) found reduced β-cell compensation primarily in individuals with overt T2DM. In prospective studies of Pima Indians across age ranges and glucose tolerance status, both reduced SI and reduced AIRg predicted subsequent T2DM (35), and AIRg was related to the age of onset of the parents’ diabetes (36). Furthermore, AIRg, when adjusted for SI, was reduced in individuals with low birth weight. In another recent small prospective study, Cnop et al. (37) showed that individuals who progressed to diabetes or impaired glucose tolerance had a greater decrease in DI compared with those who maintained normal glucose tolerance.

The results of these previous studies suggest that our ascertainment criteria, which selected relatively young, glucose-tolerant individuals, may have excluded those individuals at highest risk. Possible reasons for our results might include examination of individuals too early in their course to detect the genetic influence on β-cell compensation. By selecting obese, normoglycemic individuals, we may have selected subjects with less genetic predisposition than in our earlier studies or in Pima Indians. Indeed, by excluding subjects with glucose intolerance, we may have inadvertently selected those subjects who are less likely to progress to T2DM and who have relatively normal β-cell function. Reliable information on age of onset in parents or on birth weight of our subjects was not available in this study. Alternatively, our methods for testing β-cell function may have been insensitive compared with the more sophisticated indexes tested by Ferrannini et al. (34), although AIRg was a sensitive measure in the studies of Byrne et al. (31).

Based on the failure of β-cell compensation in both family members and controls in our earlier study of experimental insulin resistance, we speculated that β-cell compensation might require an expansion of β-cell mass. Indeed, in murine models of obesity and insulin resistance, increased first-phase insulin secretion (β-cell compensation) was mediated in large part through increased β-cell mass, and loss of compensation is reflected in reduced β-cell mass and β-cell apoptosis (38). Human pregnancy may represent a similar state, although the degree to which β-cell mass expands in humans has been difficult to assess. A potential surrogate measure for β-cell mass is the AIRmax, the insulin response to arginine measured at a glucose over 25 mM (21). In the subset of 80 individuals for whom this measure was available, we saw no significant reduction in mass with a strong family history of T2DM, even when corrected for SI (DImax).

A striking finding of this study was the marked difference in metabolic parameters between Caucasian and African-American subjects without regard to family history. Although African-American subjects were more insulin resistant, their AIRg was almost 2-fold higher than in Caucasians, resulting in over a 25% increase in DI. These differences could not be explained by BMI, waist circumference, or waist-hip ratio. Interestingly, β-cell mass, as measured by AIRmax, did not differ by ethnicity, thus arguing against a greater compensatory increase in β-cell mass in African-American individuals. Indeed, if AIRmax is examined in the context of the reduced SI in African-American individuals using SI x AIRmax, the resultant DImax is lower in African-Americans, perhaps suggesting an inadequate expansion of β-cell mass for the reduced SI. That reduction might increase the risk of T2DM in African-American individuals, independent of family history.

Several previous studies have compared SI and secretion between Caucasian and African-American individuals. The Insulin Resistance Atherosclerosis Study found a lower SI in nondiabetic African-American subjects after adjusting for weight than in Caucasians, as well as higher AIRg (15). Studies in children reported similar findings (16, 39). In both children and adults, the higher AIRg in African-Americans was attributed to both greater insulin secretion and reduced hepatic insulin extraction (39, 40). A limitation of the current study is that we did not directly measure insulin secretion using C-peptide kinetics, or directly measure hepatic insulin extraction. Because hepatic insulin extraction is an understudied but potentially important method to regulate circulating insulin levels, and may be altered by obesity and ethnicity, any studies such as ours that rely on AIRg to estimate insulin secretion are potentially limited by the uncertain changes in insulin clearance.

In summary, we were unable to demonstrate that glucose-tolerant individuals with a history of diabetes in first-degree relatives fail to compensate for obesity to a greater degree than individuals without a family history. As observed in some earlier studies, African-American individuals were more insulin resistant and yet had compensation that was out of proportion to the decrease in SI when compared with Caucasians. Although the increased AIRg and DI likely could be explained by a reduced hepatic insulin extraction in African-American individuals, the lower DImax in African-American individuals may reflect an inadequate expansion of β-cell mass. We also found that β-cell compensation was incomplete in obese individuals, regardless of familial predisposition or ethnicity. At least early in the course of T2DM, obese individuals decrease from the hyperbolic curve regardless of genetic predisposition. This failure of β-cell compensation may represent lipotoxicity at the level of the β-cell, or might be the result of chronic stress on the pancreatic β-cell resulting from long-standing, obesity-induced insulin resistance, and increased pancreatic workload. The genetic propensity to β-cell failure may reflect the subsequent compensatory mechanisms over time as the disease progresses to early stages of glucose intolerance, in which defects in insulin secretion have been well demonstrated.


   Acknowledgments
 
We thank Terri Hale, Judith Cooper, and Oksana Hackney for assistance with recruitment and data collection, and the nurses, laboratory staff, and kitchen staff of the General Clinical Research Center for their assistance with these studies.


   Footnotes
 
This work was supported by the Research Service of the Department of Veterans Affairs through Veterans Affairs Merit Review grants (to S.C.E. and N.R.), by a Department of Veterans Affairs Research Enhancement Award Program grant, and by Grant M01RR14288 from National Center for Research Resources (National Institutes of Health) to the University of Arkansas for Medical Sciences to fund the General Clinical Research Center.

Disclosure Statement: The authors have nothing to declare.

First Published Online September 18, 2007

Abbreviations: AIRg, Acute insulin response to glucose; AIRmax, maximally potentiated insulin response to arginine; BMI, body mass index; DI, disposition index; FSIGT, frequently sampled iv glucose tolerance test; OGTT, oral glucose tolerance test; SG, glucose effectiveness; SI, insulin sensitivity; T2DM, type 2 diabetes.

Received April 23, 2007.

Accepted September 10, 2007.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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