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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0048
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 10 5825-5833
Copyright © 2005 by The Endocrine Society

Effects of Short-Term Experimental Insulin Resistance and Family History of Diabetes on Pancreatic ß-Cell Function in Nondiabetic Individuals

Neda Rasouli, Terri Hale, Steven E. Kahn, Horace J. Spencer and Steven C. Elbein

Medicine and Research Services, Central Arkansas Veterans Healthcare System (N.R., T.H., S.C.E.), Little Rock, Arkansas 72205; Division of Endocrinology, Department of Medicine (N.R., T.H., S.C.E.), and Department of Biostatistics (H.J.S.), University of Arkansas for Medical Sciences Colleges of Public Health and Medicine, Little Rock, Arkansas 72205; and Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, Veterans Affairs Puget Sound Healthcare System and University of Washington School of Medicine (S.E.K.), Seattle, Washington 98108

Address all correspondence and requests for reprints to: Dr. Steven C. Elbein, Endocrinology 111J-1/LR, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205. E-mail: elbeinstevenc{at}uams.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Normal glucose homeostasis is maintained despite reductions in insulin sensitivity by increasing insulin secretion. This ability to compensate for reduced insulin sensitivity is highly heritable, but the mechanisms for this compensation or its failure in type 2 diabetes (T2DM) are unknown.

Objective: The objective of this study was to test whether individuals with a family history of T2DM have a fixed decrease in ß-cell mass or function that would be revealed as an impaired insulin secretory response to short-term insulin resistance.

Design: Glucose tolerance, insulin sensitivity (SI), and insulin response to iv glucose (AIRG) were compared in nondiabetic individuals with and without a family history of diabetes before and after nicotinic acid (NA) treatment.

Setting: This study was performed at the Ambulatory General Clinical Research Center.

Subjects: Healthy, nonobese, nondiabetic individuals with or without a family history of T2DM were studied.

Interventions: Oral NA was given, with a final dose of 2 g/d, for at least 7 d.

Main Outcome Measure: The main outcome measure was the disposition index (insulin sensitivity x insulin response) in response to NA.

Results: Postchallenge plasma glucose levels rose during NA therapy regardless of family history. Neither group adequately increased their AIRG to maintain the disposition index. Family members did not differ from controls at baseline or after NA treatment for any outcome measure, but only 28 of 52 subjects experienced a 25% or greater fall in SI with NA treatment.

Conclusions: Short-term ß-cell compensation to NA-induced insulin resistance was incomplete and did not differ by genetic predisposition. A genetic defect controlling ß-cell growth in response to chronic insulin resistance better explains differences in the ability to compensate for insulin resistance than an inherited, fixed defect in ß-cell mass.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CONSIDERABLE DATA SUPPORT combined defects of ß-cell function and insulin sensitivity in the pathogenesis of type 2 diabetes (T2DM) (1, 2). Absolute insulin levels frequently increase before the onset of T2DM, including in individuals with impaired glucose tolerance. However, when viewed in the context of the reduced insulin sensitivity that typically accompanies the early pathogenesis of T2DM and impaired glucose tolerance (3, 4), ß-cell function is diminished. This concept of a closed feedback loop determining ß-cell compensation for insulin sensitivity was proposed by Bergman (5), was demonstrated in humans in a cross-sectional analysis by Kahn et al. (6), and is now widely accepted (7). Thus, insulin responses and insulin sensitivity (SI) have a nonlinear relationship in nondiabetic individuals such that the product of insulin sensitivity and the insulin response describes the hyperbolic relationship between the two parameters, which, in turn, characterizes ß-cell function. When insulin release is measured as the first phase insulin response to an iv glucose bolus [acute insulin response to glucose (AIRG)], this measure of ß-cell function (SI x AIRG) is known as the disposition index (DI). If the islet ß-cell response to decreasing insulin sensitivity (decreased SI) is appropriate, AIRG will increase, DI will remain constant, and glucose homeostasis will be maintained.

In previous studies we demonstrated that DI was strongly heritable among nondiabetic members of families at high risk for T2DM and was highly correlated with T2DM susceptibility (8). Subsequent studies have replicated this finding (9, 10, 11). Furthermore, among nondiabetic family members at risk, we and others have shown that DI was reduced in individuals with impaired glucose tolerance (IGT) (7, 12). Finally, contrary to predictions that nondiabetic individuals would increase insulin secretion in response to the reduced insulin sensitivity of obesity, we reported previously in a cross-sectional study that family members, but not controls without a family history, failed to maintain DI with increasing body mass index (BMI) (12). We propose three possible explanations for these observations: 1) obese individuals with a family history of T2DM might have a functional impairment of insulin secretion as a consequence of obesity and increased circulating free fatty acids (FFA); 2) a fixed defect in ß-cell mass or function might be present in individuals with a family history of T2DM who were exposed to reduced insulin sensitivity; or 3) individuals with a genetic predisposition to T2DM might fail to increase or maintain ß-cell mass in the face of chronic insulin resistance. We propose that models 2 and 3 can be distinguished by inducing reductions in insulin sensitivity comparable to those seen with obesity, but over a short time period and in individuals who were relatively insulin sensitive.

Two options are available to induce acute, experimental insulin resistance. Fajans and Conn introduced steroids as a probe in 1954 (13), and this method has been used in many subsequent studies (14, 15, 16). However, steroids have direct effects to reduce insulin secretion in vitro (17), which complicates the interpretation of the ß-cell response to dexamethasone-induced insulin resistance (17, 18, 19, 20). In contrast, nicotinic acid (NA) reduces insulin sensitivity (19) without a known direct effect in vivo on insulin secretion (19, 21). In proof of principle, NA was used previously in baboons to unmask the effects of reduction in ß-cell mass resulting from streptozotocin (22). We hypothesized that nonobese individuals with a family history of T2DM who have an inherited, fixed defect in ß-cell mass would demonstrate an inadequate compensation to short-term, NA-induced insulin resistance. We predicted that young, glucose-tolerant individuals with a strong family history of T2DM would fail to adequately increase AIRG and thus would experience a greater fall in DI as the SI declined than individuals with no family history of T2DM, who would better maintain their DI by increasing the AIRG despite falling SI. Alternatively, if the genetic predisposition to T2DM were the result, instead, of a failure to increase or maintain ß-cell mass in the face of chronic insulin resistance, both groups would probably respond similarly to short-term, experimentally induced insulin resistance.


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

Volunteers were recruited by advertisement. Participants from earlier studies of the genetics of T2DM in families were also invited to return. All subjects were 18–45 yr old and had a BMI between 20 and 30 kg/m2. Subjects were recruited into two groups in a matched pair design: subjects with a family history of T2DM, defined as having at least one diabetic first degree relative and one additional first or second degree relative with T2DM; and subjects with no history of T2DM in a first or second degree relative. Individuals were excluded on screening for any of the following: elevated triglycerides (>450 mg/dl), a history of liver disease or abnormal liver enzymes, a history of heavy alcohol use, any allergy or inability to take aspirin, a history of gestational diabetes or glucose intolerance, and an abnormal baseline glucose tolerance test. The study was approved by the University of Arkansas for Medical Sciences institutional review board, and written consent was obtained before enrollment in the study.

Twenty-six individuals with a family history of T2DM and 26 control subjects were studied; an additional three individuals with a family history and 10 subjects without a family history of T2DM failed to complete the study and were not included in the analyses. Reasons for failure to complete the study included screening failures, poor venous access, inability to tolerate NA, or inability to return for post-NA visits. No single category of exclusion was present more often in family members or controls; hence, no selection bias was apparent upon inspection of those who could not complete the study. The study was powered based on the expectation that 20 individuals in each group provided 80% power for a two-sample t test to detect an effect size of more than 0.91 SD units. This corresponds to a fall in DI among family members that would be comparable to the difference between lean and obese subjects from Utah families. Hence, lean individuals with a family history of T2DM were expected to experience a fall in DI from 0.0181 to 0.0115, whereas individuals without a family history were expected to compensate adequately and maintain their DI .

Study design

All studies were performed at the General Clinical Research Center of University of Arkansas for Medical Sciences. The study design is shown in Fig. 1Go. Visits for menstruating women were timed such that the first frequently sampled iv glucose tolerance test (FSIGT) was performed during the follicular phase of the menstrual cycle, with the timing of the second FSIGT visit approximately 2–3 wk later.



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  		FIG. 1. Study protocol. Subjects underwent a screening visit and OGTT, followed by an FSIGT for calculation of insulin responses and SI. Subjects then initiated an escalating dose of NA to 1 g twice daily, which was continued for 1 wk (range, 6–13 d). The post-NA OGTT and FSIGT were completed on the maximum NA dose, with the FSIGT on the morning after the last dose of niacin the previous evening.

 
On visit 1, height was measured by a wall-mounted stadiometer, and weight was measured by an electronic balance. Body composition (percent body fat) was measured by dual x-ray absorptiometry. A standard 75-g oral glucose tolerance test (OGTT) was performed, and blood was obtained for lipid and liver enzyme measurements. Individuals with normal fasting and 2-h-postchallenge glucose levels and normal laboratory values were enrolled and invited to return for a tolbutamide-modified FSIGT, as described previously (8, 23, 24). After the FSIGT, subjects were instructed to begin low dose NA with aspirin twice daily with increasing dose to achieve 1 g twice daily by 1 wk. Schedules were altered due to symptoms at lower doses or problems scheduling return visits in 10 individuals. All but one subject took 1 g NA twice daily for at least 7 d before the FSIGT; the remaining subject had only 6 d of treatment with 1 g NA twice daily. The maximum duration on the 2-g daily dosage was 13 d. The last NA dose was administered on the evening before the second FSIGT.

OGTT was performed by obtaining two baseline glucose and insulin samples, followed by drinking 75 g glucose over 2 min and repeat sampling at 30, 60, 90, and 120 min for glucose and insulin levels. FSIGT testing 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 was continued at 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 19 min. At 20 min, 125 mg/m2 iv tolbutamide was given over 30 sec, and sampling was continued at 22, 23, 24, 25, 27, 30, 40, 50, 70, 90, 100, 120, 150, and 180 min. If the glucose level between 120 and 180 min continued to change by more than 0.3 mmol/liter or showed a clear trend, we continued sampling until 240 min or until the glucose level no longer varied from the previous sample by over 0.3 mmol/liter. FFA levels were measured as the mean of the fasting samples from the OGTT and FSIGT visits, both before and after NA treatment. Fasting insulin levels were taken from the two baseline samples of the OGTT visit.

Laboratory procedures

Insulin levels were measured by the General Clinical Research Center Core Laboratory using an immunochemiluminometric assay (MLT Insulin Assay, Cardiff, Wales, UK). Plasma nonesterified fatty acids were measured using a colorimetric assay (WAKO, Richmond, VA). Plasma glucose was measured by a glucose oxidase assay, and blood lipids were measured using standard clinical assays by LabCorp, Inc. (Burlington, NC).

Statistical analysis

The AIRG was determined as the mean increment in insulin over baseline from 2–10 min after the glucose bolus at the initiation of the FSIGT. SI and glucose effectiveness at basal insulin were estimated from insulin and glucose measured during the tolbutamide-modified FSIGT using the MinMod program (25). SI was undetectable after NA treatment in four individuals, three of whom were African-American; we set the value of SI at 0.1 x 10–5 min–1/(pmol/liter) for calculation of the DI and subsequent analyses in these studies. The DI (AIRG x SI) was used a measure of the compensatory adaptation to insulin resistance.

We analyzed continuous variables using a mixed effects model to account for the repeated measurements obtained from each subject before and during NA treatment. We included the main effects of family history of diabetes and effects of NA therapy, and we included an interaction term to test the hypothesis that family history would alter the response to NA. Data that were not normally distributed (SI, AIRG, DI, and BMI) were log transformed to normality before analysis. Additionally, AIRG was modeled as the dependent variable in a linear regression model, with age, ln(BMI), and ln(SI) as covariates, and gender, race, and family history as fixed factors. All data are shown as the mean ± SD from the linear scale, but P values are based on ln-transformed data where appropriate. P < 0.05 was considered significant. Analyses were conducted in SPSS for Windows version 12 (SPSS, Inc., Chicago, IL) or SAS version 9.1 (SAS Institute, Inc., Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
In total, 52 normal glucose-tolerant individuals completed the full study protocol (Fig. 1Go), including 26 individuals with a family history of T2DM (20 Caucasian and six African-American) and 26 individuals with no family history of T2DM (21 Caucasian and five African-American). The two groups did not differ significantly at baseline in age, BMI, percent fat, SI, DI, or glucose tolerance (Table 1Go). As shown in Table 1Go and Fig. 2Go, both controls and family members showed significantly reduced SI and DI, elevated fasting and postchallenge insulin and glucose, improved lipids, and significantly increased FFA levels during NA treatment. Family members and controls did not significantly differ in any measured parameter, including those based on the 30 min insulin response to oral glucose, but 2-h-postchallenge glucose and insulin levels were higher among those with a family history of diabetes and approached significance when compared by t test (difference in 2-h glucose between family members and controls, 0.76 mmol/liter; 95% confidence intervals for difference, 0.03–1.56 mmol/liter; P = 0.054; difference in 2-h insulin, 2.28 pM; 95% confidence intervals, 0.80–5.35 pM; P = 0.058). The differences between family members and controls were 0.018 (–0.41 to 0.45) for SI, 0.072 (–0.34, 0.20) for AIRG, and 0.047 (–0.41, 0.31) for DI (all shown with 95% confidence intervals), none of which approached significance (Table 1Go). Similarly, the differences between family members and controls with respect to niacin response did not differ, with mean differences and 95% confidence intervals as follows: SI, –0.16 (–1.79, 4.46); AIRG difference, 6.35 (–5.11, 17.80); DI, 3.78 (–2.08, 9.65); 2-h glucose, 3.06 (–19.04, 25.15); and 2-h insulin, –3.04 (–24.97, 18.88).


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  		TABLE 1. Clinical and biochemical characteristics of study subjects at baseline and after NA

 


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  		FIG. 2. Individual responses of SI, AIRG, and DI before and after NA treatment. The figure shows the individual responses before (baseline) and during NA treatment. Individual data points for SI (panels 1 and 2), AIRG (panels 3 and 4), and DI (panels 5 and 6) are connected with a dotted line. Both responders and nonresponders are shown. FH, Family history; control, no family history.

 
Despite a highly significant fall in mean SI, nearly 20% of subjects did not reduce their SI in response to NA, including one of 11 African-American and 11 of 41 Caucasian subjects. SI fell by at least 25% in only 28 of 52 subjects. Because our original study design was to test the ß-cell compensatory response to an acute fall in insulin sensitivity, we believed that a post hoc analysis was appropriate to examine the parameters of insulin secretion in those individuals who did experience a fall in SI. In doing so, we recognized that this exploratory analysis lacked the power of the original study. In an analysis to determine whether any factors predicted the fall in SI in response to niacin, we examined baseline characteristics of responders and nonresponders. We found no differences in age, BMI, percent fat, baseline SI, or baseline DI (data not shown), but the waist/hip ratio was greater among responders (0.902 ± 0.093) vs. nonresponders (0.834 ± 0.054; P = 0.02). Consistent with the well-described relationship of SI and AIRG (6), Responders experienced a greater increase in AIRG in response to the decrease in SI when compared with nonresponders, in whom SI showed little change (29.7 ± 20.9% increase vs. 4.8 ± 33.5% decrease; P = 0.002). However, this increase failed to compensate for the fall in SI. Hence, the decrement in DI after NA therapy was significantly greater among responders (49.8 ± 18.6%) than among nonresponders (10.8 ± 39.3%; P = 0.00002 vs. responders). Therefore, the marked failure in ß-cell compensation was related primarily to the decrement in SI, rather than NA therapy. Responders and nonresponders did not differ in glucose tolerance, however, with similar areas under curve for insulin and glucose (data not shown). Surprisingly, responders and nonresponders had similar and statistically significant increases in fasting and 2-h-postchallenge glucose and fasting insulin levels during NA therapy. Furthermore, responders did not show a greater fall in cholesterol, triglycerides, low-density lipoprotein cholesterol, or FFA or an increase in high-density lipoprotein cholesterol compared with nonresponders. Hence, changes in SI, AIRG, and DI from the FSIGT visit were not reflected in glucose homeostasis or lipid levels from the OGTT visit.

Our primary hypothesis was that individuals with a family history of T2DM would have inadequate ß-cell compensation for falling SI compared with individuals without a family history of diabetes. Thus, we asked whether individuals who did experience a fall in SI might have differed in the insulin secretory response to NA by family history of diabetes. To address this question, we performed a post hoc analysis of the data restricted to the 28 responders (Table 2Go). Again, DI did not differ by family history (Table 2Go). These conclusions were not changed when AIRG was examined as the dependent variable in a general linear model with age, ln(SI), and obesity measures as covariates and gender, race, and family history as fixed factors; when responder status was defined as any fall in SI; or when data were restricted to Caucasian subjects. In the general linear model, post-NA DI, but not family history, was the only significant predictor of 2-h-postchallenge glucose both among responders only (P = 0.011) and among all individuals (P = 0.021).


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  		TABLE 2. Comparison of clinical and biochemical measures for responders by family history

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The failure of the pancreatic ß-cell probably drives the progression of T2DM from early insulin resistance to IGT and on to T2DM (1). In rodents, ß-cell expansion appears to be the primary means to compensate for the insulin resistance induced by diet or genetic defects (26), but the mechanism in humans is unclear. Studies from our laboratory (8) and others (9, 10, 11) have shown that measures of ß-cell compensation, such as DI, are strongly heritable. In the present study we sought to elucidate the etiology of that compensation by examining young, nonobese individuals who could probably tolerate NA without becoming glucose intolerant. We hypothesized that individuals with a fixed defect in ß-cell mass, such as those with a genetic predisposition to T2DM, would be unable to meet the challenge of an acute fall in SI. In contrast, we expected that controls would be better able to compensate by increasing AIRG, as suggested previously (19). Our results do not support this model of an inherited, fixed defect in ß-cell mass as the cause of impaired ß-cell function. Instead, our results are most consistent with the model proposed by Buchanan (27) to explain the ß-cell defect in gestational diabetes and suggest that the heritable defect may be the response to chronic insulin resistance, such as obesity, rather than an inherited, fixed defect in either ß-cell mass or function that can be revealed by an acute reduction in SI.

A surprising aspect of this study was that neither controls nor family members mounted an adequate compensatory response. Although AIRG indeed increased with NA and in response to the fall in SI, as reported previously (19), neither family members nor controls were able to increase AIRG sufficiently to maintain the DI. Consistent with this fall in DI and supporting a failure to maintain glucose homeostasis, both family members and controls had significantly increased glucose levels at all times during the OGTT on NA therapy. Our results show that the ß-cell cannot increase secretion in a relatively short period of time to adequately compensate for a 25% or greater reduction in SI. Hence, ß-cell proliferation may be required to compensate for even modest reductions in SI. These conclusions are consistent with a recent report of a mouse model of impaired ß-cell compensation, in which the defect leading to both impaired function and decreased ß-cell mass was revealed only by chronic insulin resistance (26). Our results are also consistent with other models of limited, albeit longer term, insulin resistance, such as pregnancy, in which compensation occurs in women who maintain normal glucose tolerance (27). However, the compensation for pregnancy occurs over a period of months, not weeks, and probably involves changes in ß-cell mass. In contrast, Kahn et al. (6) induced short-term insulin resistance by treating subjects for 2 wk with the full 2-g dose of NA and found that healthy subjects increased their AIRG, but failed to fully compensate for the fall in SI. Had it been calculated, subjects in this study also would have experienced a fall in DI. Nonetheless, in contrast to our study, the healthy young subjects in the Kahn study increased AIRG with NA treatment. Neither controls nor family members in our study significantly increased the AIRG to compensate for the fall in SI.

A second unanticipated finding of our study was that nearly half our subjects experienced little or no change in SI, and indeed, in some individuals SI improved. Beside a higher waist/hip ratio among responders, we could not identify any differences that explained the response to NA, including FFA. A recent study showed that FFA levels may reach a nadir in as little as 1.5 h after NA treatment and may subsequently rebound as early as 3 h after NA (28). However, our subjects were instructed to take the last dose in the evening before their FSIGT visit and to report fasting for their FSIGT. Thus, we might have expected all subjects to experience a rebound in FFA. Because we do not know the length of time that the rebound may last, some subjects may have been recovering from the rebound, whereas others may have been experiencing a rebound at the time of the study. Because we averaged the FFA levels from several fasting samples before or during NA therapy, we were unlikely to observe very short-term FFA fluctuations. Nonetheless, the conclusions of this study were not altered when we analyzed only those individuals who experienced any reduction in SI or restricted the analysis to individuals with at least a 25% decrement in SI with NA treatment.

We interpret the results of this study as consistent with a heritable defect in the chronic ß-cell response to long-term insulin resistance, such as occurs with obesity. This model is also consistent with the arguments of Buchanan and colleagues (27) to explain gestational diabetes in Hispanic women. However, our study is subject to several possible caveats. First, we chose NA for this study because in contrast to steroids, NA is not thought to have any direct effect on ß-cells to alter insulin secretion. Nonetheless, NA has limitations. In contrast to dexamethasone, which lowers insulin sensitivity by 50% in most studies, NA lowered insulin sensitivity only 28% on the average, and the reduction was less consistent than that achieved with dexamethasone. However, NA resulted in a deterioration of glucose tolerance, with 19 of 52 individuals (37%) developing impaired glucose tolerance (2-h glucose, >140 mg/dl). Second, although the impaired ß-cell compensation (decreased DI) observed with NA therapy may have been a simple failure of short-term ß-cell compensation, NA alters FFA levels, which, in turn, may impact insulin secretion (21). Acute administration of NA lowered FFA and basal insulin secretion rates in both healthy subjects and T2DM patients (21), although the effects on glucose-stimulated insulin secretion were not reported. Nonetheless, the effects of FFA on insulin secretion are complex. Although short-term elevations of FFA may potentiate insulin secretion, and conversely reductions in FFA levels decrease basal insulin secretion (21), chronic elevations in FFA may impair insulin secretion. In studies of as little as 48 h of doubled FFA levels, impaired insulin secretion may be seen (29). In contrast, NA does not appear to have any direct effect on insulin secretion independent of FFA levels (21). In the present study, FFA levels were unlikely to be either persistently elevated with NA treatment such that insulin secretion would be compromised or persistently decreased, as observed with acute NA administration, such that basal insulin secretion or FFA potentiation effects would be reduced. Furthermore, we found no correlation between DI and FFA levels. Instead, the failure of compensation appeared to be related most to the decrement in SI rather than to FFA levels. Thus, although formally possible that NA alters insulin secretion directly, we do not believe this is a very likely explanation for the observed failure of compensation.

The failure of the present study to find the hypothesized difference in DI with NA treatment between family members and controls with no family history of diabetes may have resulted from a type 2 error as a result of an inadequate sample size. We powered the present study based on the differences observed between obese and lean individuals from Caucasian families ascertained in Utah. The fall in DI among family members receiving NA was indeed comparable to that predicted and upon which the power analysis was based. However, controls also showed an unexpected failure to compensate with the same decline in DI. Our power analysis was based on a surrogate from a different study population. Our power may have been reduced further by the failure of 20% of our subjects to reduce insulin sensitivity during NA treatment. Our post hoc analysis of responders necessarily lacked the power of the original study design. Nonetheless, the difference in post-NA DI between family members and controls did not approach significance; if anything, controls showed a greater decrement than family members. To evaluate the likelihood of a type 2 error, we reestimated the sample size from the results of the present study. Based on the observed changes in pre- and post-NA intervention DI between family members and controls, we would require 240 subjects (120 in each group) to achieve 80% power for an effect size of 20%. This estimate is based on SD of 10.1 and 10.9 for family history and control groups, respectively, for pre/posttreatment changes in DI. However, the difference upon which this power analysis was based was greater among controls than family members and thus would be the opposite of our proposed hypothesis that family members would show a greater fall in DI. Our data suggest that if differences do exist, they are very small compared with the increased risk of diabetes that accompanies a positive family history of diabetes.

In addition to the interpretation we propose above, the failure to find a difference between family members and controls may have other explanations. First, we intentionally studied family members who did not have IGT at baseline and who were unlikely to have overt ß-cell defects. We may thus have eliminated those individuals at highest risk of developing T2DM and reduced our power by avoiding those with baseline glucose intolerance. Second, we conducted this study in Arkansas families, a population that probably had different environmental exposures, particularly diet, than the Utah families upon which earlier studies were based. By reducing the ability of individuals both with and without a family history to compensate, environmental factors may have obscured, rather than exposed, the effects of genetic differences despite a relative lack of obesity in both groups. Third, we cannot exclude the possibility that the families recruited in the present study have a different genetic basis for T2DM than the families of northern European Caucasian ancestry from our previous studies (8, 12). However, most genetic variants causing common complex disease are thought to be ancient and would not be expected to differ greatly across outbred populations of similar ancestry. Fourth, although we studied all women during the follicular phase of the menstrual cycle for the first visit, we were unable, with this study design, to time the second visit to a particular part of the menstrual cycle. Altered insulin sensitivity due to different phases of the menstrual cycle among family members and controls might have obscured differences due to family history, but nearly identical post-NA SI values in the two groups makes this possibility unlikely.

Other investigators have sought to understand the defects in insulin secretion that precede T2DM by modifying insulin sensitivity. Henriksen and colleagues (14), in a study design very similar to ours, used dexamethasone to induce an average 50% decrease in SI. As in our study, DI fell in both relatives and controls, but relatives had a lower DI initially and during dexamethasone treatment, whereas in our study, values in family members and controls were similar both before and during NA treatment. In the Danish study, the primary defect was restricted to seven of 20 individuals whose 2-h-postchallenge glucose level rose above that in controls, whereas the remaining relatives were not different from controls and appeared to compensate adequately. Although we observed similar trends, equal numbers of family members and controls developed IGT, and we could not identify a group of family members whose 2-h glucose levels were elevated above control values. Our study included subjects of nearly the same BMI who were only slightly older than those in the Danish study. Possible differences in our study and the Danish study beyond the greater reduction in SI with dexamethasone might include different diets and, hence, differences in pretreatment insulin sensitivity in the two populations. For example, Arkansas controls might have been more insulin resistant at baseline, thus reducing the difference in the baseline DI and SI values between family members and controls. Notably, differences in SI and DI between family members and controls are not a consistent finding in other studies (30, 31).

Other studies have stratified populations by SI and showed impaired insulin secretory responses to dexamethasone. Larsson and Ahren (16) examined 10 postmenopausal women who were selected for extremes of insulin sensitivity. The five insulin-resistant women showed no increased insulin response to arginine, whereas insulin-sensitive women showed some compensatory change. Similarly, Ehrmann and colleagues (15) showed a lower DI at baseline and during dexamethasone treatment in women with polycystic ovary syndrome compared with controls, but women with polycystic ovary syndrome were significantly more insulin resistant at baseline. In contrast, our family members and controls were matched at baseline for DI and SI. Notably, the controls in each of these other studies failed to maintain DI with dexamethasone treatment and experienced an increase in postchallenge glucose levels. Thus, using two different challenge medications, short-term compensation was incomplete. The extent of compensation appears to depend on the population, family history of T2DM, and preexisting insulin sensitivity. The most probable synthesis of these findings is that postchallenge ß-cell function reflects prechallenge reductions in ß-cell compensation, which are related, in turn, to the response to chronic reductions in insulin sensitivity. Although dexamethasone and NA may amplify the prechallenge deficits in ß-cell function, they do not appear to reveal latent defects in ß-cell mass or function, at least in individuals not selected for a specific genetic defect. This model is also consistent with the observations in gestational diabetes, in which responses to the insulin resistance of pregnancy appear to reflect nonpregnant differences between women who maintain glucose tolerance during pregnancy and those who do not (27).

In conclusion, we have confirmed earlier reports that NA, on the average, induces insulin resistance, but we found that a substantial number of subjects did not experience reduced SI. Even among those who did experience a decline in SI, ß-cell compensation was incomplete. This failure of ß-cell compensation was not different between family members and controls, although we noted a trend to worsening glucose tolerance after NA treatment among family members that could not be attributed to reduced DI. A compensatory mechanism that requires more than 2 wk, such as increased ß-cell mass, or another mechanism of slow improvement in ß-cell function would explain such results. We suggest that the genetic defects that reduce ß-cell function are only revealed by chronic reductions in SI, such as those seen with obesity, polycystic ovary disease, pregnancy, or polygenic insulin resistance, a hypotheses that is supported by available studies (12, 32).


   Acknowledgments
 
We thank Judith Johnson Cooper for assistance with recruitment, Subraman Ranganathan for insulin assays, and the General Clinical Research Center nursing staff for invaluable assistance with all aspects of the study.


   Footnotes
 
This work was supported by the Research Service of the Department of Veterans Affairs, grant support from the American Diabetes Association, and Grants DK-39311 (to S.C.E.) and DK-02654 (to S.E.K.) from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. The work was performed at the General Clinical Research Center, supported by Grant M01-RR-14288 from National Center for Research Resources, National Institutes of Health, to the University of Arkansas for Medical Sciences.

First Published Online August 9, 2005

Abbreviations: AIRG, Insulin response to iv glucose; BMI, body mass index; DI, disposition index; FFA, free fatty acid; FSIGT, frequently sampled iv glucose tolerance test; IGT, impaired glucose tolerance; NA, nicotinic acid; OGTT, oral glucose tolerance test; SI, insulin sensitivity; T2DM, type 2 diabetes.

Received January 10, 2005.

Accepted July 29, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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