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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 9 3303-3309
Copyright © 2006 by The Endocrine Society

Impaired ß-Cell Function in Human Aging: Response to Nicotinic Acid-Induced Insulin Resistance

Annette M. Chang, Marla J. Smith, Andrzej T. Galecki, Cathie J. Bloem and Jeffrey B. Halter

Department of Internal Medicine (A.M.C.), VA Ann Arbor Healthcare System, Ann Arbor, Michigan 48105; and Department of Internal Medicine (A.M.C., M.J.S., A.T.G., C.J.B., J.B.H.), University of Michigan, Ann Arbor, Michigan 49109

Address all correspondence and requests for reprints to: Annette M. Chang, M.D., 5570 MSRB II, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109-0678. E-mail: annchang{at}umich.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Glucose tolerance declines with age and may involve impaired ß-cell sensitivity to glucose and ß-cell compensation for insulin resistance.

Objective: We investigated ß-cell sensitivity to glucose and ß-cell compensation for nicotinic acid-induced insulin resistance in young (age <35 yr) people with normal glucose tolerance (NGT) and old (age >60 yr) people with NGT and impaired glucose tolerance (IGT).

Design/Patients/Setting/Intervention: Fifteen young NGT, 16 old NGT, and 14 old IGT were randomized to 2-wk treatment with nicotinic acid or placebo in a double-blind, crossover study in a university medical setting. At the end of each treatment period, participants had a frequently sampled iv glucose tolerance test and ramp clamp, in which insulin secretion rates (ISR) were determined in response to a matched 5–10 mM glucose stimulus.

Main Outcome Measures: Insulin sensitivity (SI), acute insulin response to iv glucose (AIRg), and disposition index (AIRg x SI, or ß-cell compensation for insulin resistance) from frequently sampled iv glucose tolerance testing, and ISR area under the curve (or ß-cell sensitivity to glucose) from ramp clamp were determined.

Results: Progressive impairments in insulin secretion as assessed by AIRg, disposition index, and ISR area under the curve were identified in older people with NGT, with more marked defects in older people with IGT. Nicotinic acid treatment significantly reduced SI in all groups. ß-Cell compensation for nicotinic acid-induced insulin resistance was incomplete in all three groups, with greater defects in the two older groups.

Conclusions: Human aging is associated with impaired ß-cell sensitivity to glucose and impaired ß-cell compensation to insulin resistance.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE PREVALENCE OF type 2 diabetes and impaired glucose tolerance (IGT) increases with age (1). More than 25% of the older population meets current diagnostic criteria for type 2 diabetes (2, 3). An additional 20% of this population meets criteria for IGT, defined as a 2-h glucose level equal to or greater than 7.8 mM but less than 11.1 mM by oral glucose tolerance testing (OGTT), and a fasting glucose less than 7.0 mM (2).

Multiple risk factors for type 2 diabetes associated with aging, including increased adiposity and decreased physical activity, predispose older people to develop glucose intolerance and increased insulin resistance. The progression from normal glucose tolerance (NGT) to IGT and type 2 diabetes is characterized by progressive defects in ß-cell function or impaired ß-cell compensation for insulin resistance (4). Impaired insulin secretion has been demonstrated even with normal aging (1, 5).

However, the regulation of islet function and the ability to compensate for age-related insulin resistance in older people with IGT remains unclear. This interaction between insulin sensitivity (SI) and insulin secretion can be examined by pharmacologically inducing a decline of SI and examining the impact of this insulin resistance on ß-cell function.

Acute administration of nicotinic acid has been associated with variable effects on glucose tolerance and unchanged (6) or decreased (7) insulin concentrations, without known direct or indirect effects on insulin secretion (7). In contrast, long-term treatment leads to well-described worsening glucose tolerance (8, 9) and increased insulin levels (6, 10). Kahn et al. (11) showed that prolonged nicotinic acid administration produces significant insulin resistance and that islet adaptation to insulin resistance occurs by an increase in ß-cell secretory capacity in young men with NGT. However, previous studies have not characterized ß-cell sensitivity to glucose or ß-cell compensation for nicotinic acid-induced insulin resistance in young and older people with NGT and, in particular, older people with IGT.


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

This protocol was approved by the University of Michigan Institutional Review Board and performed in accordance with the Declaration of Helsinki. Healthy, community-dwelling men and women were recruited by advertisement to participate in a study of glucose metabolism and aging. After the nature of the study was explained in detail, informed consent was obtained from all participants.

Health status and glucose tolerance were assessed by screening history, physical exam, blood chemistries, complete blood count, electrocardiogram, and 75-g OGTT. Younger people (age ≤35 yr) with NGT and older people (age >60 yr) with NGT and IGT were eligible for enrollment. Fifty-six people underwent screening by frequently sampled iv glucose tolerance testing (FSIGT). Participants with baseline severe insulin resistance (SI < 1.2 x 10–5·min–1/pM) were excluded, because a study goal was to examine the effects of nicotinic acid-induced insulin resistance on ß-cell function. The 46 enrollees were selected to have a similar range of SI. There was one dropout in the young NGT group. Data on the 45 participants who completed the study are reported.

Study design

This was a double-blind, randomized, placebo-controlled, two-period crossover study. Participants were randomized to treatment with either nicotinic acid or placebo for a 2-wk dosing period. The study medication and matching placebo were started at a dose of 500 mg daily and gradually titrated to 1000 mg twice daily. In addition to the nicotinic acid/placebo capsules, aspirin (325 mg) was taken with each dose to minimize the possible side effects of nicotinic acid. At the end of each treatment period, participants had a FSIGT and a glucose ramp clamp. There was a 2-wk washout period between dosing periods.

All participants met with the dietician before randomization and were instructed on a weight-maintenance diet for the duration of the study. The nurse study coordinator was in weekly contact with the participants to review side effects, medication compliance, and weight-maintenance diet.

Study protocols

Assessments of glucose tolerance, SI, and ß-cell function were performed in the morning after 12-h overnight fasts. OGTT, insulin-assisted FSIGT, and ramp clamp were performed on three separate study days.

OGTT

Incremental OGTT glucose and insulin area under the curve (AUC) over the 120-min interval was estimated for each subject by using the trapezoidal rule.

FSIGT

The insulin-assisted FSIGT was performed as described by Bergman (12) with the addition of insulin to enhance precision of the estimates of insulin action (13). Participants consumed a diet containing a minimum of 150 g/d of carbohydrate for 3 d before studies. After three baseline samples for fasting glucose and insulin levels were drawn, 50% dextrose (0.3 g/kg) was injected iv over 30 sec followed by injection of insulin (0.02 U/kg) over 30 sec at time 20 min. Twenty-nine blood samples were collected according to a protocol schedule over 180 min.

The SI (sensitivity to insulin index) was calculated from a least-squares fitting of the temporal pattern of glucose and insulin throughout the FSIGT using the minimal model of glucose kinetics (12). The acute insulin response to iv glucose (AIRg) was calculated as the mean rise in plasma insulin above baseline between 2 and 10 min after iv glucose administration. Kg, a measure of iv glucose tolerance, was calculated as the least square slope of the natural log of absolute glucose concentration between 10 and 19 min after the glucose bolus. The relationship between two independent measurements of insulin secretion and SI has been found to be hyperbolic, allowing calculation of the product of AIRg x SI, or the disposition index (DI) (14, 15, 16). DI provides an indirect assessment of whether insulin secretion is appropriate for the level of insulin resistance (ß-cell compensation for insulin resistance or ß-cell function).

Glucose ramp clamp

On d 2, the glucose ramp protocol was initiated after an overnight fast, as previously described (17, 18). The aim of this procedure was to assess insulin secretion in response to gradually raising plasma glucose levels from approximately 5–10 mM over 3 h, or ß-cell sensitivity to glucose. After an initial baseline sample was taken, a small iv dose of insulin (0.007 U/kg) was administered to lower the glucose level to approximately 5 mM. After allowing the insulin to decay (20 min after bolus insulin), an iv infusion of 20% dextrose was started. Samples were drawn every 10 min for determination of insulin, C-peptide, and glucose. For each of the 10-min samples, plasma glucose was measured using a Beckman glucose analyzer (Beckman Coulter, Fullerton, CA), and the glucose infusion rate was adjusted to achieve a linear increase of plasma glucose levels from 5–10 mM over 3 h, closely matching glucose levels in all subjects.

The insulin secretion rate (ISR) during the ramp clamp protocol was derived by deconvolution of peripheral C-peptide concentrations and by previously determined C-peptide kinetics (19). The total ISR over the 40- to 220-min time interval was estimated for each subject by calculating the AUC using the trapezoidal rule (ISR AUC).

Assays

Serum was stored at –20 C until analysis. Plasma glucose levels were measured using a hexokinase method with an interassay coefficient of variation of 3.1% (Roche Diagnostics Corporation, Indianapolis, IN). Plasma insulin was quantified using a double-antibody RIA with an interassay coefficient of variation of 3.4% and an intraassay variability of 2.5% (Linco Research, Inc., St. Charles, MO). C-peptide was measured using a solid-phase competitive chemiluminescent enzyme immunoassay (Diagnostic Products Corp., Los Angeles, CA) with an interassay coefficient of variation of 2.3%. Total cholesterol and triglycerides were measured using standard reagents (Roche Diagnostics Corporation) with interassay variability of 3.0 and 4.0%, respectively. Plasma catecholamines (epinephrine and norepinephrine) were measured by single-isotope enzymatic assay (20).

Statistical analysis

Data are presented as means ± SE, with the exception of participant characteristics, which are presented as means ± SD. Sample size calculations were based on variability of data from previous work (17, 18, 21) at 80% power to detect between group differences in SI and ISR AUC with an {alpha}-level of 0.05. SI, AIRg, and DI were log-transformed to approximate a normal distribution. Differences between study groups and between nicotinic acid (treatment) and placebo were assessed by repeated measures ANOVA. An interaction term was also considered to evaluate for an association between study group and treatment. Period, sequence, and gender were also included in the model, to take into account the crossover design and any potential gender effects. Appropriate tests were performed to confirm that wash-out between the two treatment periods eliminated potential carryover effects. P values less than 0.05 were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Screening participant characteristics

A total of 45 healthy men and women (age 19–86 yr) were included in this analysis. Ethnicity of the study population was primarily Caucasian (43 of 45), but included one African-American and one Asian-American individual. As shown in Table 1Go, the 45 participants were classified into young (19–35 yr) and older (62–86 yr) groups and then by glucose tolerance during OGTT (NGT or IGT). Body mass index (BMI) was well-matched in the three groups, and was in the normal-overweight range representative of the community. Fasting, 2-h OGTT glucose levels and 2-hr OGTT glucose AUC were not significantly different in young and older people with NGT, but were significantly increased in older people with IGT. Despite higher glucose levels during OGTT in older people with IGT, fasting insulin and 2-h OGTT insulin AUC were similar in the three groups. Screening SI as assessed by FSIGT was similar in the three groups, because participants were selected to have a similar range of SI.


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  		TABLE 1. Screening characteristics of study participants

 
Glucose tolerance and fasting insulin

Fasting glucose, Kg, and fasting insulin levels obtained during FSIGT studies after placebo and nicotinic acid treatment are summarized in Table 2Go.


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  		TABLE 2. Effect of nicotinic acid treatment on FSIGT measures

 
Group effects

Fasting glucose levels were significantly increased in the old IGT group compared with both young and old NGT groups (P = 0.006). Kg was lower in the old IGT vs. both young and old NGT groups and in the old NGT vs. young NGT group (P = 0.0003). There was no significant group effect on fasting insulin levels (P = 0.59).

Nicotinic acid effects

Two-week nicotinic acid treatment resulted in increased fasting glucose levels compared with placebo (P < 0.0001). There was a significant group x treatment interaction (P = 0.002), with a more marked increase in fasting glucose in the old IGT group. Kg significantly declined in all three groups with nicotinic acid treatment (P = 0.002). Fasting insulin levels significantly increased in all three groups with nicotinic acid treatment (P < 0.0001).

Insulin sensitivity

As shown in Table 2Go and Fig. 1Go, A–C, SI significantly declined with nicotinic acid treatment compared with placebo in all three groups (P < 0.0001), with no significant group effect or group x treatment interaction. SI fell in 39 of 45 (87%) participants with nicotinic acid compared with placebo treatment. There was no evidence of a significant carryover effect.


Figure 1
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  		FIG. 1. Profiles of effects of nicotinic acid compared with placebo treatment on SI, AIRg, and DI (AIRg x SI, or ß-cell compensation for insulin resistance) from FSIGT in 15 young with NGT (A, D, and G), 16 old with NGT (B, E, and H), and 14 old people with IGT (C, F, and I). Group effects: AIRg: P = 0.1, old vs. young NGT; P < 0.0001, old IGT vs. young and old NGT. DI: P < 0.0001, old IGT vs. young and old NGT. Treatment effect of nicotinic acid vs. placebo: SI: P < 0.0001, no significant group x treatment interaction. AIRg: P = 0.12, significant group x treatment interaction (P = 0.01), as AIRg failed to increase in the old IGT group. DI: P < 0.0001, significant group x treatment interaction, in which the old IGT group had a much greater decline in DI with nicotinic acid vs. both young and old NGT. Vertical bars display means ± SE.

 
FSIGT measures of insulin secretion

AIRg and DI (AIRg x SI, or ß-cell compensation for insulin resistance) from the FSIGT studies after placebo and nicotinic acid treatment are displayed in Table 2Go and Fig. 1Go, D–I.

Group effects

Insulin secretion as assessed by AIRg trended toward being lower in old vs. young NGT (P = 0.1), and was significantly decreased in old IGT vs. both young and old NGT groups (P < 0.0001). ß-Cell compensation for insulin resistance as assessed by DI was markedly decreased in old IGT vs. both young and old NGT (P < 0.0001).

Nicotinic acid effects

Although there was no significant overall treatment effect on AIRg (P = 0.12), the young and old NGT groups had increased AIRg with nicotinic acid vs. placebo treatment, whereas AIRg failed to increase in the old IGT group with a significant group x treatment interaction (P = 0.01). Nicotinic acid had an overall effect to lower DI (P < 0.0001), but there was a significant group x treatment interaction (P = 0.006), in which the old IGT group had a much greater decline in DI with nicotinic acid treatment compared with both young and old NGT groups. There was no significant gender effect on FSIGT measures.

Ramp clamp measure of ß-cell sensitivity to glucose

Assessment of ß-cell response to increasing, matched glucose levels was provided with the glucose ramp clamp. As shown in Fig. 2Go, A and B, glucose levels during the ramp clamp procedures were well-matched in the fasting state and throughout the studies in the three groups, although the young NGT group had slightly lower glucose levels achieved during the last 40 min of both postplacebo and nicotinic acid studies.


Figure 2
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  		FIG. 2. Profiles of plasma glucose concentrations and ISR over time during the glucose ramp clamp studies. Glucose (A) and ISR (C) vs. time with placebo treatment in young with NGT (triangles), old with NGT (circles), and old with IGT (squares). Glucose (B) and ISR (D) vs. time with nicotinic acid treatment in young with NGT (triangles), old with NGT (circles), and old with IGT (squares). Glucose levels during variable rate glucose infusion begun at time 0 were well-matched in the three study groups and in the nicotinic acid and placebo treatment groups. Group effects: ISR AUC was significantly and progressively decreased in the two older groups, with the greatest impairment in old IGT (P = 0.0002, old IGT vs. young and old NGT and old NGT vs. young NGT). Nicotinic acid effects: ISR AUC significantly increased with nicotinic acid vs. placebo treatment (P = 0.005), and there was no significant group x treatment interaction (P = 0.7). Data are means + SE.

 
Group effects

As shown in Fig. 2Go, C and D, ISR increased in all three groups in response to increasing glucose concentrations with both treatments during the ramp studies. The young NGT group had higher average ISR throughout the ramp clamp studies with a progressive decline in average ISR in the old NGT and old IGT groups with both placebo and nicotinic acid treatment. There was a significant group effect (P = 0.0002) on ß-cell sensitivity to glucose as assessed by ISR AUC for the old IGT vs. both young and old NGT groups as well as the old NGT vs. young NGT group in the repeated measures model. There was no significant gender effect on ISR AUC.

Nicotinic acid effects

ISR AUC significantly increased with nicotinic acid vs. placebo treatment (young NGT, 84 ± 6 vs. 78 ± 7 nmol; old NGT, 69 ± 4 vs. 60 ± 3 nmol; old IGT, 53 ± 3 vs. 48 ± 4 nmol; P = 0.005), and there was no significant group x treatment interaction (P = 0.7).

Fasting lipid and catecholamine levels

Fasting lipid and catecholamine levels obtained before the FSIGT studies after placebo and nicotinic acid treatment are displayed in Table 3Go.


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  		TABLE 3. Effect of nicotinic acid treatment on lipid and catecholamine parameters

 
Group effects

There was a trend toward elevated fasting total cholesterol levels in the older group with IGT compared with young people with NGT (P = 0.07). Norepinephrine levels were higher in older people with both NGT and IGT compared with young people with NGT (P = 0.004). Epinephrine levels were similar in the three groups.

Nicotinic acid effects

Nicotinic acid treatment resulted in significant declines in total cholesterol and triglyceride levels in all three groups. There was an overall trend (P = 0.08) toward an increase in norepinephrine levels with nicotinic acid treatment. There was no significant change in epinephrine levels with nicotinic acid treatment.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Previous studies have not characterized ß-cell sensitivity to glucose or ß-cell function in response to nicotinic acid-induced insulin resistance in young and older people with NGT and older people with IGT. In this study, the young NGT, old NGT, and old IGT groups were carefully matched to have similar baseline BMI and SI per screening FSIGT to isolate and define potential age-related differences in ß-cell function and response to nicotinic acid-induced insulin resistance. The young and older groups with NGT were also closely matched for glucose tolerance per fasting and 2-h glucose levels and glucose AUC during OGTT.

The most striking finding in our study was the marked and progressive ß-cell dysfunction in the two older groups. Islet sensitivity to glucose as assessed by the glucose ramp clamp identified absolute and progressive impairments in ß-cell function even with normal aging in the old NGT group, and with greater defects in the old IGT group. Absolute impairments in AIRg and DI were identified in the old IGT group compared with the young and old NGT groups with a trend toward a decline in the old NGT compared with the young NGT group. Although nicotinic acid treatment resulted in significantly increased fasting insulin levels in all groups, and the young and old NGT groups increased AIRg in response to nicotinic acid-induced insulin resistance, this response was inadequate and DI was unable to be maintained. The old IGT group had no increase in AIRg and had a marked decline in DI with nicotinic acid-induced insulin resistance. Although AIRg did not increase in the old IGT group with nicotinic acid treatment, ISR AUC did increase during the glucose ramp clamp studies in all three groups (including old IGT). This may represent a difference in first-phase insulin secretion as assessed by AIRg and second-phase insulin secretion in response to a physiological glucose stimulus as assessed by the ramp clamp. In addition, because people with severe insulin resistance were excluded, the study may have selected an old IGT group with a predominant ß-cell defect.

There has been great variability in previous studies examining insulin secretion in older people, with some studies suggesting decreased, normal, and even increased insulin secretion (1). Absolute impairments in insulin response to iv glucose challenge related to age alone have not been clearly or consistently defined, despite older people often being glucose intolerant (22, 23, 24, 25). However, interpretation of ß-cell function in previous studies has been difficult due to confounding effects of age-related insulin resistance with comparison of older insulin-resistant people with younger insulin-sensitive subjects. Relative defects in insulin secretion have been suggested in cross-sectional studies per indirect and mathematical adjustment of insulin secretion for the level of insulin resistance by calculation of the DI, due to significantly increased insulin resistance in older compared with younger participants (5, 22). Prior studies that have matched older and younger people to have similar levels of SI have identified impaired arginine-stimulated acute insulin response in older compared with young men, as well as decreased second phase insulin secretion in response to iv glucose challenge in older men and women (26, 27). However, by carefully matching degrees of insulin resistance, we have clearly demonstrated absolute impairments in ß-cell sensitivity to glucose with normal human aging as well as impaired ß-cell function in response to a dynamic intervention with nicotinic acid-induced insulin resistance in young and older people carefully matched to have a similar degree of SI. Our study also identified a progressive impairment in ß-cell function in older people with NGT and IGT.

In this study, nicotinic acid treatment resulted in a decline in glucose tolerance (per fasting glucose levels and Kg), with a greater increase in fasting glucose levels in the older people with IGT. As expected, nicotinic acid treatment significantly reduced SI in all three groups. This is similar to the findings of Kahn et al. (11) in young healthy men, although the baseline level of SI was much higher and no significant change in fasting glucose levels was observed in this prior study.

Our findings differ from a recent study examining nicotinic acid treatment in people with a family history of diabetes and nondiabetic controls, in which unexpectedly nearly half of the participants had little or no change in SI with nicotinic acid treatment (28). It is possible that compliance with treatment might have been an issue in this case as well as the wide variation and skewed distribution of SI levels from 2.5–30.5 x 10–5·min–1/pM at baseline. An additional strength of the current study is the use of a placebo group for comparison in a randomized crossover design, because prior studies have compared only prenicotinic and postnicotinic acid treatment parameters.

The mechanisms contributing to the age-related decline in insulin secretion cannot be determined from the current study. Aging could be associated with loss of ß-cell mass or simply impaired function of a preserved ß-cell mass or a combination of these two factors. Factors associated with aging that could influence ß-cell function such as medications, coexisting illness, and increased inflammatory markers are unlikely explanations in the healthy older people we studied. Another possibility is decreased ß-cell sensitivity to the incretin hormones (29, 30). Alterations in visceral adiposity and lipid parameters such as free fatty acids and triglycerides associated with age-related changes in body composition and increased adiposity could also be playing a role (31). In our study, free fatty acid levels were not assessed, although these have remained unchanged (11) or increased (28) in prior studies with similar nicotinic acid treatment. Triglyceride levels significantly declined in all three groups with nicotinic acid treatment in the current study.

A limitation of this study is the lack of availability of body composition or central adiposity measures. An increase in adiposity has been well-documented with advancing age and is felt to account in large part for the age-related increase in insulin resistance identified in many studies (5, 32). Intraabdominal fat has also been associated with decreased ß-cell function and age (22), and it would have been of interest to assess this relationship further in the current study. However, the careful matching of BMI and SI per screening FSIGT in the young and older groups with NGT and IGT has allowed us to isolate age-related changes in ß-cell function and is a strength of the study. The results may be generalized to both men and women, but the study group included predominantly a Caucasian population, and the findings may not apply to people of other ethnic groups. Although the older IGT group had a higher proportion of women than the young and old NGT groups, no significant gender effects were identified in the study.

In summary, in these carefully matched groups of young people with NGT, and older people with NGT and IGT, progressive impairments in insulin secretion as assessed by AIRg, DI, and ß-cell sensitivity to glucose as assessed by ISR in response to a matched increase in glucose levels were identified in older people with NGT, with more marked defects in older people with IGT. In response to nicotinic acid-induced insulin resistance, young and older people increased insulin secretion, but compensation was incomplete as indicated by a fall in DI, which was greatest in the two older groups. In conclusion, human aging is associated with impaired ß-cell sensitivity to glucose and impaired ß-cell compensation to insulin resistance.


   Acknowledgments
 
We thank the study participants for their cooperation and commitment, and the University of Michigan General Clinical Research Center nurses, dieticians, and support staff for their assistance.


   Footnotes
 
This work was supported by Department of Veterans Affairs Clinical Science Research and Development, American Diabetes Association—Association of Subspecialty Professors, the University of Michigan Claude D. Pepper Older Americans Independence Center (NIH AG008808 and AG024824), and the University of Michigan General Clinical Research Center (NIH RR0042). This work used the Chemistry Laboratory of the Michigan Diabetes Research and Training Center (NIH DK20572).

Disclosure summary: The authors have nothing to disclose.

First Published Online June 6, 2006

Abbreviations: AIRg, Acute insulin response to glucose; BMI, body mass index; DI, disposition index; FSIGT, frequently sampled iv glucose tolerance test; IGT, impaired glucose tolerance; ISR, insulin secretion rate; Kg, iv glucose tolerance; NGT, normal glucose tolerance; OGTT, oral glucose tolerance testing; SI, insulin sensitivity.

Received April 28, 2006.

Accepted May 30, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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C. J. Bloem and A. M. Chang
Short-Term Exercise Improves {beta}-Cell Function and Insulin Resistance in Older People with Impaired Glucose Tolerance
J. Clin. Endocrinol. Metab., February 1, 2008; 93(2): 387 - 392.
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