Dietary Weight Loss and Exercise Effects on Insulin Resistance in Postmenopausal Women

      Background

      Comprehensive lifestyle interventions are effective in preventing diabetes and restoring glucose regulation; however, the key stimulus for change has not been identified and effects in older individuals are not established. The aim of the study was to investigate the independent and combined effects of dietary weight loss and exercise on insulin sensitivity and restoration of normal fasting glucose in middle-aged and older women.

      Design

      Four-arm RCT, conducted between 2005 and 2009 and data analyzed in 2010.

      Setting/participants

      439 inactive, overweight/obese postmenopausal women.

      Interventions

      Women were assigned to: dietary weight loss (n=118); exercise (n=117); exercise+diet (n=117); or control (n=87). The diet intervention was a group-based reduced-calorie program with a 10% weight-loss goal. The exercise intervention was 45 min/day, 5 days/week of moderate-to-vigorous intensity aerobic activity.

      Main outcome measures

      12-month change in serum insulin, C-peptide, fasting glucose, and whole body insulin resistance (HOMA-IR).

      Results

      A significant improvement in HOMA-IR was detected in the diet (–24%, p<0.001) and exercise+ diet (–26%, p<0.001) groups but not in the exercise (–9%, p=0.22) group compared with controls (–2%); these effects were similar in middle-aged (50–60 years) and older women (aged 60–75 years). Among those with impaired fasting glucose (5.6–6.9 mmol/L) at baseline (n=143; 33%), the odds (95% CI) of regressing to normal fasting glucose after adjusting for weight loss and baseline levels were 2.5 (0.8, 8.4); 2.76 (0.8, 10.0); and 3.1 (1.0, 9.9) in the diet, exercise+diet, and exercise group, respectively, compared with controls.

      Conclusions

      Dietary weight loss, with or without exercise, significantly improved insulin resistance. Older women derived as much benefit as did the younger postmenopausal women.

      Trial registration

      This study is registered at Clinicaltrials.gov NCT00470119.

      Introduction

      Given the high prevalence of insulin resistance
      International Diabetes Federation
      Diabetes atlas.
      and its associated health burden,
      • Reaven G.M.
      Pathophysiology of insulin resistance in human disease.
      • Coutinho M.
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      • Yusuf S.
      The relationship between glucose and incident cardiovascular events A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years.
      • Folsom A.R.
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      • et al.
      Prospective associations of fasting insulin, body fat distribution, and diabetes with risk of ischemic stroke The Atherosclerosis Risk in Communities (ARIC) Study Investigators.
      • Levitzky Y.S.
      • Pencina M.J.
      • D'Agostino R.B.
      • et al.
      Impact of impaired fasting glucose on cardiovascular disease: the Framingham Heart Study.
      • Pisani P.
      Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies.
      • Rapp K.
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      • et al.
      Fasting blood glucose and cancer risk in a cohort of more than 140,000 adults in Austria.
      effective prevention strategies for high-risk individuals are a priority. Several trials have examined the efficacy of lifestyle interventions for preventing type 2 diabetes, but few have examined their effectiveness on restoring normal glucose homeostasis.
      The Diabetes Prevention Program (DPP) demonstrated that combined diet and exercise therapy is effective for diabetes prevention
      • Knowler W.C.
      • Barrett-Connor E.
      • Fowler S.E.
      • et al.
      Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.
      and restores normal glucose regulation more frequently than placebo.
      • Perreault L.
      • Kahn S.E.
      • Christophi C.A.
      • Knowler W.C.
      • Hamman R.F.
      Regression from pre-diabetes to normal glucose regulation in the diabetes prevention program.
      Moreover, the effect of lifestyle therapy was more pronounced in older compared with younger participants.
      • Crandall J.
      • Schade D.
      • Ma Y.
      • et al.
      The influence of age on the effects of lifestyle modification and metformin in prevention of diabetes.
      Yet, because the DPP did not randomly assign each lifestyle component, the relative importance of the diet and exercise components could not be adequately examined. Furthermore, the DPP lifestyle intervention was resource-intensive, providing ongoing, individualized counseling.
      • Knowler W.C.
      • Barrett-Connor E.
      • Fowler S.E.
      • et al.
      Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.
      To our knowledge, the effectiveness of group-based adaptations of the DPP program has not been widely tested.
      Because the restoration of normal glucose homeostasis is more akin to true prevention than delayed progression to overt diabetes, unraveling the relative importance of diet, exercise, and body weight in this regard has important implications for resource allocation, patient counseling, and public health.
      Although both obesity and diabetes risk increases with age in the U.S.,
      • Mokdad A.H.
      • Bowman B.A.
      • Ford E.S.
      • Vinicor F.
      • Marks J.S.
      • Koplan J.P.
      The continuing epidemics of obesity and diabetes in the U.S..
      • Houston D.K.
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      • Zizza C.A.
      Weighty concerns: the growing prevalence of obesity among older adults.
      few studies have included older individuals in large enough numbers to determine whether lifestyle changes to reduce weight can improve insulin resistance, a major predictor of diabetes risk.
      • Witham M.D.
      • Avenell A.
      Interventions to achieve long-term weight loss in obese older people: a systematic review and meta-analysis.
      Thus, the purpose of the present study was to examine the independent and combined effects of 12 months of dietary weight loss and aerobic exercise on insulin resistance and the restoration of normal fasting glucose among overweight postmenopausal women and to examine whether the magnitude of these effects differed between middle-aged (50–60 years) and older women (aged 60–75 years).
      The study also examined which factors, including weight loss, fat loss, or changes in cardiorespiratory fitness or physical activity, were most associated with changes in glucose homeostasis. It was hypothesized that insulin and glucose would improve in all intervention groups compared with controls, and that these changes would be mediated by the degree of weight loss. It was also hypothesized that younger women would experience greater metabolic improvements relative to older women.

      Methods

      Design Overview

      The Nutrition and Exercise in Women (NEW) study was a 12-month RCT testing the effects of exercise and/or dietary weight loss on circulating hormones and other outcomes.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • Duggan C.
      • et al.
      Effect of exercise and diet, alone or combined, on weight and body composition in overweight-to-obese post-menopausal women.
      The trial was conducted from 2005 to 2009; data were analyzed in 2010. Study procedures were reviewed and approved by the Fred Hutchinson Cancer Research Center IRB in Seattle WA. All participants provided informed consent.

      Setting and Participants

      Participants were overweight or obese (BMI ≥25.0, ≥23.0 if Asian American) postmenopausal women (aged 50–75 years) from the greater-Seattle area who were not meeting physical activity guidelines.
      2008 Physical Activity Guidelines for Americans.
      Women were recruited through media and mass mailings (Figure 1) . Specific exclusion criteria included diagnosed diabetes, fasting blood glucose ≥126 mg/dL or use of diabetes medications; use of postmenopausal hormones; history of other serious medical condition(s); alcohol intake >2 drinks/day; current smoking; contraindication to the study interventions for any reason (e.g., abnormal exercise tolerance test); participation in another structured weight loss program; or use of weight-loss medications.
      Figure thumbnail gr1
      Figure 1Flow of participants through the NEW
      DXA, dual-emission X-ray absorptiometry; NEW, Nutrition and Exercise in Women trial; VO2max, maximal oxygen consumption

      Randomization and Interventions

      Eligible women were randomized to (1) dietary weight loss (n=118); (2) moderate-to-vigorous intensity aerobic exercise (n=117); (3) combined diet and exercise (n=117); or (4) control (no intervention; n=87). Computerized random assignment was stratified according to BMI (≥ or <30) and participants' self-reported race/ethnicity (black, white, other). A permuted blocks randomization, wherein the control assignment was randomly eliminated from each block with a probability of approximately 1 in 4, was used to achieve a proportionally smaller control group. One participant that was randomized to diet+exercise was excluded from analysis because of missing baseline blood measures.
      The exercise intervention progressed to 45 minutes of moderate-to-vigorous intensity exercise at a target heart rate of 70%–85% observed maximum, 5 days/week, by the 7th week. Participants attended three supervised sessions/week at the study facility and exercised 2 days/week at home. Participants recorded exercise mode, duration, peak heart rate, and perceived exertion at each session. Activities of ≥4 METs
      • Ainsworth B.E.
      • Haskell W.L.
      • Whitt M.C.
      • et al.
      Compendium of physical activities: an update of activity codes and MET intensities.
      were counted toward the prescribed target.
      The dietary weight-loss intervention involved a modification of the DPP
      • Knowler W.C.
      • Barrett-Connor E.
      • Fowler S.E.
      • et al.
      Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.
      and Look AHEAD
      • Ryan D.H.
      • Espeland M.A.
      • Foster G.D.
      • et al.
      Look AHEAD (Action for Health in Diabetes): design and methods for a clinical trial of weight loss for the prevention of cardiovascular disease in type 2 diabetes.
      lifestyle behavior change programs with goals of 1200–2000 kcal/day, <30% calories from fat, and 10% weight loss by 6 months with maintenance thereafter. Participants met individually with a dietitian at least twice, followed by weekly group meetings (5–10 women) for 6 months. Thereafter, participants attended monthly group meetings, in addition to biweekly phone or email contact. A combination of individual and group-based approaches was used to maximize the benefits of personalized recommendations with the social support and cost effectiveness of a group setting. Women completed daily food logs for at least 6 months or until they reached their 10% weight-loss goal. Food logs were collected by the dietitian and returned with feedback. Logs, weekly weigh-ins, and session attendance were tracked to promote dietary adherence. Participants who did not meet their weight-loss goal by 6 months were encouraged to continue weight-loss efforts and were offered additional sessions, whereas women who reached their goal were allowed to continue losing but were monitored to ensure that BMI did not go below 18.5.
      Participants who were randomized to dietary weight loss + exercise received separate sessions and were instructed not to discuss diet during supervised exercise. The control group was instructed not to change their diet or exercise behavior for 12 months. At study completion, they were offered four group nutrition classes and 8 weeks of exercise training.

      Outcomes and Follow-Up

      All study measures were obtained and analyzed by trained personnel who were blinded to the participants' randomization status. Demographic information, medical history, dietary patterns (via 120-item self-administered food frequency questionnaire
      • Taylor H.L.
      • Jacobs Jr, D.R.
      • Schucker B.
      • Knudsen J.
      • Leon A.S.
      • Debacker G.
      A questionnaire for the assessment of leisure time physical activities.
      ) were collected at baseline and 12 months. At both time points, participants wore pedometers (Accusplit) for 7 consecutive days to determine an average daily step count. Cardiorespiratory fitness (VO2max) was assessed using a maximal graded treadmill test according to a modified branching protocol.
      • Pate R.
      • Blair S.
      • Durstine J.
      Guidelines for exercise testing and prescription.
      Heart rate and oxygen uptake were continuously monitored with an automated metabolic cart.
      Body mass index was calculated from weight and height, measured to the nearest 0.1 kg and 0.1cm, respectively, with a balance beam scale and stadiometer. Waist circumference was measured to the nearest 0.5 cm at the minimal waist. Body composition was measured on a dual-emission X-ray absorptiometry (DXA) whole-body scanner.
      Fasting venous blood samples (50 mL) were collected during clinic visits prior to randomization and at 12 months. Participants consumed no food and drank only water for 12 hours prior and were requested not to exercise for 24 hours preceding the blood draw. Blood was processed within 1 hour and samples were stored at –70°C.
      Blood samples were analyzed in batches such that each participant's samples were assayed simultaneously, the numbers of samples from each arm were approximately equal, participant randomization dates were similar, and sample order was random. All but four samples were analyzed for insulin and C-peptide in a single batch. Excluding these samples did not affect the results.
      Insulin was analyzed at the University of Washington (UW) Clinical Nutrition Research Unit Laboratory, and quantified by a 48-hour, polyethylene glycol–accelerated, double-antibody radioimmunoassay. The intra-assay coefficient of variation (CV) was 4.5%. C-peptide and glucose were analyzed at the UW Northwest Lipid Research Laboratories. C-peptide was analyzed using a two-site immunoenzymometric assay (Tosoh AIA 1800 auto analyzer). Glucose was quantified using a ClinicalChemistry Autoanalyzer with the hexokinase method. The intra-assay CV for C-peptide was 4.3%. The intra- and inter-assay CVs for glucose were 1.1% and 3.5%, respectively.
      The homeostasis assessment model (HOMA-IR=fasting insulin [mU/L] × fasting glucose [mmol/L]/22.5)
      • Matthews D.R.
      • Hosker J.P.
      • Rudenski A.S.
      • Naylor B.A.
      • Treacher D.F.
      • Turner R.C.
      Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.
      was used as a surrogate measure of whole-body insulin resistance.

      Statistical Analysis

      In cases of missing values, no change from baseline was assumed. Repeating the main analyses using a multiple imputation method did not meaningfully affect any of the findings. Age-adjusted partial Pearson correlation coefficients were calculated between baseline anthropometric and blood measures. Generalized linear models were used to test for differences in baseline values across study arms, and a chi-square test to detect differences in the prevalence of impaired fasting glucose.
      Descriptive data are presented as M (SD). Because of their non-normal distribution, blood measures were log-transformed before further analysis. These data are presented as geometric means (95% CIs) unless otherwise indicated. Mean changes in insulin, C-peptide, glucose, and HOMA-IR from baseline to 12 months, stratified by group, were computed; intervention effects on these variables were examined based on the assigned treatment at randomization, regardless of adherence or study retention (i.e., intent-to-treat). Mean 12-month changes in the exercise, diet, and diet+exercise groups were compared to controls using the generalized estimating equations (GEE) modification of linear regression to account for intra-individual correlation over time. The effect of age (50–60 years vs 60–75 years) was assessed by including interaction terms in these models. Analyses were also repeated after stratification by age group. Adjustment for multiple comparisons was made using Bonferroni correction (two-sided alpha=0.05/3).
      Changes in body weight, body composition, pedometer steps/day, and VO2max were similarly calculated and used to predict the observed change in metabolic variables by linear regression. These potential mediating variables were examined continuously, then categorically as (1) three clinically relevant categories of weight loss:
      NIH
      Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults—the evidence report.
      • Christian J.G.
      • Tsai A.G.
      • Bessesen D.H.
      Interpreting weight losses from lifestyle modification trials: using categorical data.
      <5%, ≥5%–10%, and ≥10% loss; (2) change in pedometer steps/day corresponding to a decrease/no change (≤0 steps/day); an increase up to 2 miles/day (1–3520 steps/day); or >2 miles/day (>3520 steps/day); and (3) tertiles of change in total body fat (kg) and VO2max (L/min). Models included age, group assignment, and the baseline value of the outcome variable as covariates.
      Participants' fasting glucose levels were classified as “impaired” (5.6–6.9 mmol/L) or “normal” (<5.6 mmol/L).
      Report of the expert committee on the diagnosis and classification of diabetes mellitus.
      Logistic regression was used to calculate the ORs for regression from impaired to normal fasting glucose within each intervention arm compared with controls, adjusting for age, weight loss, and baseline blood glucose level. Corresponding ORs were calculated for categories of weight loss (1%–5%, ≥5%–10%, ≥10%, relative to no change/gain) and approximate tertiles of change in VO2max. All statistical analyses were performed using SAS software, version 9.1.

      Results

      Participants

      At 12 months, 398 of 438 participants completed physical exams and provided a blood sample, 397 underwent a DXA scan, and 371 completed a treadmill test; 39 did not complete the study (Figure 1). There were no differences in relevant variables between groups at baseline, except the percentage of daily calories consumed as fat (p=0.02; Table 1).
      Table 1Selected baseline characteristics of randomized women, M (SD) unless otherwise specified
      VariableControlExerciseDietDiet+exercise
      n87117118116
      Age (years)57.4 (4.4)58.1 (5.0)58.1 (5.9)58.0 (4.4)
      Ethnicity (n [%])
       Non-Hispanic white74 (85.1)98 (83.8)101 (85.6)99 (85.3)
       Non-Hispanic black6 (6.9)15 (12.8)9 (7.6)5 (4.3)
       Hispanic3 (3.5)2 (1.7)2 (1.7)5 (4.3)
       Other (American Indian, Asian, or unknown)4 (4.6)2 (1.7)6 (5.1)7 (6.0)
      College graduate (n [%])59 (67.8)70 (59.9)76 (64.4)81 (69.8)
      Full-time employment (n [%])47 (63.5)53 (55.2)58 (55.2)64 (62.1)
      Married or living with partner (n [%])59 (73.8)71 (60.7)79 (67.0)69 (60.0)
      Weight (kg)84.2 (12.5)83.7 (12.3)84.0 (11.8)82.6 (10.8)
      BMI30.7 (3.9)30.7 (3.7)31.1 (3.9)31.0 (4.3)
      Waist circumference (cm)94.8 (10.2)95.1 (10.1)94.6 (10.2)93.7 (9.9)
      Body fat (%)47.3 (4.4)47.3 (4.1)47.0 (4.3)47.4 (4.5)
      Average energy consumed (kcal/day)
      Daily kilocalorie values derived from FFQ were truncated <600 kcal and >4000.
      1988 (669)1986 (589)1884 (661)1894 (639)
      Relative % calories from fat
      Percentage calories from fat=(total calories derived from fat/total daily caloric intake)
      35.6 (6.9)33.6 (6.9)33.1 (6.3)35.3 (7.3)
      VO2max (mL/kg/min)23.1 (4.1)22.5 (4.1)22.7 (3.8)23.6 (4.1)
      Pedometer steps/day (7-day average)5605 (2334)5777 (2129)5539 (2257)5952 (2354)
      Insulin (pmol/L)93.20 (44.80)86.95 (55.84)91.26 (60.56)87.23 (59.80)
      C-peptide (nmol/L)0.92 (0.31)0.87 (0.33)0.89 (0.36)0.86 (0.33)
      Glucose (mmol/L)5.38 (0.46)5.32 (0.45)5.37 (0.48)5.33 (0.43)
      HOMA-IR3.22 (1.65)2.99 (2.19)3.17 (2.25)3.01 (2.22)
      Note: No significant differences in baseline variables between groups, except in daily calories consumed as fat (p=0.02)
      FFQ, food frequency questionnaire; HOMA-IR, homeostasis model assessment–insulin resistance; VO2max, maximal oxygen consumption
      a Daily kilocalorie values derived from FFQ were truncated <600 kcal and >4000.
      b Percentage calories from fat=(total calories derived from fat/total daily caloric intake)

      Adherence to Interventions

      Intervention adherence and body composition changes in this sample have been recently reported.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • Duggan C.
      • et al.
      Effect of exercise and diet, alone or combined, on weight and body composition in overweight-to-obese post-menopausal women.
      Briefly, women who were randomized to exercise alone participated in moderate-to-vigorous activity for an M (SD) of 163.3 (70.6) minutes/week, whereas women who were randomized to diet+exercise participated for 171.5 (62.9) minutes/week. Both groups significantly increased average pedometer steps/day (+2416 and +3471 steps/day, respectively) and VO2max (+0.17 and +0.12 L/min, respectively) compared with baseline. Women who were randomized to diet+exercise increased pedometer steps/day more than women who did exercise alone (p=0.006).
      Percentage of calories from fat decreased in both the diet alone (−18%) and diet+exercise (−20.0%) groups. Average fiber intake and daily fruit and vegetable servings also increased in the diet alone (+3.4 g/day and +1.7 servings/day, respectively; both p<0.001) and diet+exercise (+2.8 g/day and +1.4 servings/day, respectively; both p<0.0001) groups, but not in the exercise group (+0.53 g/day and 0 servings/day, respectively; both p>0.5) compared with controls (−0.2 g/day and −0.9 servings/day, respectively). In both groups, women attended an average of 27 diet counseling sessions (86%). There were no significant differences in measures of adherence between middle-aged (n=304) and older (n=134) women (data not shown).
      At 12 months, the mean weight loss was −2.4% (p=0.03) in the exercise group, −8.5% (p<0.001) in the diet group, and −10.8% (p<0.001) in the diet+exercise group, compared with −0.8% loss among controls. Weight loss was not significantly different between middle-aged and older women within each study arm (all p>0.2). Women in all intervention groups significantly reduced waist circumference and % body fat (all p<0.01) compared with controls.
      • Foster-Schubert K.E.
      • Alfano C.M.
      • Duggan C.
      • et al.
      Effect of exercise and diet, alone or combined, on weight and body composition in overweight-to-obese post-menopausal women.
      Lean mass decreased significantly in the diet alone group (p=0.005) but was preserved in exercisers (both p>0.10).

      Baseline Associations

      Baseline BMI, waist circumference, and total fat mass (kg) were correlated with insulin (r=0.39, 0.47, and 0.25); C-peptide (r=0.43, 0.50, and 0.33); glucose (r=0.26, 0.24, and 0.24); and HOMA-IR (r=0.40, 0.47, and 0.27) (all p<0.01). VO2max and pedometer steps/day were also significantly correlated with each of the metabolic variables (r=−0.11 to −0.24, all p<0.05).

      Intervention Effects

      Compared with controls, women in the diet and diet+exercise groups experienced significant reductions in serum insulin, C-peptide, and glucose (Table 2). HOMA-IR decreased by 24% (p<0.001) in the diet alone group and by 26% (p<0.001) in the diet+exercise group, compared with 2% in controls. In contrast, no overall significant treatment effects were observed for women assigned to exercise alone (−9%, p=0.19; Table 2). Compared with diet alone, women receiving diet+exercise did not experience greater improvements in insulin (p=0.69); C-peptide (p=0.32); glucose (p=0.52); or HOMA-IR (p=0.64) but did have significantly greater improvements than women who were randomized to exercise alone (insulin, p<0.001; C-peptide, p<0.001; glucose, p=0.03; HOMA-IR, p<0.001). No significant age interactions were detected; the magnitude of metabolic improvement was similar between middle-aged and older women in each intervention group compared with controls (Table 3). However, within the exercise-alone group, middle-aged women did experience greater improvement in insulin, C-peptide, and HOMA-IR compared with older women.
      Table 2Values for serum insulin, C-peptide, glucose, and HOMA-IR across four arms of the NEW trial, geometric M (95% CI)
      ControlExerciseDietDiet+exercise
      VariableBaseline12 monthsChange (%)
      Percentage change from baseline to 12 months
      Baseline12 monthsChange (%)
      Percentage change from baseline to 12 months
      p-value
      p-value comparing change from baseline to 12 months in each intervention group versus controls
      Baseline12 monthsChange (%)
      Percentage change from baseline to 12 months
      p-value
      p-value comparing change from baseline to 12 months in each intervention group versus controls
      Baseline12 monthsChange (%)
      Percentage change from baseline to 12 months
      p-value
      p-value comparing change from baseline to 12 months in each intervention group versus controls
      Insulin (pmol/L)83.27 (75.21, 92.23)81.67 (73.83, 90.35)−1.975.98 (69.24, 83.34)70.08 (64.17, 76.46)−7.80.2276.40 (68.62, 89.94)59.38 (53.55, 65.91)−22.3<0.00174.10 (67.02, 92.02)56.32 (50.91, 62.37)−24.0<0.001
      C-peptide (nmol/L)0.87 (0.81, 0.94)0.88 (0.82, 0.94)1.10.82 (0.77, 0.87)0.79 (0.74, 0.84)−3.70.140.83 (0.77, 0.89)0.73 (0.68, 0.78)−12.0<0.0010.81 (0.76, 0.86)0.69 (0.65, 0.74)−14.8<0.001
      Glucose (mmol/L)5.37 (5.27, 5.46)5.36 (5.27, 5.45)0.25.30 (5.22, 5.38)5.25 (5.17, 5.32)−0.90.295.35 (5.27, 5.44)5.22 (5.14, 5.30)−2.40.0085.31 (5.23, 5.39)5.16 (5.07, 5.22)−2.80.002
      HOMA-IR2.83 (2.54, 3.16)2.78 (2.49, 3.09)−1.82.55 (2.31, 2.82)2.33 (2.12, 2.56)−8.60.192.59 (2.31, 2.90)1.96 (1.76, 2.19)−24.3<0.0012.50 (2.24, 2.78)1.84 (1.65, 2.05)−26.4<0.001
      Note: Bold indicates significance.
      HOMA-IR, homeostasis model assessment–insulin resistance; NEW, Nutrition and Exercise in Women study
      a Percentage change from baseline to 12 months
      b p-value comparing change from baseline to 12 months in each intervention group versus controls
      Table 3Twelve-month changes in body weight and metabolic markers in women, %
      ControlExerciseDietDiet+exercise
      Aged 50–60Aged 60–75Aged 50–60Aged 60–75p-valueAged 50–60Aged 60–75p-valueAged 50–60Aged 60–75p-value
      Body weight−0.5−1.6−2.0−3.20.83−9.1−7.20.05−10.4−11.60.75
      % body fat0.1−1.3−2.8−2.00.57−9.9−3.10.01−12−6.10.57
      Insulin−1.8−2.4−13.66.1
      p<0.01 between age groups within intervention arm
      0.12−21.8−23.10.75−23.1−26.00.78
      C-peptide0.00.1−6.42.9
      p<0.01 between age groups within intervention arm
      0.26−11.4−13.20.62−13.5−16.30.52
      Glucose0.5−1.5−1.2−3.80.45−2−0.80.77−2.6−4.20.82
      HOMA-IR−1.1−3.9−14.65.2
      p<0.01 between age groups within intervention arm
      0.11−23.1−260.80−25−29.30.82
      Note: p=age interaction effect in each intervention arm compared with controls; ages given in years
      HOMA-IR, homeostasis model assessment–insulin resistance
      low asterisk p<0.01 between age groups within intervention arm
      As expected, the magnitude of weight loss was associated with metabolic improvement in insulin, C-peptide, glucose, and HOMA-IR (Table 4). These associations were independent of change in cardiorespiratory fitness (Table 4) and pedometer steps/day. Greater metabolic improvement was observed with greater magnitude of change in average pedometer steps/day; however, these associations were not significant after adjusting for weight change, except for C-peptide. The magnitude of change in VO2max (L/min) was not associated with metabolic changes.
      Table 4Changes in metabolic markers among NEW participants stratified by intervention measures
      Weight loss (%)
      Groups include women randomized to any intervention (n=351).
      p-value for trend
      Adjusted for age, intervention arm, and baseline value of metabolic variable of interest
      <5%≥5%–10%≥10%
      n15574122
      Insulin (pmol/L)−5.83 (39.38)−17.15 (44.52)−29.66 (34.31)<0.001
      C-peptide (nmol/L)0.007 (0.17)−0.10 (0.19)−0.19 (0.18)<0.001
      Glucose (mmol/L)−0.01 (0.35)−0.20 (0.34)−0.21 (0.37)<0.001
      HOMA-IR−0.23 (1.63)−0.69 (1.74)−1.10 (1.25)<0.001
      Total fat loss (kg)
      Groups include women randomized to any intervention (n=351).
      ,
      Fat loss (group M): Tertile =0.06 kg; Tertile 2= −4.5 kg; Tertile 3= −12.0 kg.
      p-value for trend
      Adjusted for age, intervention arm, and baseline value of metabolic variable of interest
      Tertile 3Tertile 2Tertile 1
      n117117117
      Insulin (pmol/L)−1.88 (22.29)−19.65 (51.60)−27.99 (36.67)<0.001
      C-peptide (nmol/L)0.01 (0.12)−0.11 (0.23)−0.0.18 (0.17)<0.001
      Glucose (mmol/L)0.008 (0.35)−0.15 (0.36)−0.22 (0.35)<0.001
      HOMA-IR−0.06 (0.89)−0.78 (2.06)−1.06 (1.40)<0.001
      ΔVO2max (L/min)
      Groups include women randomized to exercise or exercise + diet (n=233).
      ,
      VO2max (group M): Tertile 1= −0.12 L/minute; Tertile 2=0.12 L/minute; Tertile 3=0.44 L/minute.
      p-value for trend
      Adjusted for age, intervention arm, and baseline value of metabolic variable of interest
      Tertile 3Tertile 2Tertile 1
      n807578
      Insulin (pmol/L)−8.75 (36.88)−17.36 (31.46)−17.64 (51.88)0.01
      C-peptide (nmol/L)−0.06 (0.18)−0.09 (0.17)−0.09 (0.23)0.03
      Glucose (mmol/L)−0.04 (0.32)−0.18 (0.40)−0.12 (0.38)0.08
      HOMA-IR−0.31 (1.49)−0.67 (1.18)−0.69 (2.09)0.01
      ΔSteps/day
      Groups include women randomized to exercise or exercise + diet (n=233).
      ,
      3520 steps is equivalent to ≈2 miles.
      p-value for trend
      Adjusted for age, intervention arm, and baseline value of metabolic variable of interest
      <11–3520>3520
      n687293
      Insulin (pmol/L)−9.38 (28.89)−6.04 (28.34)−24.72 (53.41)0.001
      C-peptide (nmol/L)−0.03 (0.15)−0.04 (0.16)−0.15 (0.22)<0.001
      Glucose (mmol/L)−0.07 (0.34)−0.08 (0.367)−0.19 (0.39)0.01
      HOMA-IR−0.35 (1.16)−0.25 (1.08)−0.94 (2.15)0.001
      HOMA-IR, homeostasis model assessment−insulin resistance; NEW, Nutrition and Exercise in Women study; VO2max, maximal oxygen consumption
      a Groups include women randomized to any intervention (n=351).
      b Fat loss (group M): Tertile =0.06 kg; Tertile 2= −4.5 kg; Tertile 3= −12.0 kg.
      c Groups include women randomized to exercise or exercise + diet (n=233).
      d VO2max (group M): Tertile 1= −0.12 L/minute; Tertile 2=0.12 L/minute; Tertile 3=0.44 L/minute.
      e 3520 steps is equivalent to ≈2 miles.
      f Adjusted for age, intervention arm, and baseline value of metabolic variable of interest
      Higher baseline fasting glucose was a strong predictor of metabolic improvement in participants randomized to interventions (results not shown). In analyses limited to women with impaired fasting glucose at baseline, the odds (95% CI) of regression to fasting glucose <5.6 mmol/L at 12 months, independent of baseline level, age, and percentage weight change were 3.16 (1.02, 9.75) in the exercise alone group; 1.97 (0.63, 6.16) in the diet alone group; and 2.35 (0.68, 8.18) in the diet+exercise group (Table 5). The AOR of returning to normal fasting glucose in the diet+exercise group compared with diet alone was 1.17 (0.43, 3.16). Corresponding odds associated with categories of weight loss and VO2max are also shown in Table 5. Overall, the 1-year incidence of developing impaired fasting glucose among women with normal baseline values was 18% among controls, 6% in the exercise alone group, 4% in the diet alone group, and 2% in the diet+exercise group.
      Table 5Odds of regression to NFG at 12 months among study participants with IFG at baseline
      IFGIncident IFGOdds of returning to NFG (95% CI)
      Model 1: adjusted for age, baseline serum fasting glucose; Model 2: additionally adjusted for percentage body weight change. Stratified analyses were also adjusted for group randomization.
      Baseline (n)12 months (n)12 months
      Incident IFG = new cases of IFG (100−125 mg/dL) among women with values <100 mg/dL at baseline
      Model 1Model 2
      Control302310/571.00 (ref)1.00
      Diet43233/753.19 (1.09, 9.28)1.97 (0.63, 6.16)
      Exercise35175/823.64 (1.21, 11.01)3.16 (1.02, 9.75)
      Diet+exercise35142/815.17 (1.71, 15.69)2.35 (0.68, 8.18)
      Body weight loss (%)
       ≤0% (no change or gain)35259/811.001.00
       <5%43284/611.65 (0.60, 4.51)1.62 (0.58, 4.50)
      Analyses additionally adjusted for change in VO2max
       5%−10%27101/564.97 (1.63, 15.11)5.12 (1.65, 15.86)
      Analyses additionally adjusted for change in VO2max
       ≥10%38146/886.26 (2.14, 18.29)6.86 (2.27, 20.77)
      Analyses additionally adjusted for change in VO2max
      p trend=0.001
      Change in VO2max (L/minute)
      Groups represent approximate tertiles of change in cardiorespiratory fitness
       No change or deterioration462410/1541.001.00
       +0.01−0.1450364/471.17 (0.45, 2.99)0.78 (0.27, 2.21)
      Analyses additionally adjusted for change in percentage body weight change
       ≥+0.1447176/942.78 (1.27, 6.07)2.48 (1.11, 5.57)
      Analyses additionally adjusted for change in percentage body weight change
      p trend=0.337
      IFG, impaired fasting glucose (5.6-6.9 mmol/L); NFG, normal fasting glucose (<5.6 mmol/L); VO2max, maximal oxygen consumption
      a Incident IFG = new cases of IFG (100−125 mg/dL) among women with values <100 mg/dL at baseline
      b Model 1: adjusted for age, baseline serum fasting glucose; Model 2: additionally adjusted for percentage body weight change. Stratified analyses were also adjusted for group randomization.
      c Analyses additionally adjusted for change in VO2max
      d Groups represent approximate tertiles of change in cardiorespiratory fitness
      e Analyses additionally adjusted for change in percentage body weight change

      Discussion

      A 12-month group-based modification of the DPP/LookAHEAD weight-loss interventions
      • Knowler W.C.
      • Barrett-Connor E.
      • Fowler S.E.
      • et al.
      Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.
      • Ryan D.H.
      • Espeland M.A.
      • Foster G.D.
      • et al.
      Look AHEAD (Action for Health in Diabetes): design and methods for a clinical trial of weight loss for the prevention of cardiovascular disease in type 2 diabetes.
      resulted in significant weight loss and improved insulin resistance. However, adding a prescribed 225 minutes/week of aerobic exercise did not yield significant added benefits in these outcomes up to 12 months. Furthermore, the effect of these lifestyle interventions was similar in middle-aged and older women. Although no overall improvement in HOMA-IR was detected in women randomized to exercise alone compared with controls, 12 months of exercise training was associated with improved odds of regressing from impaired to normal fasting glucose (<5.6 mmol/L), independent of weight loss. These findings support previous reports
      • Knowler W.C.
      • Barrett-Connor E.
      • Fowler S.E.
      • et al.
      Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.
      • Perreault L.
      • Kahn S.E.
      • Christophi C.A.
      • Knowler W.C.
      • Hamman R.F.
      Regression from pre-diabetes to normal glucose regulation in the diabetes prevention program.
      • Weiss E.P.
      • Racette S.B.
      • Villareal D.T.
      • et al.
      Improvements in glucose tolerance and insulin action induced by increasing energy expenditure or decreasing energy intake: a randomized controlled trial.
      • Ross R.
      • Dagnone D.
      • Jones P.J.
      • et al.
      Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men A randomized, controlled trial.
      • Tuomilehto J.
      • Lindstrom J.
      • Eriksson J.G.
      • et al.
      Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance.
      that modest weight loss (5%–10% body weight) is associated with improved insulin sensitivity and glucose tolerance. They are also consistent with reports
      • Davidson L.E.
      • Hudson R.
      • Kilpatrick K.
      • et al.
      Effects of exercise modality on insulin resistance and functional limitation in older adults: a randomized controlled trial.
      • Houmard J.A.
      • Tanner C.J.
      • Slentz C.A.
      • Duscha B.D.
      • McCartney J.S.
      • Kraus W.E.
      Effect of the volume and intensity of exercise training on insulin sensitivity.
      that regular exercise can improve insulin sensitivity, even in the absence of substantial weight reduction; however, in the current study, this effect was limited to women with impaired fasting glucose at baseline. The mechanisms postulated to account for these favorable changes include a preferential reduction in visceral fat and/or enhanced metabolic efficiency of muscle.
      • Menshikova E.V.
      • Ritov V.B.
      • Toledo F.G.
      • Ferrell R.E.
      • Goodpaster B.H.
      • Kelley D.E.
      Effects of weight loss and physical activity on skeletal muscle mitochondrial function in obesity.
      • Hughes V.A.
      • Fiatarone M.A.
      • Fielding R.A.
      • et al.
      Exercise increases muscle GLUT-4 levels and insulin action in subjects with impaired glucose tolerance.
      In the DPP, increasing age was associated with more physical activity, greater weight loss, and a lower incidence of diabetes but not with reported caloric intake or reversion to normal fasting glucose.
      • Crandall J.
      • Schade D.
      • Ma Y.
      • et al.
      The influence of age on the effects of lifestyle modification and metformin in prevention of diabetes.
      Other large type 2 diabetes prevention trials
      • Li G.
      • Zhang P.
      • Wang J.
      • et al.
      The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study.
      • Saaristo T.
      • Moilanen L.
      • Korpi-Hyovalti E.
      • et al.
      Lifestyle intervention for prevention of type 2 diabetes in primary health care: one-year follow-up of the Finnish National Diabetes Prevention Program (FIN-D2D).
      • Ramachandran A.
      • Snehalatha C.
      • Mary S.
      • Mukesh B.
      • Bhaskar A.D.
      • Vijay V.
      The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1).
      have not included older adults or have been unable to examine age-related differences in the response to lifestyle interventions. To our knowledge, no previous randomized trial has examined differences in the response to weight-loss and exercise interventions in middle-aged and older women. In the current study, there were no significant differences in any measure of intervention adherence between middle-aged and older women, and the magnitude of the difference between middle-aged and older women was not significantly different from controls in any of the intervention arms. Because of limited sample size, it was not possible to examine the reversion to normal fasting glucose by age group.
      Although women assigned to exercise alone failed to achieve significant weight loss compared with controls, they experienced significant reductions in waist circumference and body fat. Larson-Meyer et al.
      • Larson-Meyer D.E.
      • Redman L.
      • Heilbronn L.K.
      • Martin C.K.
      • Ravussin E.
      Caloric restriction with or without exercise: the fitness versus fatness debate.
      recently demonstrated that under conditions of equal energy deficits, overweight men and women who were randomized to caloric restriction alone or in combination with exercise showed similar reductions in body weight, total body fat, and visceral fat. Yet, those who performed exercise had significantly greater improvements in insulin sensitivity and other markers of cardiovascular risk. Enhanced parasympathetic tone and endothelial function have been proposed as pathways through which exercise may influence cardiometabolic health beyond “traditional” risk factors.
      • Joyner M.J.
      • Green D.J.
      Exercise protects the cardiovascular system: effects beyond traditional risk factors.
      A limitation of the current study is that the sample was predominantly Caucasian and therefore it was not possible to examine the consistency of the current findings across racial/ethnic groups. In addition, fasting glucose was used rather than glucose tolerance testing or HgA1C, and potential differences in insulin secretion versus insulin action could not be compared between treatment arms. However, impaired fasting glucose is an important clinical marker in itself.
      Report of the expert committee on the diagnosis and classification of diabetes mellitus.
      Additional strengths of the present study include its relatively large size and adequate statistical power to examine differences in insulin sensitivity between middle-aged and older women assigned to multiple interventions. Furthermore, the group-based lifestyle interventions used in the current study were less staff-time intensive than those used in the DPP
      • Knowler W.C.
      • Barrett-Connor E.
      • Fowler S.E.
      • et al.
      Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.
      and many other large trials,
      • Walker K.Z.
      • O'Dea K.
      • Gomez M.
      • Girgis S.
      • Colagiuri R.
      Diet and exercise in the prevention of diabetes.
      yet yielded substantial weight loss and simprovements in glucose homeostasis. This suggests that group-based diet and exercise programs may be as effective as one-on-one counseling in eliciting favorable improvements, at least among postmenopausal women. Future studies to determine the comparative effectiveness of these programs with larger and more diverse groups, and in other settings, would provide an important contribution to the current literature.
      The current study provides evidence that clinically meaningful improvements in insulin sensitivity can be achieved through caloric restriction alone or with the addition of exercise. Furthermore, a prescribed exercise dose of 225 minutes/week resulted in regression to normal glucose levels for more than half of women with impaired fasting glucose at baseline. In the DPP, individuals who were randomized to lifestyle intervention who did not achieve the desired goal of 7% reduction in body weight but attained the physical activity goal of >150 minutes/week experienced a 44% reduction in the risk of progression to diabetes.
      • Perreault L.
      • Kahn S.E.
      • Christophi C.A.
      • Knowler W.C.
      • Hamman R.F.
      Regression from pre-diabetes to normal glucose regulation in the diabetes prevention program.
      The optimal exercise dose for “treatment” of impaired fasting glucose remains unknown but clearly warrants further investigation.
      Weight loss among older people remains controversial, primarily because of concern over the potentially deleterious loss of muscle and bone mass. The exercise program tested in the current study did not include resistance training; however, resistance exercise has been shown to have favorable effects on glycemic control
      • Sigal R.J.
      • Kenny G.P.
      • Boule N.G.
      • et al.
      Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial.
      and to help preserve lean mass during weight loss.
      • Ross R.
      • Dagnone D.
      • Jones P.J.
      • et al.
      Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men A randomized, controlled trial.
      An earlier study
      • Davidson L.E.
      • Hudson R.
      • Kilpatrick K.
      • et al.
      Effects of exercise modality on insulin resistance and functional limitation in older adults: a randomized controlled trial.
      has shown that the combination of resistance and aerobic exercise is the optimal exercise strategy for simultaneous reduction in insulin resistance and functional limitation in obese older adults. The current findings and those of others therefore suggest that weight loss combined with exercise is likely to be the safest and most effective approach to glycemic control among older adults.
      In the U.S., approximately 57 million adults have impaired fasting glucose, and up to 70% will progress to overt type 2 diabetes in their lifetime without effective intervention.
      • Cowie C.C.
      • Rust K.F.
      • Byrd-Holt D.D.
      • et al.
      Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population: National Health And Nutrition Examination Survey 1999–2002.
      True disease prevention should be counted as the maintenance or restoration of normal glucose regulation rather than a prolonged prediabetic state, with which there remains significant health risk.
      • Reaven G.M.
      Pathophysiology of insulin resistance in human disease.
      The American Diabetes Association
      American Diabetes Association
      Executive summary: Standards of medical care in diabetes–2010.
      currently recommends that people with prediabetes be referred to an effective program promoting 5%–10% body weight loss and at least 150 minutes/week of moderate physical activity. Although maximum benefit will be achieved with successful weight loss, ongoing effort to promote regular physical activity has the potential for health benefits among women with impaired fasting glucose, and to help prevent the potentially deleterious loss of lean mass in older individuals undergoing weight loss.
      This work was supported by the National Cancer Institute at the NIH (grant number: R01 CA102504 , U54-CA116847 , and 5KL2RR025015-03 to KFS, R25 CA94880 and 2R25CA057699-16 to AK) and the Canadian Institutes of Health Research (Fellowship to KLC and CM). None of the funding agencies were involved in the trial design or conduct. While working on the trial, CMA was employed at the Ohio State University, and located to NCI following completion of her effort on the NEW trial.
      No financial disclosures were reported by the authors of this paper.

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