Diabetes Prevention Program Participants Research Articles

The Influence of Rare Genetic Variation in SLC30A8 on Diabetes Incidence and β-Cell Function

The variant rs13266634 in SLC30A8, encoding a β-cell-specific zinc transporter, is associated with type 2 diabetes. We aimed to identify other variants in SLC30A8 that increase diabetes risk and impair β-cell function, and test whether zinc intake modifies this risk. DESIGN/OUTCOME: We sequenced exons in SLC30A8 in 380 Diabetes Prevention Program (DPP) participants and identified 44 novel variants, which were genotyped in 3445 DPP participants and tested for association with diabetes incidence and measures of insulin secretion and processing. We examined individual common variants and used gene burden tests to test 39 rare variants in aggregate. We detected a near-nominal association between a rare-variant genotype risk score and diabetes risk. Five common variants were associated with the oral disposition index. Various methods aggregating rare variants demonstrated associations with changes in oral disposition index and insulinogenic index during year 1 of follow-up. We did not find a clear interaction of zinc intake with genotype on diabetes incidence. Individual common and an aggregate of rare genetic variation in SLC30A8 are associated with measures of β-cell function in the DPP. Exploring rare variation may complement ongoing efforts to uncover the genetic influences that underlie complex diseases.

Sex Hormone Binding Globulin and Sex Steroids Among Premenopausal Women in the Diabetes Prevention Program

It is unknown whether intensive lifestyle modification (ILS) or metformin changes sex steroids among premenopausal women without a history of polycystic ovarian syndrome (PCOS). We examined 1-year intervention impact on sex steroids (estradiol, testosterone, dehydroepiandrosterone, and androstenedione [A4]) and SHBG and differences by race/ethnicity. A subgroup of Diabetes Prevention Program participants who were premenopausal, not using estrogen, without a history of PCOS or irregular menses, and who reported non-Hispanic white (NHW), Hispanic, or African-American race/ethnicity (n = 301). Randomization arms were 1) ILS with the goals of weight reduction of 7% of initial weight and 150 minutes per week of moderate intensity exercise, 2) metformin 850 mg twice a day, or 3) placebo. Neither intervention changed sex steroids compared to placebo. ILS, but not metformin, increased median SHBG by 3.1 nmol/L (~11%) compared to decreases of 1.1 nmol/L in the placebo arm (P < .05). This comparison remained significant after adjustment for changes in covariates including waist circumference. However, associations with glucose were not significant. Median baseline A4 was lower in Hispanics compared to NHWs (5.7 nmol/L vs 6.5 nmol/L, P < .05) and increases in A4 were greater in Hispanics compared to NHWs (3.0 nmol/ vs 1.2 nmol/L, P < .05), and these differences did not differ significantly by intervention arm. No other racial/ethnic differences were significant. Among premenopausal glucose-intolerant women, no intervention changed sex steroids. ILS increased SHBG, although associations with glucose were not significant. SHBG and sex steroids were similar by race/ethnicity, with the possible exception of lower baseline A4 levels in Hispanics compared to NHWs.

Long‐term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: a report from the DPP Outcomes Study

Diabet. Med. 30, 46–55 (2013)AbstractAims Whether long‐term cardiovascular risk is reduced by the Diabetes Prevention Program interventions is unknown. The aim of this study was to determine the long‐term differences in cardiovascular disease risk factors and the use of lipid and blood pressure medications by the original Diabetes Prevention Program intervention group.Methods This long‐term follow‐up (median 10 years, interquartile range 9.0–10.5) of the three‐arm Diabetes Prevention Program randomized controlled clinical trial (metformin, intensive lifestyle and placebo), performed on 2766 (88%) of the Diabetes Prevention Program participants (who originally had impaired glucose tolerance), comprised a mean of 3.2 years of randomized treatment, approximately 1‐year transition (during which all participants were offered intensive lifestyle intervention) and 5 years follow‐up (Diabetes Prevention Program Outcomes Study). During the study, participants were followed in their original groups with their clinical care being provided by practitioners outside the research setting. The study determined lipoprotein profiles and blood pressure and medication use annually.Results After 10 years’ follow‐up from Diabetes Prevention Program baseline, major reductions were seen for systolic (−2 to −3) and diastolic (−6 to −6.5 mmHg) blood pressure, and for LDL cholesterol (−0.51 to −0.6 mmol/l) and triglycerides (−0.23 to −0.25 mmol/l) in all groups, with no between‐group differences. HDL cholesterol also rose significantly (0.14 to 0.15 mmol/l) in all groups. Lipid (P = 0.01) and blood pressure (P = 0.09) medication use, however, were lower for the lifestyle group during the Diabetes Prevention Program Outcomes Study.Conclusion Overall, intensive lifestyle intervention achieved, with less medication, a comparable long‐term effect on cardiovascular disease risk factors, to that seen in the metformin and placebo groups.

Effects of Genetic Variants Previously Associated with Fasting Glucose and Insulin in the Diabetes Prevention Program

Common genetic variants have been recently associated with fasting glucose and insulin levels in white populations. Whether these associations replicate in pre-diabetes is not known. We extended these findings to the Diabetes Prevention Program, a clinical trial in which participants at high risk for diabetes were randomized to placebo, lifestyle modification or metformin for diabetes prevention. We genotyped previously reported polymorphisms (or their proxies) in/near G6PC2, MTNR1B, GCK, DGKB, GCKR, ADCY5, MADD, CRY2, ADRA2A, FADS1, PROX1, SLC2A2, GLIS3, C2CD4B, IGF1, and IRS1 in 3,548 Diabetes Prevention Program participants. We analyzed variants for association with baseline glycemic traits, incident diabetes and their interaction with response to metformin or lifestyle intervention. We replicated associations with fasting glucose at MTNR1B (P<0.001), G6PC2 (P = 0.002) and GCKR (P = 0.001). We noted impaired β-cell function in carriers of glucose-raising alleles at MTNR1B (P<0.001), and an increase in the insulinogenic index for the glucose-raising allele at G6PC2 (P<0.001). The association of MTNR1B with fasting glucose and impaired β-cell function persisted at 1 year despite adjustment for the baseline trait, indicating a sustained deleterious effect at this locus. We also replicated the association of MADD with fasting proinsulin levels (P<0.001). We detected no significant impact of these variants on diabetes incidence or interaction with preventive interventions. The association of several polymorphisms with quantitative glycemic traits is replicated in a cohort of high-risk persons. These variants do not have a detectable impact on diabetes incidence or response to metformin or lifestyle modification in the Diabetes Prevention Program.

The C Allele of ATM rs11212617 Does Not Associate With Metformin Response in the Diabetes Prevention Program

OBJECTIVEThe C allele at the rs11212617 polymorphism in the ataxia-telangiectasia–mutated (ATM) gene has been associated with greater clinical response to metformin in people with type 2 diabetes. We tested whether this variant modified the effect of metformin in the Diabetes Prevention Program (DPP), in which metformin reduced diabetes incidence by 31% in volunteers with impaired glucose tolerance.RESEARCH DESIGN AND METHODSWe genotyped rs11212617 in 2,994 DPP participants and analyzed its effects on diabetes incidence and related traits.RESULTSContrary to expectations, C carriers enjoyed no preventive advantage on metformin; their hazard ratio, compared with A carriers, was 1.17 ([95% CI 0.96–1.42], P = 0.13) under metformin. There were no significant differences by genotype in metformin’s effects on insulin sensitivity, fasting glucose, glycated hemoglobin, or disposition index.CONCLUSIONSThe reported association of rs11212617 with metformin response was not confirmed for diabetes prevention or for effects on relevant physiologic parameters in the DPP.

Association of the SLC30A8 missense polymorphism R325W with proinsulin levels at baseline and after lifestyle, metformin or troglitazone intervention in the Diabetes Prevention Program

Individuals with impaired glucose tolerance have increased proinsulin levels, despite normal glucose or C-peptide levels. In the Diabetes Prevention Program (DPP), increased proinsulin levels predicted type 2 diabetes and proinsulin levels were significantly reduced following treatment with metformin, lifestyle modification or troglitazone compared with placebo. Genetic and physiological studies suggest a role for the zinc transporter gene SLC30A8 in diabetes risk, possibly through effects on insulin-processing in beta cells. We hypothesised that the risk allele at the type 2 diabetes-associated missense polymorphism rs13266634 (R325W) in SLC30A8 would predict proinsulin levels in individuals at risk of type 2 diabetes and may modulate response to preventive interventions. We genotyped rs13266634 in 3,007 DPP participants and examined its association with fasting proinsulin and fasting insulin at baseline and at 1 year post-intervention. We found that increasing dosage of the C risk allele at SLC30A8 rs13266634 was significantly associated with higher proinsulin levels at baseline (p = 0.002) after adjustment for baseline insulin. This supports the hypothesis that risk alleles at SLC30A8 mark individuals with insulin-processing defects. At the 1 year analysis, proinsulin levels decreased significantly in all groups receiving active intervention and were no longer associated with SLC30A8 genotype (p = 0.86) after adjustment for insulin at baseline and 1 year. We found no genotype × treatment interactions at 1 year. In prediabetic individuals, genotype at SLC30A8 predicts baseline proinsulin levels independently of insulin levels, but does not predict proinsulin levels after amelioration of insulin sensitivity at 1 year.

Triglyceride Response to an Intensive Lifestyle Intervention Is Enhanced in Carriers of theGCKRPro446Leu Polymorphism

Glucokinase regulatory protein (GCKR) regulates the trafficking and enzymatic activity of hepatic glucokinase, the rate-limiting enzyme in glycogen synthesis and glycolysis. The intronic single-nucleotide polymorphism (SNP) rs780094 (intron 16) and the missense SNP rs1260326 (P446L) in the GCKR gene are strongly associated with increased circulating triglyceride and C-reactive protein levels and, paradoxically, reductions in diabetes incidence, fasting glucose levels, and insulin resistance. OBJECTIVE, SETTING, AND PATIENTS: We sought to replicate these associations and evaluate interactions with lifestyle and metformin interventions in the multiethnic Diabetes Prevention Program (DPP). We genotyped the two GCKR SNP in 3346 DPP participants and evaluated association with progression to diabetes and both baseline levels and changes in triglycerides, homeostasis model assessment of insulin resistance (HOMA-IR), oral disposition index, and inflammatory markers along with their interactions with DPP interventions. GCKR variation did not predict development of type 2 diabetes. At baseline, the 446L allele was associated with higher triglyceride and C-reactive protein levels (both P < 0.0001) and lower fasting glucose (P = 0.001) and HOMA-IR (P = 0.06). The lifestyle intervention was associated with a decrease in magnitude of the effect of the 446L allele on triglyceride levels (interaction P = 0.04). Metformin was more effective in reducing HOMA-IR in carriers of the P446 allele (interaction P = 0.05). Intensive lifestyle intervention appears to partially mitigate the effect of the 446L allele on higher triglycerides, whereas the P446 allele appears to enhance responsiveness to the HOMA-IR-lowering effect of metformin.

Updated Genetic Score Based on 34 Confirmed Type 2 Diabetes Loci Is Associated With Diabetes Incidence and Regression to Normoglycemia in the Diabetes Prevention Program

OBJECTIVEOver 30 loci have been associated with risk of type 2 diabetes at genome-wide statistical significance. Genetic risk scores (GRSs) developed from these loci predict diabetes in the general population. We tested if a GRS based on an updated list of 34 type 2 diabetes–associated loci predicted progression to diabetes or regression toward normal glucose regulation (NGR) in the Diabetes Prevention Program (DPP).RESEARCH DESIGN AND METHODSWe genotyped 34 type 2 diabetes–associated variants in 2,843 DPP participants at high risk of type 2 diabetes from five ethnic groups representative of the U.S. population, who had been randomized to placebo, metformin, or lifestyle intervention. We built a GRS by weighting each risk allele by its reported effect size on type 2 diabetes risk and summing these values. We tested its ability to predict diabetes incidence or regression to NGR in models adjusted for age, sex, ethnicity, waist circumference, and treatment assignment.RESULTSIn multivariate-adjusted models, the GRS was significantly associated with increased risk of progression to diabetes (hazard ratio [HR] = 1.02 per risk allele [95% CI 1.00–1.05]; P = 0.03) and a lower probability of regression to NGR (HR = 0.95 per risk allele [95% CI 0.93–0.98]; P < 0.0001). At baseline, a higher GRS was associated with a lower insulinogenic index (P < 0.001), confirming an impairment in β-cell function. We detected no significant interaction between GRS and treatment, but the lifestyle intervention was effective in the highest quartile of GRS (P < 0.0001).CONCLUSIONSA high GRS is associated with increased risk of developing diabetes and lower probability of returning to NGR in high-risk individuals, but a lifestyle intervention attenuates this risk.

Common Variants in 40 Genes Assessed for Diabetes Incidence and Response to Metformin and Lifestyle Intervention in the Diabetes Prevention Program

OBJECTIVEGenome-wide association studies have begun to elucidate the genetic architecture of type 2 diabetes. We examined whether single nucleotide polymorphisms (SNPs) identified through targeted complementary approaches affect diabetes incidence in the at-risk population of the Diabetes Prevention Program (DPP) and whether they influence a response to preventive interventions.RESEARCH DESIGN AND METHODSWe selected SNPs identified by prior genome-wide association studies for type 2 diabetes and related traits, or capturing common variation in 40 candidate genes previously associated with type 2 diabetes, implicated in monogenic diabetes, encoding type 2 diabetes drug targets or drug-metabolizing/transporting enzymes, or involved in relevant physiological processes. We analyzed 1,590 SNPs for association with incident diabetes and their interaction with response to metformin or lifestyle interventions in 2,994 DPP participants. We controlled for multiple hypothesis testing by assessing false discovery rates.RESULTSWe replicated the association of variants in the metformin transporter gene SLC47A1 with metformin response and detected nominal interactions in the AMP kinase (AMPK) gene STK11, the AMPK subunit genes PRKAA1 and PRKAA2, and a missense SNP in SLC22A1, which encodes another metformin transporter. The most significant association with diabetes incidence occurred in the AMPK subunit gene PRKAG2 (hazard ratio 1.24, 95% CI 1.09–1.40, P = 7 × 10−4). Overall, there were nominal associations with diabetes incidence at 85 SNPs and nominal interactions with the metformin and lifestyle interventions at 91 and 69 mostly nonoverlapping SNPs, respectively. The lowest P values were consistent with experiment-wide 33% false discovery rates.CONCLUSIONSWe have identified potential genetic determinants of metformin response. These results merit confirmation in independent samples.

Changes in Health State Utilities With Changes in Body Mass in the Diabetes Prevention Program

Health utilities are measures of health-related quality of life (HRQL) used in cost-effectiveness research. We evaluated whether changes in body weight were associated with changes in health utilities in the Diabetes Prevention Program (DPP) and whether associations differed by treatment assignment (lifestyle intervention, metformin, placebo) or baseline obesity severity. We constructed physical (PCS-36) and mental component summary (MCS-36) subscales and short-form-6D (SF-6D) health utility index for all DPP participants completing a baseline 36-item short form (SF-36) HRQL assessment (N = 3,064). We used linear regression to test associations between changes in body weight and changes in HRQL indicators, while adjusting for other demographic and behavioral variables. Overall differences in HRQL between treatment groups were highly statistically significant but clinically small after 1 year. In multivariable models, weight change was independently associated with change in SF-6D score (increase of 0.007 for every 5 kg weight loss; P < 0.001), but treatment effects independent of weight loss were not. We found no significant interaction between baseline obesity severity and changes in SF-6D with changes in body weight. However, increases in physical function (PCS-36) with weight loss were greater in persons with higher baseline obesity severity. In summary, improvements in HRQL are associated with weight loss but not with other effects of obesity treatments that are unrelated to weight loss. Although improvements in the SF-6D did not exceed commonly reported thresholds for a minimally important difference (0.04), these changes, if causal, could still have a significant impact on clinical cost-effectiveness estimates if sustained over multiple years.

10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study

In the 2.8 years of the Diabetes Prevention Program (DPP) randomised clinical trial, diabetes incidence in high-risk adults was reduced by 58% with intensive lifestyle intervention and by 31% with metformin, compared with placebo. We investigated the persistence of these effects in the long term. All active DPP participants were eligible for continued follow-up. 2766 of 3150 (88%) enrolled for a median additional follow-up of 5.7 years (IQR 5.5-5.8). 910 participants were from the lifestyle, 924 from the metformin, and 932 were from the original placebo groups. On the basis of the benefits from the intensive lifestyle intervention in the DPP, all three groups were offered group-implemented lifestyle intervention. Metformin treatment was continued in the original metformin group (850 mg twice daily as tolerated), with participants unmasked to assignment, and the original lifestyle intervention group was offered additional lifestyle support. The primary outcome was development of diabetes according to American Diabetes Association criteria. Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00038727. During the 10.0-year (IQR 9.0-10.5) follow-up since randomisation to DPP, the original lifestyle group lost, then partly regained weight. The modest weight loss with metformin was maintained. Diabetes incidence rates during the DPP were 4.8 cases per 100 person-years (95% CI 4.1-5.7) in the intensive lifestyle intervention group, 7.8 (6.8-8.8) in the metformin group, and 11.0 (9.8-12.3) in the placebo group. Diabetes incidence rates in this follow-up study were similar between treatment groups: 5.9 per 100 person-years (5.1-6.8) for lifestyle, 4.9 (4.2-5.7) for metformin, and 5.6 (4.8-6.5) for placebo. Diabetes incidence in the 10 years since DPP randomisation was reduced by 34% (24-42) in the lifestyle group and 18% (7-28) in the metformin group compared with placebo. During follow-up after DPP, incidences in the former placebo and metformin groups fell to equal those in the former lifestyle group, but the cumulative incidence of diabetes remained lowest in the lifestyle group. Prevention or delay of diabetes with lifestyle intervention or metformin can persist for at least 10 years. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

The Association ofENPP1K121Q with Diabetes Incidence Is Abolished by Lifestyle Modification in the Diabetes Prevention Program

Insulin resistance is an important feature of type 2 diabetes. Ectoenzyme nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin signaling, and a recent meta-analysis reported a nominal association between the Q allele in the K121Q (rs1044498) single nucleotide polymorphism in its gene ENPP1 and type 2 diabetes. OBJECTIVE AND INTERVENTION: We examined the impact of this polymorphism on diabetes incidence as well as insulin secretion and sensitivity at baseline and after treatment with a lifestyle intervention or metformin vs. placebo in the Diabetes Prevention Program (DPP). DESIGN, SETTING, PARTICIPANTS, AND OUTCOME: We genotyped ENPP1 K121Q in 3548 DPP participants and performed Cox regression analyses using genotype, intervention, and interactions as predictors of diabetes incidence. Fasting glucose and glycated hemoglobin were higher in QQ homozygotes at baseline (P < 0.001 for both). There was a significant interaction between genotype at rs1044498 and intervention under the dominant model (P = 0.03). In analyses stratified by treatment arm, a positive association with diabetes incidence was found in Q allele carriers compared to KK homozygotes [hazard ratio (HR), 1.38; 95% confidence interval (CI), 1.08-1.76; P = 0.009] in the placebo arm (n = 996). Lifestyle modification eliminated this increased risk. These findings persisted after adjustment for body mass index and race/ethnicity. Association of ENPP1 K121Q genotype with diabetes incidence under the additive and recessive genetic models showed consistent trends [HR, 1.10 (95% CI, 0.99-1.23), P = 0.08; and HR, 1.16 (95% CI, 0.92-1.45), P = 0.20, respectively] but did not reach statistical significance. ENPP1 K121Q is associated with increased diabetes incidence; the DPP lifestyle intervention eliminates this increased risk.

Extension of type 2 diabetes genome-wide association scan results in the diabetes prevention program.

OBJECTIVE— Genome-wide association scans (GWASs) have identified novel diabetes-associated genes. We evaluated how these variants impact diabetes incidence, quantitative glycemic traits, and response to preventive interventions in 3,548 subjects at high risk of type 2 diabetes enrolled in the Diabetes Prevention Program (DPP), which examined the effects of lifestyle intervention, metformin, and troglitazone versus placebo.RESEARCH DESIGN AND METHODS— We genotyped selected single nucleotide polymorphisms (SNPs) in or near diabetes-associated loci, including EXT2, CDKAL1, CDKN2A/B, IGF2BP2, HHEX, LOC387761, and SLC30A8 in DPP participants and performed Cox regression analyses using genotype, intervention, and their interactions as predictors of diabetes incidence. We evaluated their effect on insulin resistance and secretion at 1 year.RESULTS— None of the selected SNPs were associated with increased diabetes incidence in this population. After adjustments for ethnicity, baseline insulin secretion was lower in subjects with the risk genotype at HHEX rs1111875 (P = 0.01); there were no significant differences in baseline insulin sensitivity. Both at baseline and at 1 year, subjects with the risk genotype at LOC387761 had paradoxically increased insulin secretion; adjustment for self-reported ethnicity abolished these differences. In ethnicity-adjusted analyses, we noted a nominal differential improvement in β-cell function for carriers of the protective genotype at CDKN2A/B after 1 year of troglitazone treatment (P = 0.01) and possibly lifestyle modification (P = 0.05).CONCLUSIONS— We were unable to replicate the GWAS findings regarding diabetes risk in the DPP. We did observe genotype associations with differences in baseline insulin secretion at the HHEX locus and a possible pharmacogenetic interaction at CDKNA2/B.

Elevated depression symptoms, antidepressant medicine use, and risk of developing diabetes during the diabetes prevention program.

To assess the association between elevated depression symptoms or antidepressant medicine use on entry to the Diabetes Prevention Program (DPP) and during the study and the risk of developing diabetes during the study. DPP participants (n = 3,187) in three treatment arms (intensive lifestyle [ILS], metformin [MET], and placebo [PLB]) completed the Beck Depression Inventory (BDI) and reported their use of antidepressant medication at randomization and throughout the study (average duration in study 3.2 years). When other factors associated with the risk of developing diabetes were controlled, elevated BDI scores at baseline or during the study were not associated with diabetes risk in any arm. Baseline antidepressant use was associated with diabetes risk in the PLB (hazard ratio 2.25 [95% CI 1.38-3.66]) and ILS (3.48 [1.93-6.28]) arms. Continuous antidepressant use during the study (compared with no use) was also associated with diabetes risk in the same arms (PLB 2.60 [1.37-4.94]; ILS 3.39 [1.61-7.13]), as was intermittent antidepressant use during the study in the ILS arm (2.07 [1.18-3.62]). Among MET arm participants, antidepressant use was not associated with developing diabetes. A strong and statistically significant association between antidepressant use and diabetes risk in the PLB and ILS arms was not accounted for by measured confounders or mediators. If future research finds that antidepressant use independently predicts diabetes risk, efforts to minimize the negative effects of antidepressant agents on glycemic control should be pursued.

Testing of diabetes-associated WFS1 polymorphisms in the Diabetes Prevention Program.

Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy and deafness) is caused by mutations in the WFS1 gene. Recently, single nucleotide polymorphisms (SNPs) in WFS1 have been reproducibly associated with type 2 diabetes. We therefore examined the effects of these variants on diabetes incidence and response to interventions in the Diabetes Prevention Program (DPP), in which a lifestyle intervention or metformin treatment was compared with placebo. We genotyped the WFS1 SNPs rs10010131, rs752854 and rs734312 (H611R) in 3,548 DPP participants and performed Cox regression analysis using genotype, intervention and their interactions as predictors of diabetes incidence. We also evaluated the effect of these SNPs on insulin resistance and beta cell function at 1 year. Although none of the three SNPs was associated with diabetes incidence in the overall cohort, white homozygotes for the previously reported protective alleles appeared less likely to develop diabetes in the lifestyle arm. Examination of the publicly available Diabetes Genetics Initiative genome-wide association dataset revealed that rs10012946, which is in strong linkage disequilibrium with the three WFS1 SNPs (r(2)=0.88-1.0), was associated with type 2 diabetes (allelic odds ratio 0.85, 95% CI 0.75-0.97, p=0.026). In the DPP, we noted a trend towards increased insulin secretion in carriers of the protective variants, although for most SNPs this was seen as compensatory for the diminished insulin sensitivity. The previously reported protective effect of select WFS1 alleles may be magnified by a lifestyle intervention. These variants appear to confer an improvement in beta cell function.

Physical activity in individuals at risk for diabetes: Diabetes Prevention Program.

Leisure physical activity was assessed using questionnaires with different time frames in the Diabetes Prevention Program (DPP) cohort of 3234 overweight individuals aged > 25 yr with impaired glucose tolerance (IGT) from 27 centers across the United States. The three questionnaires were the Modifiable Activity Questionnaire (MAQ; past year), the Low-Level Physical Activity Recall (LOPAR; past 7 d), and the Third National Health and Nutrition Examination Survey (NHANES III; past month). This provided the opportunity to examine the relationship between the three activity measures and to compare activity levels of the DPP sample with that of a national sample with IGT. Leisure activity determined by the three questionnaires significantly correlated with each other, although the correlations between MAQ and NHANES III were stronger (men: rho = 0.52; women: rho = 0.49; P < 0.01) than between LOPAR and either measure (men: rho = 0.20 for MAQ, 0.24 for NHANES; women: rho = 0.10 for MAQ, 0.13 for NHANES). In the DPP, measures of obesity and glucose tolerance were significantly correlated with activity levels determined by MAQ and NHANES, but not LOPAR. Activity levels in DPP participants determined by the NHANES III questionnaire were generally higher than those reported by individuals meeting DPP eligibility criteria who were part of the NHANES cohort for similar age, body mass index, and race or ethnicity. If the DPP participants were more active than a national sample of individuals with IGT, this would have implications for translation when using the DPP lifestyle intervention in less active or less motivated populations. Finally, the weak relationship between activity levels obtained with MAQ and LOPAR may result from the fact that they encompass different time frames and different components of leisure activity.

The Association Among Autonomic Nervous System Function, Incident Diabetes, and Intervention Arm in the Diabetes Prevention Program

Autonomic nervous system dysfunction, a correlate of obesity and poor cardiorespiratory fitness, is associated with the development of diabetes. We tested whether estimates of autonomic nervous system function improved in the intensive lifestyle versus metformin or placebo arms of the Diabetes Prevention Program (DPP) and whether baseline or a change in autonomic nervous system function was associated with the development of diabetes over 3.2 years. In 2,980 DPP participants, 12-lead electrocardiograms were measured at baseline and annually. Heart rate, heart rate variability (HRV), and QT duration were used to estimate fitness and autonomic nervous system function. In the lifestyle arm, heart rate and QT indexes decreased, and HRV increased over time. The magnitude of decline in heart rate and QT duration was substantially smaller in the other arms, whereas HRV did not increase. Baseline heart rate was the only index significantly (P < 0.05) associated with incident diabetes after adjustment for demographics and weight change (hazard ratio for lifestyle and metformin arms = 1.19 and 1.17 per 10.6 beats/min, respectively). Decreases in heart rate and QT indexes and increases in HRV over time were associated with a lower risk of developing diabetes. The protective association between decreased heart rate and incident diabetes in the lifestyle arm remained significant after accounting for change in weight and physical activity. Indexes that reflect autonomic function and fitness improved (i.e., heart rate decreased and HRV increased) in the lifestyle modification arm of the DPP. Improvements in these indexes are inversely associated with the development of diabetes independent of weight change.