document: the design and principal findings of the dream trial have been presented in previous publications ( 17 ) . 
   briefly , the dream trial was a large , international , multicenter , double - blind , randomized controlled trial designed to determine whether ramipril and/or rosiglitazone could prevent or delay the development of type 2 diabetes in people with ifg or igt , metabolic states that indicate very high risk for eventual progression to diabetes ( 17 ) . 
   eligibility for the dream trial included a diagnosis of ifg , igt , or both ifg and igt based on a screening 75-g oral glucose tolerance test ( ogtt ) ( 17 ) . 
   a total of 5,269 participants with these disorders were recruited and randomized to either ramipril and/or rosiglitazone using a two - by - two factorial design and followed for a median of 3 years after randomization . 
   participants were assessed at regular intervals to ascertain the occurrence of the primary outcome , which included new - onset diabetes or all - cause mortality . as part of a substudy 
   , 982 dream trial participants attending canadian study centers had ogtts at baseline , after 2 years , and at the end of the study , with blood samples drawn fasting as well as 30 and 120 min after the glucose challenge . 
   the primary outcome variable in the present study was change in -cell function over the course of follow - up . 
   -cell function was assessed using two measures : the insulinogenic index ( igi ) and proinsulin ( pi ) concentration , with igi defined as ( 30-min insulin  fasting insulin)/(30-min glucose  fasting glucose ) . 
   both indexes have previously been validated against gold - standard measures of insulin secretion ( 18,19 ) and have been shown to be significant predictors of incident diabetes in large epidemiological studies . to account for the compensatory response of insulin secretion in relation to background insulin resistance , 
   igi was divided by the homeostasis model assessment of insulin resistance index ( homa - ir ) ( defined as fasting glucose  fasting insulin/22.5 ) ( igi / ir ) for univariate analysis or adjusted for homa - ir in multivariate analysis . 
   similarly , pi concentration was divided by c - peptide concentration ( i.e. , the pi / c - peptide ratio [ pi / c ] ) for univariate analysis or adjusted for insulin secretion using c - peptide as a covariate in multivariate analysis . 
   although the pi - to - insulin ratio is often used to identify disproportionate elevations in pi , c - peptide offers advantages over insulin as a denominator for pi because it is cosecreted with insulin in an equimolar ratio , but unlike insulin it is not extracted by the liver and thus it has a constant peripheral clearance . 
   glucose concentration was determined using an enzymatic reference method on a roche hitachi 917 instrument and a roche reagent kit ( roche diagnostics , indianapolis , in ) . 
   serum insulin and c - peptide were measured on the roche elecsys 2010 immunoassay analyzer using an electrochemiluminescence immunoassay . 
   the insulin assay had a sensitivity of 1.39 pmol / l , an interassay coefficient of variation ( cv ) of < 4.6% at all levels , and < 0.05% cross - reactivity with human c - peptide and pi . 
   the c - peptide assay had a sensitivity of 3.0 pmol / l , an interassay cv of < 3% at all levels , and < 0.005% cross - reactivity with human insulin . 
   pi concentration was measured using a sandwich enzyme - linked immunosorbent assay manufactured by linco research ( linco research , st . 
   this assay had a sensitivity of 2.0 pmol / l , an interassay cv of < 9% at all levels , and no cross - reactivity with human insulin or des ( 31,32 ) split pi , although this assay does cross - react with human des ( 64,65 ) split pi . 
   statistical analyses were conducted using sas version 9.1 ( sas institute , cary , nc ) , and p values < 0.05 were considered statistically significant . 
   the distributions of continuous variables were assessed for normality , and transformations of skewed variables were used in the analysis as appropriate . means and sds for primary -cell function measures ( igi / ir and pi / c ) were calculated for each time point ( baseline , at 2 years , and final visit ) , according to the marginal treatment group . 
   p values for change were based on a t test of the average change being different from zero , while p values for treatment difference were calculated using the wilcoxon 's rank - sum test . 
   similar analyses were conducted within subgroups of isolated ifg ( iifg ) , isolated igt ( iigt ) , and combined ifg and igt ( ifg+igt ) . 
   as there was no significant interaction between ramipril and rosiglitazone 's effect on -cell function , main - effects analyses were conducted according to marginal randomization groups ( i.e. , rosiglitazone versus placebo , ramipril versus placebo ) . 
   longitudinal analyses of the associations between treatments and changes over time in -cell function measures were examined using random - effects models in proc mixed , which provides appropriate options for handling the covariance structure of the repeated - measures ( longitudinal ) data . 
   specifically , we ran four models , which assessed the impact of treatment group on 1 ) igi , with age and homa - ir as covariates ; 2 ) igi / homa - ir , with age as a covariate ; 3 ) pi , with age and c - peptide as covariates ; and 4 ) pi / c , with age as a covariate . 
   finally , using cox proportional hazards regression , we assessed whether the impact of ramipril and/or rosiglitazone treatment on diabetes incidence was independent of baseline levels and changes over the course of the trial in -cell function . 
   the outcome variable in these analyses was diabetes status at the final visit , and the primary exposures were the marginal treatment groups ( rosiglitazone , ramipril ) . in separate models , we assessed the impact of treatment on diabetes incidence , adjusting for either baseline -cell function ( including baseline igi and homa - ir or baseline pi and c - peptide as covariates ) or change over the course of the trial in -cell function ( including changes in the above - mentioned covariates ) . 
   baseline models were also adjusted for age and baseline waist circumference , fasting glucose , triglycerides , and hdl , while change models were also adjusted for age and changes in these covariates . 
   statistical analyses were conducted using sas version 9.1 ( sas institute , cary , nc ) , and p values < 0.05 were considered statistically significant . 
   the distributions of continuous variables were assessed for normality , and transformations of skewed variables were used in the analysis as appropriate . means and sds for primary -cell function measures ( igi / ir and pi / c ) were calculated for each time point ( baseline , at 2 years , and final visit ) , according to the marginal treatment group . 
   p values for change were based on a t test of the average change being different from zero , while p values for treatment difference were calculated using the wilcoxon 's rank - sum test . 
   similar analyses were conducted within subgroups of isolated ifg ( iifg ) , isolated igt ( iigt ) , and combined ifg and igt ( ifg+igt ) . 
   as there was no significant interaction between ramipril and rosiglitazone 's effect on -cell function , main - effects analyses were conducted according to marginal randomization groups ( i.e. , rosiglitazone versus placebo , ramipril versus placebo ) . 
   longitudinal analyses of the associations between treatments and changes over time in -cell function measures were examined using random - effects models in proc mixed , which provides appropriate options for handling the covariance structure of the repeated - measures ( longitudinal ) data . specifically , we ran four models , which assessed the impact of treatment group on 1 ) igi , with age and homa - ir as covariates ; 2 ) igi / homa - ir , with age as a covariate ; 3 ) pi , with age and c - peptide as covariates ; and 4 ) pi / c , with age as a covariate . finally , using cox proportional hazards regression , we assessed whether the impact of ramipril and/or rosiglitazone treatment on diabetes incidence was independent of baseline levels and changes over the course of the trial in -cell function . 
   the outcome variable in these analyses was diabetes status at the final visit , and the primary exposures were the marginal treatment groups ( rosiglitazone , ramipril ) . in separate models , we assessed the impact of treatment on diabetes incidence , adjusting for either baseline -cell function ( including baseline igi and homa - ir or baseline pi and c - peptide as covariates ) or change over the course of the trial in -cell function ( including changes in the above - mentioned covariates ) . 
   baseline models were also adjusted for age and baseline waist circumference , fasting glucose , triglycerides , and hdl , while change models were also adjusted for age and changes in these covariates . 
   the average age and bmi were 54 years and 31.5 kg / m , respectively , and 60% of participants were female . the majority ( 81% ) were of european origin , and substantial proportions had a family history of diabetes or a history of gestational diabetes ( 61 and 16% , respectively ) , characteristics that were consistent with the recruiting strategy for the dream trial ( 17 ) . 
   there were no significant differences between the marginal randomization groups for any of the baseline characteristics other than family history of diabetes in the ramipril versus placebo marginal group ( p = 0.02 ) ( table 1 ) . 
   baseline characteristics of participants with measures of -cell function overall and by allocation data are means  sd or n ( % ) . 
   no significant differences between rosiglitazone versus placebo or ramipril versus placebo other than family history of diabetes in the ramipril versus placebo group ( p = 0.02 ) . 
   changes in markers of -cell function in marginal randomization groups are presented in table 2 . 
   participants receiving rosiglitazone versus placebo had a significant increase in igi / ir during the study ( 25.59 vs. 1.94 , p < 0.0001 ) and a significant decrease in pi / c ( 0.010 vs. 0.006 , p < 0.0001 ) . 
   in contrast , there were no significant changes in igi / ir or pi / c in participants receiving ramipril versus placebo ( 11.71 vs. 18.15 , p > 0.05 , and 0.007 vs. 0.008 , p > 0.05 , respectively ) ( table 2 ) . in the rosiglitazone group , 
   changes in the -cell function measures were more substantial between the baseline and 2-year visits compared with changes that occurred between the 2-year and final visits ( table 2 ) . 
   the impact of rosiglitazone on igi / ir and pi / c was similar within subgroups of iigt and ifg + igt ( iigt , igi / ir : 27.74 vs. 2.76 , p < 0.0001 ; pi / c : 0.009 vs. 0.008 , p < 0.001 ; ifg + igt , igi / ir : 27.39 vs. 0.70 , p < 0.0001 ; pi / c : 0.014 vs. 0.002 , p < 0.0001 ) , although effects were more modest in those with iifg ( igi / ir : 8.95 vs. 2.13 , p = 0.03 ; pi / c : 0.003 vs. 0.001 , p > 0.05 ) ( supplemental table , available at http://care.diabetesjournals.org/cgi/content/full/dc09-1579/dc1 ) . 
   changes in markers of -cell function data are means  sd and are reported for marginal treatment groups . 
   p value for change were based on a t test of the average change being different from zero . 
   we further assessed the impact of treatment on markers of -cell function by utilizing longitudinal data from multiple study time points in mixed - model analyses . compared with placebo , 
   rosiglitazone significantly increased igi after adjustment for age and homa - ir ( p = 0.015 ) ( table 3 ) . 
   in contrast , ramipril did not significantly affect adjusted igi ( p > 0.05 ) . 
   similar findings were seen using pi concentration as a measure of -cell function . specifically , rosiglitazone significantly reduced pi concentrations over time after adjustment for age and c - peptide concentration ( p = 0.0064 ) ( table 3 ) . 
   in contrast , ramipril did not significantly change adjusted pi concentrations ( p > 0.05 ) . 
   longitudinal changes in markers of -cell function in dream trial : analysis of slopes using mixed - model analysis analysis in table are based on full data ; results essentially unchanged when analysis repeated on subjects with information from all visits . 
   we assessed whether the impact of ramipril and/or rosiglitazone on diabetes incidence was independent of baseline levels or changes in indexes of -cell function with time ( fig . 
   1 ) . after accounting for baseline -cell function as measured by either igi or pi in models that adjusted for insulin resistance and other covariates , 
   rosiglitazone significantly reduced the risk of developing diabetes ( hazard ratio 0.32 [ 95% ci 0.220.45 ] , p < 0.001 , and 0.33 [ 0.230.47 ] , p < 0.001 , in igi and pi models , respectively ) . adjusting for the change in -cell function as measured by igi attenuated the preventive effect of rosiglitazone on incident diabetes ( 0.53 [ 0.280.99 ] , p = 0.046 ) . 
   such attenuation was not noted when the change in -cell was measured using pi ( 0.28 [ 0.180.42 ] , p < 0.0001 ) ( fig . 
   association of treatment allocation with risk of diabetes : impact of baseline levels and changes in -cell function . for igi / ir models : model 1 adjusted for age and baseline igi , homa - ir , fasting glucose , waist circumference , triglyceride , and hdl ; model 2 adjusted for age and changes in igi , homa - ir , fasting glucose , waist circumference , triglyceride , and hdl . 
   for pi / c models : model 1 adjusted for age and baseline pi , c - peptide , fasting glucose , waist circumference , triglyceride , and hdl ; model 2 adjusted for age and changes in pi , c - peptide , fasting glucose , waist circumference , triglyceride , and hdl . 
   rosiglitazone , but not ramipril , improved measures of -cell function over time in people with ifg and/or igt . 
   specifically , rosiglitazone increased igi / ir and reduced pi / c by 86 and 42% , respectively . 
   these findings were consistent across glucose tolerance subgroups ( iifg , iigt , and ifg+igt ) , although there was the suggestion of a more modest effect in the subgroup with iifg . 
   finally , rosiglitazone 's effect on diabetes prevention persisted after adjustment for baseline -cell function . 
   the demonstration that an agent that reduces diabetes incidence also improves -cell function invites the hypothesis that measures of change in -cell function in response to therapy are indexes of that therapy 's ability to reduce the incidence of diabetes . 
   the modest attenuation of rosiglitazone 's effect after accounting for the change in -cell function suggests that some but not all of the effect of rosiglitazone on diabetes prevention / delay is mediated through its effects on -cell function . whereas a number of previous studies ( 911 ) have documented improvements in -cell function with tzd treatment in people with diabetes , only four studies ( 1215 ) have investigated this question in people with ifg and/or igt . 
   the results of these studies have been inconsistent , with two studies ( 12,15 ) indicating a significant improvement in measures of -cell function with tzd treatment and two studies ( 13,14 ) reporting no change . 
   these studies all had small sample sizes ( n  30 ) , and the methods used to assess -cell function varied widely from intensive approaches ( insulin responses to glucose infusion ) to simple fasting - based indexes ( homa - b ) . 
   interestingly , the complexity of the method used to assess -cell function did not appear to explain the differences in findings of these previous studies ( 12,14 ) . 
   finally , in a diabetes prevention trial among hispanic women with previous gestational diabetes , 70% of whom had igt at enrollment , treatment with troglitazone resulted in significant improvements in the frequently sampled intravenous glucose tolerance 
   our results suggest a significant improvement in -cell function with tzd treatment in pre - diabetic subjects . 
   first , the sample size of our study ( n = 982 ) was much larger that previous investigations . 
   second , we demonstrated improvements in -cell function under tzd treatment using two validated , widely used proxy measures of -cell function , namely igi and pi . 
   third , in our analysis we accounted for the compensatory impact on -cell function of background insulin resistance . specifically , in analyses of igi we used homa - ir either as a covariate in multivariate analysis or as the denominator in the igi  to  homa - ir ratio . 
   accounting for background insulin resistance is crucial to the interpretation of -cell function measures in this study because tzds improved insulin sensitivity , thus reducing pancreatic -cell demand . 
   the exact mechanisms responsible for the increases in igi / ir and the reductions in pi / c documented in the present study are not known , although a number of possibilities exist . the reduction in insulin resistance with tzds 
   would be expected to reduce insulin secretory demand on the -cells and thus reduce -cell stress . 
   in addition , tzds such as rosiglitazone may improve -cell function indirectly by ameliorating a number of pathogenic processes that have been shown to be detrimental to the -cells , including lipotoxicity , glucotoxicity , and inflammation ( 7,8 ) . 
   tzds lower free fatty acids ( 22 ) , elevated levels of which result in excess deposition of lipid within -cells , which in turn leads to increases in ceremide and the stimulation of nitric oxide 
   mediated -cell apoptosis . as well , the glucose - lowering effect of tzds may reduce the impact of reactive oxygen species on the -cells , which are known to be especially susceptible to oxidative damage ( 23 ) . 
   finally , tzds have been demonstrated to reduce levels of inflammatory cytokines ( 24 ) , which may induce -cell apoptosis when chronically elevated . 
   tzds may also impact -cell function directly by maintaining -cell proliferation and/or reducing -cell apoptosis ( 25 ) . in the hope study , 
   treatment with ramipril was shown to reduce the incidence of diabetes in middle - aged individuals with vascular disease . in the dream trial , although ramipril did not significantly reduce the incidence of diabetes in people with ifg and/or igt , it did significantly increase regression to normoglycemia . 
   the mechanism by which ramipril might reduce glucose levels and/or prevent / delay diabetes is unknown , although vascular and metabolic effects on the muscle and pancreatic -cell have been proposed ( 16 ) . 
   the results of the present study suggest that ramipril does not have significant effects on -cell function compared with placebo in people at high risk for diabetes , and thus its glucose - lowering effects may operate through other metabolic mechanisms . 
   the improvement in -cell function in the placebo arm of the ramipril marginal group analysis may be explained by the fact that under the factorial design of the dream trial , half of the participants on ramipril placebo were receiving active rosiglitazone . the major strengths of the present study include the large sample size , the randomized , double - blind design , and the completeness of follow - up ( 92.6% ) . 
   further , participants were thoroughly characterized in terms of glucose tolerance status and were all in the pre - diabetic range ( either iifg , iigt , or ifg+igt ) . 
   the major limitation of the present study is the lack of detailed measures of -cell function , such as those obtained from the hyperglycemic clamp technique or the frequently sampled intravenous glucose tolerance test . 
   notwithstanding , we used two proxy measures of -cell function that have been extensively validated and used in previous studies including the diabetes prevention program and the american diabetes association genetics of type 2 diabetes study ( in the case of igi / ir ) and the iras study ( in the case of pi ) . in conclusion , 
   rosiglitazone , but not ramipril , resulted in significant improvements in measures of -cell function over time . 
   these findings demonstrate that the diabetes preventive effect of rosiglitazone may in part be a consequence of improved -cell function . 
   
summary: objectivethe objective of this study was to determine the degree to which ramipril and/or rosiglitazone changed -cell function over time among individuals with impaired fasting glucose ( ifg ) and/or impaired glucose tolerance ( igt ) who participated in the diabetes reduction assessment with ramipril and rosiglitazone medication ( dream ) trial , which evaluated whether ramipril and/or rosiglitazone could prevent or delay type 2 diabetes in high - risk individuals.research design and methodsthe present analysis included subjects ( n = 982 ) from dream trial centers in canada who had oral glucose tolerance tests at baseline , after 2 years , and at the end of the study . 
   -cell function was assessed using the fasting proinsulin  to  c - peptide ratio ( pi / c ) and the insulinogenic index ( defined as 300 min insulin/300 min glucose ) divided by homeostasis model assessment of insulin resistance ( insulinogenic index [ igi]/insulin resistance [ ir]).resultssubjects receiving rosiglitazone had a significant increase in igi / ir between baseline and end of study compared with the placebo group ( 25.59 vs. 1.94 , p < 0.0001 ) and a significant decrease in pi / c ( 0.010 vs. 0.006 , p < 0.0001 ) . 
   in contrast , there were no significant changes in igi / ir or pi / c in subjects receiving ramipril compared with placebo ( 11.71 vs. 18.15 , p = 0.89 , and 0.007 vs. 0.008 , p = 0.64 , respectively ) . 
   the impact of rosiglitazone on igi / ir and pi / c was similar within subgroups of isolated igt and ifg + igt ( all p < 0.001 ) . 
   effects were more modest in those with isolated ifg ( igi / ir : 8.95 vs. 2.13 , p = 0.03 ; pi / c : 0.003 vs. 0.001 , p = 0.07).conclusionstreatment with rosiglitazone , but not ramipril , resulted in significant improvements in measures of -cell function over time in pre - diabetic subjects . although the long - term sustainability of these improvements can not be determined from the present study , these findings demonstrate that the diabetes preventive effect of rosiglitazone was in part a consequence of improved -cell function .