study participants were members of the cardiovascular health study ( chs ) , a prospective cohort consisting of 5,888 men and women aged 65 years who were randomly selected from medicare - eligibility lists in four u.s . communities ( forsyth county , nc ; washington county , md ; sacramento county , ca ; and pittsburgh , pa ) . a detailed description of methods and procedures in the chs has previously been published ( 26 ) . briefly , persons eligible to participate were not institutionalized or wheelchair dependent , did not require a proxy for consent , were not receiving treatment for cancer , and were expected to remain in their respective regions for 3 years . from 1989 to 1990 , 5,201 participants were recruited in the original cohort . between 1992 and 1993 , 687 subjects ( predominantly african american ) were also recruited . baseline evaluation of study participants included standardized questionnaires , physical examination , anthropometric measurements , resting electrocardiography , and laboratory examinations . from 1989 through 1999 , participants were followed up every 6 months , alternating between telephone calls and clinic visits ; biennial telephone calls have continued since then . the institutional review board at each center approved the study , and each participant gave informed consent . for this analysis , the 19921993 clinic visit was used as baseline . of the 5,553 participants alive at the 19921993 clinic visit , we excluded 773 people with prevalent diabetes , 780 people with missing data on fabp4 and nefa , 205 people with missing data on prevalent or incident type 2 diabetes , and 55 individuals with missing covariate information . plasma samples collected at the 19921993 examination were stored at 70c until analyzed at the central laboratory at the university of vermont . the interassay coefficient of variation ( cv ) was 2.615.32% ( detectable range 5250 ng / ml ) . this technique relies on the acylation of coa by the fatty acids in the presence of added acyl - coa synthetase . acyl - coa produced is oxidized by added acyl - coa oxidase with generation of hydrogen peroxide and in the presence of peroxidase permits the oxidative condensation of 3-methy - n - ethyl - n(-hydroxyethyl)-aniline with 4-aminoantipyrine to form a purple - colored adduct . we assessed medication use at baseline and annually by a validated medication inventory ( 27 ) through 2007 . in addition , fasting glucose was measured on blood specimens from the examinations in years 19921993 , 19961997 , 19981999 , and 20052006 ; nonfasting glucose was measured on blood specimens from 1994 to 1995 . a participant was classified as having type 2 diabetes if any of the following conditions were met : 1 ) use of insulin or oral hypoglycemic agents , 2 ) fasting glucose level of 7 mmol / l ( 126 mg / dl ) , or 3 ) a nonfasting glucose level of 11.1 mmol / l ( 200 mg / dl ) . age , sex , race , years of education , smoking status , and alcohol consumption were based on self - report . leisure - time activity ( kilocalories per week ) was assessed using a modified minnesota leisure - time activities questionnaire ( 28 ) . bmi was calculated as weight in kilograms divided by the square of height in meters . missing values for smoking and height to calculate bmi were carried forward from previous years if available . serum albumin was assessed using the kodak ektachem 700 analyzer ( eastman kodak , rochester , ny ) . plasma triglyceride was measured by enzymatic methods on an olympus demand system ( olympus , lake success , ny ) . hdl was measured by an enzymatic method after precipitation of apolipoprotein b  containing lipoproteins with dextran sulfate / magnesium sulfate . interassay cvs using reference standards for triglycerides and hdl were 1.78 and 2.15% , respectively . cystatin c was measured by nephelometer using a particle - enhanced immunonephelometric assay ( n latex cystatin c ; dade behring , newark , de ) ( 30 ) with a interassay cv of 2.93.3% . baseline characteristics of study participants were summarized according to categories of fabp4 and nefa ; continuous variables were presented as means  sd and categorical variables as percentages . cox proportional hazards regression was used to estimate the association of fabp4 and nefa with incident type 2 diabetes to allow adjustment for covariates . because the distribution of fabp4 differed appreciably between men and women , fabp4 was modeled as sex - specific tertiles with the lowest tertile as the referent category . nefa was similarly modeled as tertiles based on the overall distribution and also continuously per sd . individuals were censored for death , loss to follow - up , or end of diabetes ascertainment ( 20062007 ) . potential confounders included in adjusted models were age , race , and sex ( where appropriate ) ( model 1 ) with the addition of bmi ( included in nefa model only ) , education ( less than high school versus high school or more ) , cystatin c ( log transformed and included in fabp4 model only ) , serum albumin ( included in nefa model only ) , kilocalories of physical activity ( log transformed ) , alcohol intake ( none and < 0.5 , 0.51 , and > 1 drinks / day for women ; none and < 1 , 12 , and > 2 drinks / day for men ) , smoking status ( never , former , and current ) , self - reported health status ( fair / poor versus better ) , and estrogen use for women ( model 2 ) . given the production of fabp4 in adipocytes , we examined interaction between bmi and fabp4 . to evaluate intermediate pathways by which fabp4 might lead to type 2 diabetes , we adjusted for c - reactive protein ( log transformed ) , homa - ir , triglycerides ( log transformed ) , hdl , and ldl . to evaluate the joint impact of fabp4 and nefa on diabetes risk we also tested for an interaction between fabp4 and nefa on the risk of incident type 2 diabetes . in secondary analyses , we evaluated whether there were statistically significant interactions between log fabp4 and age or waist circumference or between nefa and sex or bmi . because measured weight may not always reflect adiposity in older adults , we excluded participants with unintentional weight loss ( defined as self - reported loss of 10 pounds not due to diet or exercise during the past 12 months ) , prevalent cardiovascular disease ( coronary heart disease or stroke ) , or cancer in a sensitivity analysis . since plasma nefa varies with dietary intake ( 31 ) and lipid metabolism and a single measure may not be a good estimate of average concentrations over the long term , we repeated the analysis while restricting follow - up to the first 5 years . schoenfeld residuals and plots of the residuals over time were used to evaluate proportional hazards assumptions ; there were no meaningful violations . stata , version 11.1 ( statacorp , college station , texas ) , was used for all analyses , and p values < 0.05 were considered statistically significant . plasma samples collected at the 19921993 examination were stored at 70c until analyzed at the central laboratory at the university of vermont . the interassay coefficient of variation ( cv ) was 2.615.32% ( detectable range 5250 ng / ml ) . this technique relies on the acylation of coa by the fatty acids in the presence of added acyl - coa synthetase . acyl - coa produced is oxidized by added acyl - coa oxidase with generation of hydrogen peroxide and in the presence of peroxidase permits the oxidative condensation of 3-methy - n - ethyl - n(-hydroxyethyl)-aniline with 4-aminoantipyrine to form a purple - colored adduct . we assessed medication use at baseline and annually by a validated medication inventory ( 27 ) through 2007 . in addition , fasting glucose was measured on blood specimens from the examinations in years 19921993 , 19961997 , 19981999 , and 20052006 ; nonfasting glucose was measured on blood specimens from 1994 to 1995 . a participant was classified as having type 2 diabetes if any of the following conditions were met : 1 ) use of insulin or oral hypoglycemic agents , 2 ) fasting glucose level of 7 mmol / l ( 126 mg / dl ) , or 3 ) a nonfasting glucose level of 11.1 mmol / l ( 200 mg / dl ) . age , sex , race , years of education , smoking status , and alcohol consumption were based on self - report . leisure - time activity ( kilocalories per week ) was assessed using a modified minnesota leisure - time activities questionnaire ( 28 ) . bmi was calculated as weight in kilograms divided by the square of height in meters . missing values for smoking and height to calculate bmi were carried forward from previous years if available . serum albumin was assessed using the kodak ektachem 700 analyzer ( eastman kodak , rochester , ny ) . plasma triglyceride was measured by enzymatic methods on an olympus demand system ( olympus , lake success , ny ) . hdl was measured by an enzymatic method after precipitation of apolipoprotein b  containing lipoproteins with dextran sulfate / magnesium sulfate . interassay cvs using reference standards for triglycerides and hdl were 1.78 and 2.15% , respectively . cystatin c was measured by nephelometer using a particle - enhanced immunonephelometric assay ( n latex cystatin c ; dade behring , newark , de ) ( 30 ) with a interassay cv of 2.93.3% . baseline characteristics of study participants were summarized according to categories of fabp4 and nefa ; continuous variables were presented as means  sd and categorical variables as percentages . cox proportional hazards regression was used to estimate the association of fabp4 and nefa with incident type 2 diabetes to allow adjustment for covariates . because the distribution of fabp4 differed appreciably between men and women , fabp4 was modeled as sex - specific tertiles with the lowest tertile as the referent category . nefa was similarly modeled as tertiles based on the overall distribution and also continuously per sd . individuals were censored for death , loss to follow - up , or end of diabetes ascertainment ( 20062007 ) . potential confounders included in adjusted models were age , race , and sex ( where appropriate ) ( model 1 ) with the addition of bmi ( included in nefa model only ) , education ( less than high school versus high school or more ) , cystatin c ( log transformed and included in fabp4 model only ) , serum albumin ( included in nefa model only ) , kilocalories of physical activity ( log transformed ) , alcohol intake ( none and < 0.5 , 0.51 , and > 1 drinks / day for women ; none and < 1 , 12 , and > 2 drinks / day for men ) , smoking status ( never , former , and current ) , self - reported health status ( fair / poor versus better ) , and estrogen use for women ( model 2 ) . given the production of fabp4 in adipocytes , we examined interaction between bmi and fabp4 . to evaluate intermediate pathways by which fabp4 might lead to type 2 diabetes , we adjusted for c - reactive protein ( log transformed ) , homa - ir , triglycerides ( log transformed ) , hdl , and ldl . to evaluate the joint impact of fabp4 and nefa on diabetes risk we also tested for an interaction between fabp4 and nefa on the risk of incident type 2 diabetes . in secondary analyses , we evaluated whether there were statistically significant interactions between log fabp4 and age or waist circumference or between nefa and sex or bmi . because measured weight may not always reflect adiposity in older adults , we excluded participants with unintentional weight loss ( defined as self - reported loss of 10 pounds not due to diet or exercise during the past 12 months ) , prevalent cardiovascular disease ( coronary heart disease or stroke ) , or cancer in a sensitivity analysis . since plasma nefa varies with dietary intake ( 31 ) and lipid metabolism and a single measure may not be a good estimate of average concentrations over the long term , we repeated the analysis while restricting follow - up to the first 5 years . schoenfeld residuals and plots of the residuals over time were used to evaluate proportional hazards assumptions ; there were no meaningful violations . stata , version 11.1 ( statacorp , college station , texas ) , was used for all analyses , and p values < 0.05 were considered statistically significant . among 3,740 participants , 2,259 were women ( 60% ) and the mean age at baseline was 74.8 years ( range 6598 ) . median plasma fabp4 was 29.5 ng / ml ( interquartile range 22.039.3 ) , and women had substantially higher concentrations of fabp4 ( median 34.4 ng / ml ) than men ( median 22.8 ng / ml ) . compared with the lowest tertile of fabp4 , those in the highest tertile had higher measures of adiposity and were more likely to have insulin resistance , higher prevalence of dyslipidemia , poorer health , higher levels of cystatin c , and lower physical activity . details on correlation coefficients between fabp4 and risk factors for type 2 diabetes are presented in supplementary table 1 . characteristics of 3,740 participants by sex - specific tertiles of fabp4 in the chs during a mean follow - up of 9.5 years , 305 cases of incident diabetes occurred . hazard ratios ( hrs ) associated with each sd increase in log fabp4 were 1.39 ( 95% ci 1.191.62 ) overall , 1.35 ( 1.101.65 ) for women , and 1.45 ( 1.131.85 ) for men after adjustment for age , race , sex , education , physical activity , cystatin c , alcohol intake , smoking , self - reported health status , and estrogen use for women ( table 2 ) , p for sex - by - fabp4 interaction 0.10 ) . there was evidence for an interaction between bmi and fabp4 on the risk of diabetes ( p value for interaction between continuous bmi and log fabp4 : p = 0.009 overall , 0.02 for women , and 0.135 for men ) ( table 3 ) . fabp4 was associated with diabetes in people with lower bmi in both sexes , but the only significantly elevated risk was among lean men ( table 3 ) . incidence rate and hrs of type 2 diabetes according to fabp4 tertiles or sd of log fabp4 ( 0.46 ) in the chs hr of diabetes per sd increase in log fabp4 stratified by bmi in the chs * as expected , additional adjustment for potential mediating factors ( c - reactive protein , homa - ir , ldl and hdl cholesterol , and triglycerides ) attenuated the observed association further ( relative risk [ rr ] per sd increase of log fabp4 of 1.25 [ 95% ci 1.011.55 ] ) for women and 1.17 [ 0.901.53 ] for men ) . relations between each potential mediator and type 2 diabetes when added individually to the full model are shown in supplementary table 2 . there was no statistically significant interaction between fabp4 and nefa ( p = 0.16 ) , and results were similar with the addition of nefa to these models ( data not shown ) . in a sensitivity analysis , exclusion of individuals with reported unintentional weight loss , prevalent cardiovascular disease , and cancer tended to strengthen the association ( hr per sd increase in log fabp4 from 1.39 [ 95% ci 1.191.62 ] before exclusion to 2.42 [ 1.563.73 ] after exclusion for men and women combined ) . participants with higher concentrations of nefa were older , were more likely to be female , had higher measures of adiposity , and had higher levels of total cholesterol , triglycerides , hdl , and c - reactive protein levels ( supplementary table 3 ) . in a multivariable model adjusted for age , sex , ethnicity , education , bmi , leisure - time physical activity ( kilocalories ) , smoking , alcohol use , health status , estrogen use ( in women ) , and serum albumin , the hr associated with each sd of nefa ( 0.20 meq / l ) was 1.08 ( 95% ci 0.961.23 ) ( table 4 ) . results were similar with the addition of fabp4 to these models ( data not shown ) . when stratified by bmi ( < 25 , 2529.9 , and 30 kg / m ) , the results did not change materially and the p value for bmi - by - nefa interaction was 0.13 . in a secondary analysis restricted to the first 5 years of follow up , each sd of higher nefa was associated with an hr of 1.15 ( 0.971.36 ) in a fully adjusted model , and there was evidence for increased risk of diabetes at higher levels of nefa when analyzed by tertiles of nefa ( 1.0 [ ref . ] , 1.68 [ 95% ci 1.122.53 ] , and 1.63 [ 1.072.50 ] ) ( table 4 ) . there was no evidence for sex - by - nefa interaction ( p = 0.97 ) . hr ( 95% ci ) of diabetes by category of and per sd ( 0.20 meq / l ) increase in nefas in the chs table 1 presents baseline characteristics of subjects according to tertiles of fabp4 by sex . compared with the lowest tertile of fabp4 , those in the highest tertile had higher measures of adiposity and were more likely to have insulin resistance , higher prevalence of dyslipidemia , poorer health , higher levels of cystatin c , and lower physical activity . details on correlation coefficients between fabp4 and risk factors for type 2 diabetes are presented in supplementary table 1 . characteristics of 3,740 participants by sex - specific tertiles of fabp4 in the chs during a mean follow - up of 9.5 years , 305 cases of incident diabetes occurred . hazard ratios ( hrs ) associated with each sd increase in log fabp4 were 1.39 ( 95% ci 1.191.62 ) overall , 1.35 ( 1.101.65 ) for women , and 1.45 ( 1.131.85 ) for men after adjustment for age , race , sex , education , physical activity , cystatin c , alcohol intake , smoking , self - reported health status , and estrogen use for women ( table 2 ) , p for sex - by - fabp4 interaction 0.10 ) . there was evidence for an interaction between bmi and fabp4 on the risk of diabetes ( p value for interaction between continuous bmi and log fabp4 : p = 0.009 overall , 0.02 for women , and 0.135 for men ) ( table 3 ) . fabp4 was associated with diabetes in people with lower bmi in both sexes , but the only significantly elevated risk was among lean men ( table 3 ) . incidence rate and hrs of type 2 diabetes according to fabp4 tertiles or sd of log fabp4 ( 0.46 ) in the chs hr of diabetes per sd increase in log fabp4 stratified by bmi in the chs * as expected , additional adjustment for potential mediating factors ( c - reactive protein , homa - ir , ldl and hdl cholesterol , and triglycerides ) attenuated the observed association further ( relative risk [ rr ] per sd increase of log fabp4 of 1.25 [ 95% ci 1.011.55 ] ) for women and 1.17 [ 0.901.53 ] for men ) . relations between each potential mediator and type 2 diabetes when added individually to the full model are shown in supplementary table 2 . there was no statistically significant interaction between fabp4 and nefa ( p = 0.16 ) , and results were similar with the addition of nefa to these models ( data not shown ) . in a sensitivity analysis , exclusion of individuals with reported unintentional weight loss , prevalent cardiovascular disease , and cancer tended to strengthen the association ( hr per sd increase in log fabp4 from 1.39 [ 95% ci 1.191.62 ] before exclusion to 2.42 [ 1.563.73 ] after exclusion for men and women combined ) . participants with higher concentrations of nefa were older , were more likely to be female , had higher measures of adiposity , and had higher levels of total cholesterol , triglycerides , hdl , and c - reactive protein levels ( supplementary table 3 ) . in a multivariable model adjusted for age , sex , ethnicity , education , bmi , leisure - time physical activity ( kilocalories ) , smoking , alcohol use , health status , estrogen use ( in women ) , and serum albumin , the hr associated with each sd of nefa ( 0.20 meq / l ) was 1.08 ( 95% ci 0.961.23 ) ( table 4 ) . results were similar with the addition of fabp4 to these models ( data not shown ) . when stratified by bmi ( < 25 , 2529.9 , and 30 kg / m ) , the results did not change materially and the p value for bmi - by - nefa interaction was 0.13 . in a secondary analysis restricted to the first 5 years of follow up , each sd of higher nefa was associated with an hr of 1.15 ( 0.971.36 ) in a fully adjusted model , and there was evidence for increased risk of diabetes at higher levels of nefa when analyzed by tertiles of nefa ( 1.0 [ ref . ] , 1.68 [ 95% ci 1.122.53 ] , and 1.63 [ 1.072.50 ] ) ( table 4 ) . there was no evidence for sex - by - nefa interaction ( p = 0.97 ) . hr ( 95% ci ) of diabetes by category of and per sd ( 0.20 meq / l ) increase in nefas in the chs in this prospective study of 3,740 people , we demonstrate a positive association between plasma fabp4 and incident type 2 diabetes in older adults and such association was modified by bmi in a way that a statistically significant higher risk of diabetes with fabp4 was observed in lean men only . we also observed a significant positive association between plasma nefa and incident type 2 diabetes during the first 5 years that was attenuated and not statistically significant when the total follow - up period was considered . this association was not materially altered with adjustments for fabp4 , and there was no interaction between fabp4 and nefa with incident type 2 diabetes . to the best of our knowledge , this is the first large prospective study to evaluate associations between plasma fabp4 and incident type 2 diabetes among older men and women in a community setting . while several animal studies have examined the effects of fabp4 expression on adiposity , insulin resistance , and type 2 diabetes risk ( 7,10,11,32 ) , there are only limited data available in humans . in a cross - sectional study of 98 patients with coronary artery disease , serum levels of fabp4 were positively correlated with the prevalence of metabolic syndrome ( mets ) ( p = 0.037 ) and the number of mets components ( p = 0.035 ) ( 33 ) . in another cross - sectional study of 806 middle - aged men and women , each sd of higher log fabp4 was associated with a 1.85-fold increased odds of mets ( 95% ci 1.532.23 ) controlling for age , sex , and race ( 5 ) . ( 8) ( n = 229 ) and stejskal and karpisek ( 6 ) ( n = 138 ) have reported positive associations between serum concentrations of fabp4 and mets . baseline fabp4 was also shown to be associated with incident mets after 5 years of follow - up in 356 chinese individuals ( 9 ) . only one study has evaluated the association of fabp4 levels with incident type 2 diabetes . in a 10-year prospective study of 544 chinese participants with a mean age of 50 years , fabp4 levels above the population median ( 15.3 ng / ml for men and 20.4 ng / ml for women ) were associated with a twofold increased risk of type 2 diabetes after controlling for bmi and other confounding factors ( rr 2.25 [ 95% ci 1.403.65 ] ) ( 16 ) . we found that the association of fabp4 with type 2 diabetes risk was most pronounced in persons with bmi < 25 kg / m . in light of this finding , it is notable that the above chinese study has a lower bmi ( mean  sd 24.3  3.7 kg / m ) than the chs study ( 26.4  4.6 kg / m ) ( 16 ) . the interaction between bmi and fabp4 is consistent with the positive association seen in the leaner chinese cohort . our working hypothesis is that expression of fabp4 may be directly associated with the size of adipocytes ; furthermore , we are hypothesizing that overweight / obese subjects have larger adipocyte size than lean people . our findings of no overall significant association between nefa and type 2 diabetes in older adults are contrary to other reports . ( 19 ) reported a 63% higher risk of type 2 diabetes in the fourth relative to the first quartile of nefa ( rr 1.63 [ 1.04 2.57 ] ) in middle - aged adults . similar results were noted in the pima study ( 18 ) with a 2.3-fold greater risk of type 2 diabetes comparing the highest with the lowest decile of plasma nefa . the mean duration of follow - up in our study ( 9.5 years ) was at least twice as long as that reported in the pima study ( 18 ) and nearly five times longer than the 2 years reported in the paris prospective study ( 34 ) . furthermore , subjects in our study were much older ( mean age 74.8 years ) compared with a mean age of 26 years in the pima study ( 18 ) , 48.9 years for the paris study ( 34 ) , and 52.8 years for atherosclerosis risk in communities ( aric ) study ( 19 ) . the longer follow - up duration and older age of participants in our cohort might explain the lack of an association in our data . in particular , it is possible that a single nefa concentration may be less strongly associated with type 2 diabetes risk over long - term follow - up compared with in the short term . nefa may better predict diabetes risk within a shorter period of follow - up as observed in the paris and pima studies ( 18,34 ) . this hypothesis is consistent with the larger effect size ( hr 1.63 [ 95% ci 1.072.50 ] comparing the 3rd to the 1st tertile of nefa ) observed in our analysis when follow - up time was restricted to the first 5 years of follow - up . if this hypothesis is correct , it suggests that it might be necessary to update nefa measurements over time to fully characterize nefa exposure . nonetheless , our findings also differ from the 53% lower risk of type 2 diabetes ( 95% ci 1973 ) per unit of log nefa observed in the insulin resistance atherosclerosis study ( iras ) ( 20 ) . iras showed that 2-h glucose was a major confounder ; unfortunately , we did not conduct an oral glucose tolerance test in our cohort at the time of fabp4 and nefa measurement ( 20 ) . further , iras was multiethnic with younger average age ( 55 vs. 75 years in the chs ) . what potential biologic mechanisms could causally relate fabp4 and nefa to type 2 diabetes ? as a lipid chaperone , fabp4 is expressed in adipocytes and macrophages and plays an important role in lipid metabolism and perhaps glucose utilization ( 35 ) . as such , it is possible that fabp4 is a mediator of the obesity  type 2 diabetes association . such a hypothesis would be consistent with the fact that compared with wild - type mice , fabp4 knockout mice do not develop insulin resistance despite extreme adiposity when fed a high - fat diet ( 10 ) . on the other hand , fabp4 might influence the size of fat cells through de novo lipogenesis and lead to obesity . at this point fabp4 also inhibits stearoyl - coa desaturase-1 , an enzyme that plays a key role in de novo lipogenesis ( 36 ) and could influence plasma nefa . during de novo lipogenesis , plasma glucose is metabolized to saturated fatty acids ( myristic acid [ c14 ] and palmitic acid [ c16 ] ) ( 37 ) . stearoyl - coa desaturase-1 catalyzes the conversion of palmitic to palmitoleic acid and stearic ( c18 ) to oleic acid ( c18 ) , a glucose - requiring process ( 36 ) . in fabp4-deficient mice , there is an increased ratio of short - chain fatty acids ( c14 ) to longer chain ( c18 ) in muscle and adipose tissues ; a more favorable ratio leads to enhanced insulin receptor signaling , amp - activated kinase activity , and insulin - stimulated glucose uptake ( 38 ) . in addition , fabp4 attenuates the inhibition of hepatic sensitive lipase through its binding of fatty acids ( 17 ) . hepatic sensitive lipase activity can lead to lipolysis with elevated triglycerides and release of free fatty acids , thus leading to insulin resistance . higher nefa concentrations can increase insulin resistance ( 21,22 ) , exert toxic effects on pancreatic -cells ( 23,24 ) , and increase glucose production ( 25 ) . in addition , treatment with pioglitazone ( which reduces insulin resistance ) has been associated with reduced nefa and lipotoxicity ( 39 ) . additional adjustment for fabp4 did not alter the point estimate for nefa in this study , suggesting that the contribution of fabp4 to nefa concentration may be negligible . hence , we were unable to account for change in these biomarkers resulting from change in weight or other factors over time . weight loss is associated with a reduction in serum fabp4 in humans ( 40 ) , and in our study , subjects in the highest tertile of fabp4 were more likely to report unintentional weight loss . the fact that we observed a stronger association between fabp4 and diabetes risk after exclusion of subjects who reported unintentional weight loss , cancer , or cvd suggests that repeated measures of fabp4 might lead to even stronger relationships . as an observational study , we can not exclude residual or unmeasured confounding as an alternative explanation of observed associations . our sample consisted of caucasian and , to a lesser degree , african american adults , all of whom were aged 65 years ; results may not generalize to younger individuals or other race / ethnicities . we did not have measures of fasting glucose in all years , and , hence , we likely missed type 2 diabetes cases in intervening years . we did not have 2-h glucose at the time of fabp4 and nefa measurement for further adjustment . we can not exclude the possibility that obese people were less likely to attend clinic and have their blood glucose measured ; missing data on glucose that was differential based on obesity may have led to an underestimate of type 2 diabetes events . however , the fact that a similar proportion of obese subjects attended the baseline ( 17.6% ) and 19961997 ( 18.1% ) examination is reassuring . despite these limitations , our study has numerous strengths including a large sample size , a representative sample of older adults , inclusion of both men and women , the use of a valid and reproducible method to assess fabp4 and nefa , availability of data on numerous potential confounders , and long - term and nearly complete follow - up . in summary , we observed a positive association between plasma fabp4 and incident type 2 diabetes that was statistically significant only among lean men . lastly , our data support a statistically significant association between a single measure of nefa and incident type 2 diabetes in older adults during a shorter but not a longer follow - up period .