High Plasma Nonesterified Fatty Acids Are Predictive of Cancer Mortality but Not of Coronary Heart Disease Mortality: Results from the Paris Prospective Study

Marie Aline Charles1, Annick Fontbonne1, Nadine Thibult1, Jean-Roger Claude2, Jean-Michel Warnet3, Gabriel Rosselin4, Pierre Ducimetière1 and Eveline Eschwège1

1 Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 258, Villejuif, France.
2 Laboratoire de Toxicologie, Faculté des Sciences Pharmaceutiques, Paris, France.
3 Pharmacie, Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris, France.
4 Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 55, Hôpital St. Antoine, Paris, France.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
To assess the association of fasting plasma nonesterified fatty acid (NEFA) concentration with the risk of death from coronary heart disease and cancer, the authors computed 15-year mortality rates for the 4,589 working men aged 43–53 years who were included in the Paris Prospective Study between 1967 and 1972. A total of 251 and 126 men died from cancer and coronary heart disease, respectively. For coronary heart disease death, the age- and tobacco-adjusted relative risk for men in the highest 20% of the fasting plasma NEFA concentrations compared with those in the lowest 80% was 1.54 (95% confidence interval (CI): 1.01, 2.34). It became nonsignificant after further adjustment for blood pressure, iliac/thigh ratio, and plasma insulin and cholesterol concentrations. In contrast, a high fasting plasma NEFA concentration exhibited a strong independent relation with cancer mortality (relative risk = 1.66, 95% CI: 1.25, 2.21, after adjustment for age, cigarette consumption, heart rate, and body mass index). Despite pathophysiologic mechanisms linking NEFA metabolism with visceral fat and plasma glucose, insulin, and triglyceride concentrations, the plasma NEFA concentration does not appear to be a good marker for coronary heart disease risk. In contrast, an unexpected association with cancer mortality was found that may point to the need for further investigation.

coronary disease; fatty acids, nonesterified; mortality; neoplasms; prospective studies

Abbreviations: CI, confidence interval; NEFA, nonesterified fatty acid.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Frayn et al. (1Go), in a thorough review of the implication of nonesterified fatty acid (NEFA) metabolism in human disease, suggested that high plasma NEFA concentrations might be a risk marker for coronary heart disease and other chronic diseases. Indeed, an increased plasma NEFA concentration is associated with several conditions that convey a high risk of cardiovascular disease, such as diabetes mellitus, high blood pressure, and dyslipidemia (1GoGo–3Go). Moreover, ever since upper-body fat distribution has been found to be a cardiovascular risk factor, it has been hypothesized that visceral obesity and altered NEFA metabolism might play a central role in this relation (4Go). Our aim was to evaluate whether high plasma NEFA concentrations were a risk marker for coronary heart disease mortality. Because of the association between visceral obesity and some types of cancers (5Go, 6Go), and because cancer represents the main cause of death in the Paris Prospective Study (7Go, 8Go), the relation of high plasma NEFA with cancer mortality was also studied.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study population and design
The subjects were participants in the Paris Prospective Study of risk factors for cardiovascular mortality, in which 7,746 male employees of the Paris Police aged 43–53 years were included between 1967 and 1972 (9Go, 10Go). The study comprised five annual clinical and biochemical examinations and a follow-up of mortality and causes of death. The annual clinical evaluation included a medical history questionnaire and measurements of heart rate and blood pressure with a standard cuff technique on a sitting subject and of height and weight in light clothes without shoes. The iliac and left thigh circumferences were measured, respectively, at the iliac crest level and at the midlevel between the trochanter and lateral femoral condyle only at the first examination. The iliac/thigh ratio, which has been shown in the Paris Prospective Study to be a predictor of both coronary heart disease mortality (11Go) and deterioration of glucose tolerance (2Go), was used as an index of central fat distribution. The body mass index (weight (kg)/height (m)2) was used as an index of obesity. A complete biochemical evaluation with a 2-hour 75-g oral glucose tolerance test was done at the second examination. It included a blood count and measurements of fasting plasma cholesterol (12Go), triglycerides (13Go), and fasting and 2-hour plasma NEFA (14Go), glucose (15Go), and insulin (16Go).

The inquiry on vital status was made through official sources to ascertain the dates of death. The causes of death, coded using the International Classification of Diseases, Revision 8 and Revision 9 (17Go), were obtained whenever possible from the treating physicians, hospital records, or the families through 1988 and from the officially certified causes of death from 1989 onward or for those with missing causes in the earlier period. Coronary heart disease death was defined by codes 410.0–414.9 (myocardial infarction), 795.0 (sudden death), and 782.0–782.9, 427.0, 427.1, and 519.1 (heart failure), and cancer death was defined by codes 140–209. Cancer deaths were categorized into smoking- and/or alcohol-related cancers (codes 140–150, 155, 157, 161, 162, and 188–189 (includes upper aerodigestive, liver, pancreas, lung, kidney, and bladder cancers)) and into nonsmoking- and nonalcohol-related cancers (all cancers except smoking- and alcohol-related cancers and cancers from multiple or unspecified sites) (18Go).

Of the men born in continental France and free from cardiovascular disease at entry into the study, 7,152 attended the second examination, which is considered to be the baseline for this survival analysis. A fasting plasma NEFA measurement was available for 5,483 men. Because the iliac and thigh circumferences were measured 1 year before, only those with a weight change of less than 3 kg between the first two examinations (n = 4,589) were eventually included in the analysis. Of these, 188 subjects (4.1 percent) could not be traced after the first 5 years of clinical follow-up, and their mortality status is unknown thereafter. The 15-year mortality follow-up was complete for all the other subjects, but the cause of death was missing or indefinite for 52 subjects (1.1 percent).

Statistical analysis
The concentrations of insulin, triglycerides, and NEFA were log-transformed because of skewed distributions, and univariate statistics are presented with geometric means and 95 percent confidence intervals. The univariate comparisons between groups at baseline were by analysis of variance. The 15-year mortality rates were calculated with the actuarial method, and log-rank tests were used for between-group comparisons. Adjusted relative risks were computed with the Cox proportional hazards model.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The mean fasting plasma NEFA concentration in this population was 0.31 (standard deviation, 0.14) mmol/liter. At baseline, men in the highest quintile of plasma NEFA concentration were more frequently diabetic (p < 0.001) and treated for hypertension (p < 0.001) (table 1). Age, body mass index, and the fasting plasma insulin concentration were the only variables studied that did not exhibit a progressive rise with increasing fasting plasma NEFA concentration (table 1). In current smokers, the number of cigarettes smoked per day was positively associated with the fasting plasma NEFA concentration (r = 0.09, p < 0.001) (data not shown).


View this table:
[in this window]
[in a new window]
 
TABLE 1. Description of the 4,589 subjects divided by quintiles of fasting plasma nonesterified fatty acid (NEFA) at baseline, Paris Prospective Study, 1967–1972

 
A total of 636 (14 percent) of the 4,589 participants died during the first 15 years of follow-up. Cancer and coronary heart disease were the causes of 39 percent (n = 251) and 20 percent (n = 126) of the deaths, respectively. There was a slight nonsignificant (p < 0.13) increase in the 15-year mortality rate from coronary heart disease above the highest quintile of fasting plasma NEFA concentration (figure 1). In contrast, the increase in the death rate from cancer was significant (p < 0.001) and was mainly due to an almost doubling of the death rate in the upper quintile of the fasting plasma NEFA concentration (figure 1). Death rates according to 2-hour plasma NEFA quintiles were 2.7, 3.8, 2.7, 2.4, and 3.7 percent (p < 0.4) for coronary heart disease and 5.2, 6.0, 5.5, 5.2, and 7.9 percent (p < 0.001) for cancer. The relation between the fasting plasma NEFA concentration and cancer mortality remained significant when the analysis was restricted to the subjects who were alive after 5 years of follow-up, with 15-year death rates increasing from 3.8 percent in the lowest quintile to 8.2 percent in the highest quintile (p < 0.001). Smoking- and/or alcohol-related cancers (n = 139) were responsible for most of this relation. There was only a nonsignificant trend for the other cancers (figure 2).



View larger version (16K):
[in this window]
[in a new window]
 
FIGURE 1. Fifteen-year cumulative death rates from coronary heart disease (left) and cancer (right) by fasting plasma nonesterified fatty acid (NEFA) concentration at baseline (defined by the following quintiles: 0.19, 0.25, 0.31, 0.41 mmol/liter), Paris Prospective Study, 1967–1972. The p value corresponds to the log-rank test for comparison of survival curves.

 


View larger version (19K):
[in this window]
[in a new window]
 
FIGURE 2. Fifteen-year cumulative death rates from smoking- and/or alcohol-related cancers (left) or nonsmoking- and nonalcohol-related cancers (right) by fasting plasma nonesterified fatty acid (NEFA) concentration at baseline (defined by the following quintiles: 0.19, 0.25, 0.31, 0.41 mmol/liter), Paris Prospective Study, 1967–1972. The p value corresponds to the log-rank test for comparison of survival curves.

 
Multivariate analyses were performed in 4,328 subjects not known as diabetic and not treated for hypertension. In a multiple proportional hazard model adjusted for age and the number of cigarettes smoked per day, the relative risks of death from coronary heart disease associated with high fasting and 2-hour plasma NEFA concentrations (highest 20 percent vs. lowest 80 percent) were 1.54 (95 percent confidence interval (CI): 1.01, 2.34) and 1.18 (95 percent CI: 0.75, 1.85), respectively. They decreased to 1.19 (95 percent CI: 0.77, 1.83) (table 2) and 1.10 (95 percent CI: 0.71, 1.73) with further adjustment for blood pressure, iliac/thigh ratio, and high 2-hour plasma insulin and cholesterol. Most of this decrease was related to the introduction of blood pressure into the model. The relative risk associated with an increase of iliac/thigh ratio of 1 standard deviation was similar whether or not high fasting plasma NEFA concentrations were in the model: 1.45 (95 percent CI: 1.23, 1.71) and 1.43 (95 percent CI: 1.22, 1.69), respectively. In multivariate analyses, a high fasting plasma NEFA concentration remained predictive of death from cancer when cancer risk factors such as age, number of cigarettes smoked per day, heart rate, and body mass index were taken into account. The relative risk associated with a fasting plasma NEFA concentration of greater than or equal to 0.41 mmol/liter (upper quintile) was 1.66 (95 percent CI: 1.25, 2.21) for all cancers and 1.83 (95 percent CI: 1.27, 2.63) (table 3) and 1.60 (95 percent CI: 0.93, 2.76) (table 4) for cancers related or not related to smoking and/or alcohol. It decreased for these two types of cancers to 1.65 (95 percent CI: 1.12, 2.43) and 1.49 (95 percent CI: 0.85, 2.63), respectively, when further adjustments were made for 2-hour glucose and cholesterol concentrations, blood pressure, and the iliac/thigh ratio, which have been shown to be predictive of cancer death in the Paris Prospective Study (18Go, 19Go).


View this table:
[in this window]
[in a new window]
 
TABLE 2. Relative risks of death from coronary heart disease in a Cox proportional hazard model in 4,328 subjects not known as diabetic and not treated for hypertension, Paris Prospective Study (1967–1972), 15-year mortality follow-up

 

View this table:
[in this window]
[in a new window]
 
TABLE 3. Relative risks of death from smoking- and/or alcohol-related cancer (n = 139) in a Cox proportional hazard model in 4,328 subjects not known as diabetic and not treated for hypertension, Paris Prospective Study (1967–1972), 15-year mortality follow-up

 

View this table:
[in this window]
[in a new window]
 
TABLE 4. Relative risks of death from cancer not related to smoking and/or alcohol (n = 71) in a Cox proportional hazard model in 4,328 subjects not known as diabetic and not treated for hypertension, Paris Prospective Study (1967–1972), 15-year mortality follow-up

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In this longitudinal study of middle-aged men, plasma NEFA concentrations at fasting or 2 hours after a 75-g oral glucose tolerance test were not significantly predictive of mortality from coronary heart disease after 15 years of follow-up, but they were found to be strong predictors of mortality from cancer, especially smoking- and/or alcohol-related cancers.

There are direct and indirect effects of the plasma NEFA concentration that could have led to an association with the risk of death from coronary heart disease. First, in ischemic situations such as myocardial infarction, a high plasma NEFA concentration may promote the occurrence of arrythmia (1Go, 20Go). An association between the high plasma NEFA concentration and ventricular premature complexes has also been described in conditions where the NEFA plasma concentration can reach high levels, such as in non-insulin-dependent diabetic subjects (21Go). Indirectly, a high plasma NEFA concentration is a risk marker for the development of type 2 diabetes (2Go, 22Go), which by itself is associated with an excess of coronary heart disease mortality (19Go, 23Go).

A third reason for studying the plasma NEFA concentration as a risk marker for death from coronary heart disease was its relation with upper-body fat distribution (1Go, 4Go, 24Go). Indeed, one of the potential explanations for the well-known association between upper-body fat distribution and the risk of coronary heart disease (11Go, 25GoGo–27Go) involves the high lipolytic activity of visceral adipose tissue. An excess of fat deposition at this level leads to an increased release of NEFA in the portal circulation. The increased NEFA flux to the liver stimulates hepatic gluconeogenesis and very low density lipoprotein secretion and decreases insulin clearance (1Go, 4Go, 24Go). One limitation of our study is that it is based on peripheral and not portal NEFA concentration. The plasma systemic NEFA concentration is chronically elevated in obesity (24Go) and, in conditions where lipolysis is stimulated such as in the fasting state, one expects the level of the plasma free fatty acid concentration to reflect the amount of the adipose tissue that is the most sensitive to lipolysis, namely, the visceral adipose tissue. Moreover, 2 hours after insulin stimulation by a glucose load, the visceral adipose tissue may contribute even more to the systemic NEFA concentration since lipolysis is more resistant to insulin suppression in the visceral adipose tissue than in the peripheral adipose tissue (28Go).

Our aim was, therefore, first to test whether there was a relation between the plasma NEFA concentration and coronary heart disease mortality and second, to examine whether the plasma NEFA concentration could explain the association between central fat distribution and coronary heart disease death. Our results show a weak association between the fasting plasma NEFA concentration and age- and tobacco-adjusted coronary heart disease mortality, which disappeared when blood pressure was added to the model. A high iliac/thigh ratio maintained a basically unchanged predictive effect of coronary heart disease death whether or not plasma NEFA was in the model. Therefore, we found no evidence that plasma NEFA could be linked to the causal pathway between upper-body fat distribution and coronary heart disease mortality. To our knowledge, only one prospective epidemiologic study has addressed this question, and preliminary results (29Go) suggest that plasma NEFA was not an independent predictor of ischemic heart disease in men.

This negative result could be due to the high within-subject variability of plasma NEFA concentration that is influenced by factors such as nutritional status, stress, and smoking (1Go). However, despite this variability, it was possible to demonstrate significant relations between the plasma NEFA concentration and cancer mortality. Another explanation could be that, even with abdominal obesity, the visceral adipose tissue contributes too little to the systemic NEFA concentration. A last hypothesis is that the fraction of NEFA from visceral adipose tissue origin that reaches the systemic circulation, namely, the fraction not taken up by the liver (which may vary between individuals), represents the part that does not contribute to the cardiovascular risk.

In contrast to the results for coronary heart disease mortality, a high plasma NEFA concentration was predictive of death from cancer. The relation was particularly marked in the highest 20 percent of the NEFA distribution and appeared stronger for smoking- and/or alcohol-related cancers. To our knowledge, no other previous study has shown such a relation, although there have been reports of an association between high NEFA concentrations and hormone-dependent cancers, possibly a consequence of increased plasma levels of free sex hormones as they compete with NEFA for transport by albumin (1Go, 30Go). There have also been reports of a relation between specific types of free fatty acids and the risk of cancer (31GoGo–33Go), and it is well known that diet, especially when rich in saturated fats, is related to certain types of tumors (5Go, 34Go). There is, however, little knowledge about the relation between the fatty acid composition of the diet and the plasma NEFA composition, especially at fasting when circulating NEFA concentrations come mainly from the hydrolysis of stored triglycerides. Hypertension and diabetes mellitus, which are associated with insulin resistance, central obesity, and elevated portal and/or systemic NEFA flux, have been shown to be risk factors for some cancers, such as pancreatic, liver, kidney, and (in women) endometrial cancers (35GoGoGo–38Go). Elevated plasma NEFA might be considered a common marker in the causal pathway among these diseases.

The fact that the relation between NEFA and cancer death was more apparent for smoking- and/or alcohol-related tumors led us to hypothesize that high levels of circulating plasma NEFA could be an indicator of excessive alcohol consumption. We could not find any report directly supporting the relation, but indirect evidence is the well-known susceptibility of heavy drinkers to alcohol-induced hypertriglyceridemia and fatty liver (39Go). Moreover, insulin resistance is common in liver disease (40Go), and chronic alcohol abuse is associated with central obesity and other features of the insulin resistance syndrome (41Go, 42Go), all circumstances where plasma free fatty acid concentrations are increased. Models using an available surrogate marker of alcohol consumption, mean corpuscular volume, did not yield any modifications in our results, but this can be due to the poor specificity of this marker (43Go).

As for a possible general implication of NEFA regarding tumor promotion or growth, no explanation is readily available, although there have been some laboratory studies that have shown effects on gene expression with possible carcinogenic consequences (44Go). In addition, growth hormone, a lipolytic hormone, has been shown to be a predictor of cancer mortality in the Paris Prospective Study; however, the predictive model included the systemic plasma NEFA concentration, which maintained an independent relation with the endpoint (45Go). Our result can also be compared with other results that show a positive relation between the heart rate and noncardiovascular mortality, since circulating NEFA concentrations and heart rate are both markers of adrenergic activity (46Go). However, this relation has not been evidenced in all studies (47Go) and remains largely unexplained. Besides, the heart rate has been considered in our multivariate model, and the NEFA predictive power remained significant. A last possible explanation is that a high fasting plasma NEFA concentration reflects an increased lipolysis as part of an underlying catabolic effect of cancer in a preclinical stage. This catabolic process has been held as a possible explanation to the well-known negative relation between cancer risk and plasma cholesterol levels and body mass index (18Go, 48Go). However, our results were not modified when the analysis was restricted to the subjects who were alive after 5 years of follow-up.

In conclusion, despite pathophysiologic mechanisms suggesting a relation between altered NEFA metabolism and cardiovascular disease, systemic plasma NEFA did not show any significant predictive power toward coronary heart disease mortality in our analysis. Conversely, we found an unexpected association with cancer mortality, which needs to be further investigated.


    ACKNOWLEDGMENTS
 
The authors are indebted to the Paris Prospective Study and to the GREA, the coordinating group of the study, which associated the INSERM (units 21, 55, 169, 258) and the Directorate of Social Affairs, Childhood, and Health, Paris, France.


    NOTES
 
Correspondence to Marie Aline Charles, INSERM U 258, 16 avenue Paul Vaillant Couturier, F-94807 Villejuif, France (e-mail: charles{at}vjf.inserm.fr).


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Frayn KN, Williams CM, Arner P. Are increased plasma non-esterified fatty acid concentrations a risk marker for coronary heart disease and other chronic diseases? Clin Sci (Colch) 1996;90:243–53.[ISI][Medline]
  2. Charles MA, Eschwège E, Thibult N, et al. The role of non-esterified fatty acids in the deterioration of glucose tolerance in Caucasian subjects: results of the Paris Prospective Study. Diabetologia 1997;40:1101–6.[Medline]
  3. Fagot-Campagna A, Balkau B, Simon D, et al. High free fatty acid concentration: an independent risk factor for hypertension in the Paris Prospective Study. Int J Epidemiol 1998;27:808–13.[Abstract]
  4. Björntorp P. "Portal" adipose tissue as a generator of risk factors for cardiovascular disease and diabetes. Arteriosclerosis 1990;10:493–6.[Medline]
  5. Giovanucci E, Goldin B. The role of fat, fatty acids, and total energy intake in the etiology of human colon cancer. Am J Clin Nutr 1997;66(suppl):1564S–71S.[Abstract]
  6. Schapira DV, Clark RA, Wolff PA, et al. Visceral obesity and breast cancer risk. Cancer 1994;74:632–9.[ISI][Medline]
  7. Filipovsky J, Ducimetière P, Darné B, et al. Abdominal body mass distribution and elevated blood pressure are associated with increased risk of death from cardiovascular diseases and cancer in middle-aged men. The results of a 15- to 20-year follow-up in the Paris Prospective Study I. Int J Epidemiol 1993;17:197–203.
  8. Balkau B, Shipley M, Jarret RJ, et al. High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men: 20-year follow-up in the Whitehall Study, the Paris Prospective Study, and the Helsinki Policemen Study. Diabetes Care 1998;21:360–7.[Abstract]
  9. Richard JL, Ducimetière P, Bonnaud G, et al. Incidence et évaluation du risque de maladie coronarienne. L'Etude Prospective Parisienne. (In French). Arch Mal Coeur Vaiss 1977;70:531–7.[ISI][Medline]
  10. Ducimetière P, Eschwège E, Papoz L, et al. Relationship of plasma insulin level to the incidence of myocardial infarction and coronary heart disease mortality in a middle-aged population. Diabetologia 1980;19:205–10.[ISI][Medline]
  11. Cassasus P, Fontbonne A, Thibult N, et al. Upper-body fat distribution: a hyperinsulinemia-independent predictor of coronary heart disease mortality. The Paris Prospective Study. Arterioscler Thromb Vasc Biol 1992;12:1387–92.[Abstract]
  12. Etienne G, Papin JP, Renault M. Une méthode simple de dosage du cholestérol par voie automatique. (In French). Ann Biol Clin (Paris) 1963;21:851–3.
  13. Claude JR, Corre F. Considérations pratiques sur le dosage semiautomatique des triglycérides sériques par fluorométrie (méthode de Kessler et Lederer). Comparaison avec la méthode manuelle colorimétrique de Van Handel et Zilversmit. (In French). Ann Biol Clin (Paris) 1968;26:451–4.[ISI][Medline]
  14. Antonis A. Semi-automated method for the colorimetric determination of plasma free fatty acid. J Lipid Res 1965;6:307–12.[Abstract/Free Full Text]
  15. Méthodologie technichon auto-analyser no. 2a. 2nd ed. Tarrytown, NY: Technicon, Ltd, 1963.
  16. Rosselin GE, Assan R, Yalow RS, et al. Separation of antibody bound and unbound peptide hormone labelled with iodine 131 by talcum powder and precipitated silica. Nature 1966;212:355–7.[ISI][Medline]
  17. World Health Organization. International classification of diseases. Manual of the international statistical classification of diseases, injuries, and causes of death. Ninth Revision. Geneva, Switzerland: World Health Organization, 1979.
  18. Zureik M, Courbon D, Ducimetière P. Decline in serum total cholesterol and the risk of death from cancer. Epidemiology 1997;8:137–43.[ISI][Medline]
  19. Balkau B, Eschwège E, Papoz L, et al. Risk factors for early death in non-insulin dependent diabetes and men with known glucose tolerance status. BMJ 1993;307:295–9.[ISI][Medline]
  20. Olivier MF, Opie LH. Effects of glucose and fatty acids on myocardial ischaemia and arrhythmias. Lancet 1994;343:155–8.[ISI][Medline]
  21. Paolisso G, Gualdiero P, Manzella D, et al. Association of fasting plasma free fatty acid concentration and frequency of ventricular premature complexes in nonischemic non-insulin-dependent diabetic patients. Am J Cardiol 1997;80:932–7.[ISI][Medline]
  22. Paolisso G, Tataranni PA, Foley JE, et al. A high concentration of fasting plasma non-esterified fatty acids is a risk factor for the development of NIDDM. Diabetologia 1995;38:1213–17.[ISI][Medline]
  23. Panzram G. Mortality and survival in type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1987;30:123–31.[ISI][Medline]
  24. Bonadonna R, Bonora E. Glucose and free fatty acid metabolism in human obesity. Relationship to insulin resistance. Diabetes Rev 1997;5:21–51.[ISI]
  25. Larsson B, Svärdsudd K, Welin L, et al. Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: a 12 year follow-up of participants in the study of men born in 1913. Br Med J 1984;288:1401–4.[ISI][Medline]
  26. Kannel WB, Cupples LA, Ramaswami R, et al. Regional obesity and the risk of cardiovascular disease: The Framingham Study. J Clin Epidemiol 1991;44:183–90.[ISI][Medline]
  27. Freeman DS, Williamson DF, Croft JB, et al. Relation of body fat distribution to ischemic heart disease. The National Health and Nutrition Examination Survey I (NHANES I) epidemiologic follow-up study. Am J Epidemiol 1995;142:53–63.[Abstract]
  28. Meek SE, Nair KS, Jensen MD. Insulin regulation of regional free fatty acid metabolism. Diabetes 1999;48:10–14.[Abstract]
  29. Lamarche B, Mauriège P, Cantin B, et al. Plasma free fatty acids concentrations and the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study. (Abstract). Diabetes 1999;48(suppl 1):A171.
  30. Bruning PF, Bonfrer JMG, Hart AAM, et al. Body measurements, estrogen availability and the risk of human breast cancer. Int J Cancer 1992;51:14–19.[ISI][Medline]
  31. Gann PH, Hennekens CH, Sacks FM, et al. Prospective study of plasma fatty acids and risk of prostate cancer. J Natl Cancer Inst 1994;86:281–6.[Abstract]
  32. Zureik M, Ducimetière P, Warnet JM, et al. Fatty acid proportions in cholesterol esters and risk of premature death from cancer in middle aged French men. BMJ 1995;311:1251–4.[Abstract/Free Full Text]
  33. Simon JA, Fong J, Bernert JT, et al. Serum fatty acids and the risk of fatal cancer. Am J Epidemiol 1998;148:854–8.[Abstract]
  34. Bakker N, Vant Veer P, Zock PL. Adipose fatty acids and cancers of the breast, prostate and colon: an ecological study. EURAMIC Study Group. Int J Cancer 1997;72:587–91.[ISI][Medline]
  35. Wideroff L, Gridley G, Mellemkjaer L, et al. Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. J Natl Cancer Inst 1997;89:1360–5.[Abstract/Free Full Text]
  36. Lindblad P, Chow WH, Chan J, et al. The role of diabetes mellitus in the aetiology of renal cell cancer. Diabetologia 1999;42:107–12.[ISI][Medline]
  37. Wannamethee G, Shaper AG. Blood pressure and cancer in middle-aged British men. Int J Epidemiol 1996;25:22–31.[Abstract]
  38. Coughlin SS, Neaton JD, Randall B, et al. Predictors of mortality from kidney cancer in 332,547 men screened for the Multiple Risk Factor Intervention Trial. Cancer 1997;79:2171–7.[ISI][Medline]
  39. Lieber CS. Hepatic and metabolic effects of alcohol. Gastro-enterology 1966;50:119–33.[ISI][Medline]
  40. Merli M, Leonetti F, Riggio O, et al. Resistance to insulin suppression of plasma free fatty acids in liver cirrhosis. J Endocrinol Invest 1990;13:787–95.[ISI][Medline]
  41. Lindegard B, Langman MJS. Marital state, alcohol consumption, and liability to myocardial infarction, stroke, diabetes mellitus, or hypertension in men from Gothenburg. Br Med J 1985;291:1529–33.[ISI][Medline]
  42. Balkau B, Eschwège E, Fontbonne A, et al. Cardiovascular and alcohol-related deaths in abnormal glucose tolerant and diabetic subjects. Diabetologia 1992;35:39–44.[ISI][Medline]
  43. Chick J, Kreitman N, Plant M. Mean cell volume and gamma-glutamyl-transpeptidase as markers of drinking in working men. Lancet 1981;1:1249–51.[Medline]
  44. Vanden Heuvel JP. Peroxisome proliferator-activated receptors: a critical link among fatty acids, gene expression and carcinogenesis. J Nutr 1999;129(suppl):575S–80S.[ISI][Medline]
  45. Maison P, Balkau B, Simon D, et al. Growth hormone as a risk for premature mortality in healthy subjects: data from the Paris Prospective Study. BMJ 1998;316:1132–3.[Free Full Text]
  46. Wannamethee G, Shaper AG, Macfarlane PW. Heart rate, physical activity, and mortality from cancer and other noncardiovascular diseases. Am J Epidemiol 1993;137:735–48.[Abstract]
  47. Mensink GB, Hoffmeister H. The relationship between resting heart rate and all-cause, cardiovascular and cancer mortality. Eur Heart J 1997;18:1404–10.[Abstract]
  48. Wallace RB, Rost C, Burmeister LF, et al. Cancer incidence in humans: relationship to plasma lipids and relative weight. J Natl Cancer Inst 1982;68:915–18.[ISI][Medline]
Received for publication February 9, 2000. Accepted for publication May 18, 2000.