Papers

Increased risk of non-insulin dependent diabetes mellitus at low plasma vitamin E concentrations: a four year follow up study in men

^a Research Institute of Public Health, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland, ^b Department of Biochemistry and Biotechnology, University of Kuopio, ^c Department of Community Health and General Practice, University of Kuopio, ^d Human Population Laboratory, California Department of Health Services, Berkeley, California, USA

Correspondence to: Professor Salonen.

Abstract

Objective: To investigate whether low vitamin E status is a risk factor for incident non-insulin dependent diabetes mellitus.
Design: Population based follow up study with diabetes assessed at baseline and at four years.
Setting: Eastern Finland.
Subjects: Random sample of 944 men aged 42-60 who had no diabetes at the baseline examination.
Intervention: Oral glucose tolerance test at four year follow up.
Main outcome measures: A man was defined diabetic if he had either (a) a fasting blood glucose concentration >/=6.7 mmol/l, or (b) a blood glucose concentration >/=10.0 mmol/l two hours after a glucose load, or (c) a clinical diagnosis of diabetes with either dietary, oral, or insulin treatment.
Results: 45 men developed diabetes during the follow up period. In a multivariate logistic regression model including the strongest predictors of diabetes, a low lipid standardised plasma vitamin E (below median) concentration was associated with a 3.9-fold (95% confidence interval 1.8-fold to 8.6-fold) risk of incident diabetes. A decrement of 1 µmol/l of uncategorised unstandardised vitamin E concentration was associated with an increment of 22% in the risk of diabetes when allowing for the strongest other risk factors as well as serum low density lipoprotein cholesterol and triglyceride concentrations.
Conclusions: There was a strong independent association between low vitamin E status before follow up and an excess risk of diabetes at four years. This supports the theory that free radical stress has a role in the causation of non-insulin dependent diabetes mellitus.

Introduction

Free radical mechanisms have been implicated in the pathogenesis of tissue damage in diabetes.^{1 2 3 4 5} Various sources of free radicals may modulate oxidative stress in diabetes, including non-enzymatic glycosylation of proteins and monosaccharide auto-oxidation, polyol pathway activity, indirect production of free radicals through cell damage from other causes, and reduced antioxidant reserves.³

There are few data on the role of oxidative stress in the causation of diabetes, though some workers have suggested a role for free radicals and lipid peroxidation.¹ It has been speculated that as pancreatic islet cells have low antioxidative enzyme activities they might be sensitive to free radical injury.^{2 6} Diabetes can be induced in animals by free radicals producing substances such as catalytic iron, alloxan, and streptozocin, and free radical scavengers are effective in preventing diabetes in animal models.^{1 2 6 7 8 9 10}

In humans the evidence concerning the role of free radicals and antioxidants in diabetes is very limited. Increased lipid peroxidation has been detected in diabetic patients by several different methods.^{11 12 13 14} In a small randomised trial in non-insulin dependent diabetic and healthy subjects supplementation with vitamin E reduced oxidative stress and improved insulin action.^{15 16} There is, however, no previous prospective population study of the role of either free radical stress or antioxidants with regard to the incidence of diabetes. We tested the hypothesis that the incidence of non-insulin dependent diabetes mellitus is increased at low concentrations of plasma vitamin E.

Subjects and methods

The Kuopio ischaemic heart disease risk factor study is a population study of the role of lipid peroxidation, pro-oxidative minerals, and antioxidants in atherosclerosis, coronary heart disease, and diabetes.¹⁷ Baseline examinations were conducted between March 1984 and December 1989. The study sample comprised 3235 men in eastern Finland aged 42, 48, 54, or 60 years at the baseline examination. Of these, 2682 (82.9%) eligible men participated. No appreciable sociodemographic differences have been found between participants and non-participants.¹⁸

Men who participated in the baseline examinations during September 1986 to December 1989 and had ultrasonography of the carotid arteries were invited for re-examination four years later. Of the 1229 eligible men who were invited, 1038 participated, 107 refused, and 84 could not participate. Forty five subjects had diabetes at the baseline examination, as defined by a fasting blood glucose concentration >/=6.7 mmol/l or diagnosed diabetes with dietary, oral, or insulin treatment. As this study was concerned with the risk of the first manifestation of diabetes, these subjects were excluded from analysis. Plasma vitamin E, serum total cholesterol, or serum triglyceride concentrations were missing for 49 other subjects, so that data were available for 944 men.

NON-INSULIN DEPENDENT DIABETES MELLITUS STATUS

The examination protocol and measurements were as detailed elsewhere.^{17 18 19} An oral glucose tolerance test with 75 g glucose was performed at the four year follow up visit. Incident diabetes was defined by means of the WHO criteria for diabetes,²⁰ complemented by a clinical diagnosis that had led to treatment, which had thus influenced the glucose concentration. A man was defined diabetic at the four year follow up if he had either (a) a fasting blood glucose concentration >/=6.7 mmol/l, or (b) a blood glucose concentration >/= 10.0 mmol/l two hours after a glucose load, or (c) a clinical diagnosis of diabetes with either dietary, oral, or insulin treatment. Forty five subjects became diabetic during the four years of follow up (table I).

TABLE I--Distribution of diagnostic criteria in 45 subjects who became diabetic during four year follow up
--------------------------------------------------------------------------------------------------------------------------
                                       Fasting blood glucose >/=6.7 mmol/l  Fasting blood glucose <6.7 mmol/l
--------------------------------------------------------------------------------------------------------------------------
                                         2 hour blood       2 hour blood       2 hour blood       2 hour blood
                                           glucose             glucose           glucose             glucose
                                         >/=10.0 mmol/l     <10.0 mmol/l       >/=10.0 mmol/l     <10.0 mmol/l   Total
--------------------------------------------------------------------------------------------------------------------------
Clinical diagnosis of diabetes                 5                 2                   2                 7           16
No clinical diagnosis of diabetes             12                 2                  15                 0           29
--------------------------------------------------------------------------------------------------------------------------
Total                                         17                 4                  17                 7           45

OTHER MEASUREMENTS

Vitamin E concentration was measured in deep frozen (-80°C) heparinised plasma as (alpha) tocopherol by high performance liquid chromatography.²¹ The freezing time was less than a year. For serum low density lipoprotein cholesterol analysis fresh serum was centrifuged for 16 hours at 115000 g at 10°C (TGA-65 ultracentrifuge, Kontron Instruments, Italy), as described.¹⁹ Plasma cholesterol concentrations were determined by enzymatic colorimetry (CHOD.PAP, Boehringer Mannheim, Germany). Serum triglyceride and fructosamine concentrations were measured in frozen samples by an autoanalyser (Kone Specific, Kone Inc, Finland) with the use of reagents from Boehringer Mannheim. Serum fatty acid concentrations were measured by gas chromatography (Hewlett Packard 5890 series II with a flame ionisation detector, Avondale, Philadelphia). An NB-351 capillary column was used (HNU-Nordion, Finland).

The number of cigarettes, cigars, and pipefuls of tobacco smoked daily and the years of regular smoking were recorded with a self administered questionnaire, which was checked by an interviewer. Reinterviews for a medical history were conducted by a physician. A family history of diabetes was recorded as positive if either the biological father, mother, sister, or brother of the subject had a history of diabetes. Consumption of alcohol in the previous 12 months was assessed by the quantity-frequency method with the Nordic alcohol consumption inventory, which contains 15 items.²² Socioeconomic status was measured with a summary index that combined income, education, occupation, occupational prestige, material standard of living, and housing conditions.²³

STATISTICAL METHODS

The association of baseline plasma vitamin E concentration and other risk factors for diabetes with the risk of incident diabetes was estimated and tested for statistical significance by the SPSS software for multivariate logistic regression analysis.²⁴ Other risk factors for incident diabetes and thus potential confounders of the relation between vitamin E status and diabetes were explored by step up logistic regression analysis. The strongest predictors were then included as covariates in a fixed logistic model jointly with lipid standardised vitamin E concentration. The purpose of also including baseline blood glucose and serum fructosamine concentrations in the model was to control for any association between baseline vitamin E value and indicators of early diabetes. Baseline serum insulin concentration was also tested for entry but did not have any additional predictive value.

To separate the effect of vitamin E from that of serum lipids, lipid standardised vitamin E concentration was used in the statistical analysis. The lipid standardised vitamin E concentration was computed as the ratio of the measured plasma vitamin E concentration to the vitamin E concentration predicted by a linear regression equation based on serum total cholesterol and serum triglyceride concentrations. The alternative approach, to enter these three variables jointly into a model, was also used to confirm the results. To ensure maximal statistical power the lipid standardised vitamin E concentration was dichotomised by using the median as a cut off point.

Results

The baseline characteristics of the study subjects are shown in table II. The mean plasma vitamin E concentration was comparatively low (19.4 µmol/l). The mean daily dietary intake of vitamin E was 9.9 mg (SD 4.3 mg; range 2.8-38.9 mg). For 566 (60%) subjects the daily intake was less than 10 mg, the recommended dietary allowance. Only 12 subjects (1.3%) had used vitamin E supplements in the seven days before the baseline examination.

TABLE II--Baseline characteristics of subjects who developed diabetes during follow up and of those who did not
------------------------------------------------------------------------------------------------------------------------------------------------
                               Incident diabetic subjects    Non-diabetic subjects    P value for               All subjects
-------------------------------------------------------------------------------------- difference ----------------------------------------------
Baseline characteristic              Mean        SD               Mean     SD          in means         Mean     SD     Minimum     Maximum
------------------------------------------------------------------------------------------------------------------------------------------------
Plasma vitamin E (µmol/l)         18.9       6.3               19.4     5.2           0.662          19.4     5.2      6.5        54.9
Lipid standardised vitamin E         0.906     0.178              1.005   0.206          0.001          0.96     0.20     0.36       2.22
Dietary vitamin E intake (mg/d)       9.3       3.4               10.0     4.3           0.240           9.9     4.3      2.8        38.9
Serum total cholesterol
  (mmol/l)                           5.74       1.05              5.76    0.99          0.901           5.76     1.00     2.60       10.09
Serum low density lipoprotein
  cholesterol (mmol/l)               3.75       0.96              3.87    0.93          0.422           3.86     0.93     0.82       8.46
Serum triglycerides (mmol/l)         2.12       1.34              1.37    0.79          0.001           1.41     0.84     0.25       7.84
Age (years)                          52.1       6.1               51.9     6.7           0.888          52.0     6.7      42.0       61.3
Socioeconomic status (higher
  the score, lower the status)        9.3       4.6               10.3     4.5           0.160          10.3     4.5       0          21
Body mass index (kg/m2)        30.0       4.3               26.5     3.2          <0.001          26.7     3.3      18.8       40.3
Cigarettes smoked daily               7.0       10.7               5.3     9.4           0.287           5.3     9.5       0          60
Blood glucose (mmol/l)                5.3       0.6                4.5     0.4          <0.001           4.6     0.5      3.2         6.5
Serum fructosamine (mmol/l)           258        24                246      25           0.002           246      25      132         386
Ratio of serum saturated fatty
  acids to sum of monoenes and
  polyenes                            0.57      0.07              0.52     0.06         <0.001          0.52     0.06     0.15        0.77

Lipid standardised baseline plasma vitamin E concentration was 10% (P=0.001 for difference) lower among men who became diabetic during follow up than among those who did not develop incident diabetes (table II). The unstandardised plasma vitamin E concentration did not differ significantly between these two groups. Men who later developed diabetes also had a raised baseline body mass index (weight (kg)/height (m)²), raised blood glucose and serum fructosamine concentrations, a higher ratio of saturated fatty acids to the sum of monounsaturated and polyunsaturated fatty acids, and a higher serum triglyceride concentration.

Lipid standardised plasma vitamin E concentration had only weak correlations with other potential risk factors for diabetes. It correlated inversely with cigarette smoking (r=-0.143; P<0.001) and the ratio of saturated to other fatty acids in serum (r=-0.137; P</=0.001) and directly with socioeconomic status (r=0.126; P</=0.001) and age (r=0.115; P</=0.001). There were no strong intercorrelations among the variables that predicted the risk of diabetes.

In a multivariate logistic regression model including the strongest predictors of diabetes the baseline body mass index was the strongest predictor (table III). Other factors with significant associations with an excess risk of diabetes were a high ratio of saturated to other fatty acids in serum, low plasma vitamin E concentration, and high socioeconomic status. The number of cigarettes smoked daily and age had weak, non-significant associations with diabetes risk. A low lipid standardised vitamin E (below median) concentration was associated with a 3.9-fold (95% confidence interval 1.8-fold to 8.6-fold; P=0.0008) risk of incident diabetes (table III).

TABLE III--Relative risk of diabetes associated with low plasma vitamin E concentration and other risk
factors
--------------------------------------------------------------------------------------------------------------------
                                                                                    95% confidence
Risk factor for diabetes                                          Relative risk       interval           P value
--------------------------------------------------------------------------------------------------------------------
Lipid standardised vitamin E below median (0.98)                       3.90         1.76 to 8.61          0.0008
Age (years)                                                            1.02         0.97 to 1.07          0.5401
Socioeconomic status                                                   1.10         1.02 to 1.19          0.0122
Body mass index (kg/m2)                                          1.23         1.13 to 1.33         <0.0001
Cigarettes smoked daily                                                1.015        0.985 to 1.046        0.3274
Ratio of serum saturated fatty acids to sum of monoenes and
 polyenes                                                              1.09         1.036 to 1.143        0.0007
--------------------------------------------------------------------------------------------------------------------
Model 2=71.82 (df=6); P<0.0001.

In another model that included the baseline blood glucose and serum fructosamine concentrations as additional variables, a low lipid standardised vitamin E (below median) concentration was associated with a 5.1-fold (2.0-fold to 12.8-fold; P=0.0006) risk of incident diabetes. In an identical model in which dichotomised vitamin E was replaced by uncategorical lipid standardised vitamin E the association was also significant (P=0.0022). In another model, in which lipid standardised vitamin E concentration was replaced by unstandardised vitamin E concentration and serum low density lipoprotein cholesterol and triglyceride concentrations, plasma vitamin E had, if anything, a stronger association with the risk of diabetes (22% increment in risk per 1 µmol/l decrement in plasma vitamin E; P=0.0004). The addition (including maximal oxygen uptake, alcohol intake, systolic blood pressure, and serum high density lipoprotein cholesterol concentration) or depletion of any variable tested did not substantially weaken the association between low vitamin E concentration and diabetes risk. The relation between a low vitamin E concentration and increased risk of diabetes was significant in all models. When added to the model in table III neither family history of diabetes nor the ratio of waist to hip circumference had any residual association with diabetes risk.

All analyses were also repeated by using another definition of incident diabetes. Subjects diagnosed as diabetic but who had only dietary treatment were not included in the incident diabetic group. This reduced the number of subjects who became diabetic during follow up from 45 to 38. The relative risk for lipid standardised vitamin E concentration below median was then 3.3 (95% confidence interval 1.4 to 7.7; P=0.0057) in a logistic model with the same six variables as in table III. With the inclusion of blood glucose and serum fructosamine concentrations in the model the relative risk for lipid standardised vitamin E below median was 4.5 (1.6 to 12.8; P=0.0045).

Discussion

We found a strong independent association between low vitamin E status before follow up and an excess risk of diabetes in a cohort of almost 1000 randomly sampled men in eastern Finland. This observation supports the theory that free radical stress has a role in non-insulin dependent diabetes mellitus. The strength of the association is remarkable and militates against a chance finding. Our cohort was too small to allow tests of the dose-response relation and effect modifiers. However, any reasonable possibility of confounding was excluded statistically by adjustment for the main known risk factors for non-insulin dependent diabetes, such as obesity and other predictors of diabetes in the cohort.

The prevalence of non-insulin dependent diabetes mellitus is high in Finland²⁵ and has increased in the past few decades.²⁶ The mean plasma concentrations of the main dietary antioxidants, vitamins C and E, are low in men in eastern Finland.²⁷ The mean plasma vitamin E concentration in our cohort was 19 µmol/l. Mean plasma concentrations of between 24 and 28 µmol/l have been reported from continental Europe.²⁸ Also the dietary intake of vitamin E was low (mean 10 mg daily). In 566 (60%) men the vitamin E intake was below the recommended 10 mg daily.²⁹ Use of antioxidant supplements was rare. Only 12 men (1.3%) reported using any vitamin E product.

An important question is whether a low vitamin E concentration preceded the onset of diabetes and thus acted in its causation or whether the low concentration was a consequence of latent diabetes at the time of the baseline examination. We addressed this issue statistically by adjusting for measures of glucose metabolism at baseline. Besides fasting blood glucose concentration, the serum concentration of glycosylated protein as measured by fructosamine value was available. If the baseline vitamin E concentration had been influenced by a latent and unmanifested diabetes the control for glucose status at baseline should have eliminated this effect--certainly to the extent to which the validity and precision of these measurements allowed.

Our findings should be retested in other cohort studies with repetitive measurements of fasting blood glucose concentrations and possibly blood glucose concentrations after loading. Also randomised trials of vitamin E should include repeated measurements of blood glucose status to test whether the incidence of non-insulin dependent diabetes mellitus can be reduced by vitamin E supplementation. If our results are confirmed in other studies they will support the importance of free radical mechanisms in diabetes and suggest that a high vitamin E diet and vitamin E supplementation would be useful in the primary prevention of non-insulin dependent diabetes mellitus.

In a small randomised double blind crossover trial in 15 non-insulin dependent diabetic and 10 healthy subjects upplementation with 900 mg vitamin E daily for four months reduced oxidative stress and improved insulin action in a euglycaemic hyperinsulinaemic glucose clamp.^{15 16} Vitamin E reduced the area under the curve and increased the total body glucose disposal and non-oxidative glucose metabolism in both healthy and diabetic subjects.

We can speculate that though susceptibility to non-insulin dependent diabetes mellitus is to a large extent determined genetically, manifestation of the disease may be more influenced by exogenous factors such as obesity. Golay and Felber have suggested that the resistance of peripheral tissues to glucose uptake is a consequence of permanently high lipid oxidation.³⁰ On the other hand, the oxidation of lipids could be enhanced if the concentrations of lipid soluble antioxidants such as vitamin E are low. The finding that vitamin E supplementation improved insulin sensitivity¹⁵ supports this. To what extent vitamin E and possibly other antioxidants participate in the regulation of energy metabolism in muscle cells is an important basic research question.

We thank Kimmo Ronkainen for data analyses and our staff of almost 20 people for helping with data collection.

Funding: The Academy of Finland; the Finnish Ministry of Education; and the National Heart, Lung and Blood Institute of the United States (grant HL44199).

Conflict of interest: None.

1. Oberley L. Free radicals and diabetes. Free Radic Biol Med 1988;5:113-24. [Medline]
2. Halliwell B, Gutteridge JMC. Free radicals in biology and medicine. Oxford: Clarendon Press, 1989.
3. Sinclair AJ, Lunec J, Cirling AJ, Barnett AH. Modulators of free radical activity in diabetes mellitus: role of ascorbic acid. In: Emerit I, Change B, eds. Free radicals and aging. Basle: Birkhauser Verlag, 1992:342-52.
4. Packer L. The role of anti-oxidative treatment in diabetes mellitus. Diabetologia 1993;36:1212-3. [Medline]
5. Wolff SP. Diabetes mellitus and free radicals. Free radicals, transition metals and oxidative stress in the aetiology of diabetes mellitus and complications. Br Med Bull 1993;49:642-52. [Abstract/Free Full Text]
6. Loven DP, Oberley LW. Free radicals, insulin action, and diabetes. In: Oberley LW, ed. Superoxide dismutase. Vol III. Boca Raton, Florida: CRC Press, 1985.
7. Cohen G. Oxy-radical production in alloxan-induced diabetes: an example of an in vivo metal-catalyzed Haber-Weiss reaction. In: Armstron D, Sohal RS, Cutler RG, Slater TF, eds. Free radicals in molecular biology, aging and disease. Aging series. Vol. 27. New York: Raven Press, 1983:307-16.
8. Flechner I, Maruta K, Burkart V, Kawai K, Kolb H, Kiesel U. Effects of radical scavengers on the development of experimental diabetes. Diabetes Res 1990;13:67-73. [Medline]
9. Hayward AR, Shriber M, Sokol R. Vitamin E supplementation reduces the incidence of diabetes but not insulitis in NOD mice. J Lab Clin Med 1992;119:503-7. [Medline]
10. Murthy VK, Shipp JC, Hanson C, Shipp DM. Delayed onset and decreased incidence of diabetes in BB rats fed free radical scavengers. Diabetes Res Clin Pract 1992;18:11-6. [Medline]
11. Sato Y, Hotta N, Sakamoto N, Matsuoka S, Ohishi N, Yagi K. Lipid peroxide level in plasma of diabetic patients. Biochemical Medicine 1979;21:104-7. [Medline]
12. Nishigaki I, Hagihara M, Tsunekawa H, Maseki M, Yagi K. Lipid peroxide levels of serum lipoprotein fractions of diabetic patients. Biochemical Medicine 1981;25:373-8. [Medline]
13. Gallou G, Ruelland A, Legras B, Maugendre D, Allannic H, Cloarec L. Plasma malondialdehyde in type 1 and type 2 diabetic patients. Clin Chim Acta 1993;214:227-34. [Medline]
14. Tsai EC, Hirsch IB, Brunzell JD, Chait A. Reduced plasma peroxyl radical trapping capacity and increased susceptibility of low density lipoprotein to oxidation in poorly controlled IDDM. Diabetes 1994;43:1010-4. [Abstract]
15. Paolisso G, D'Amore A, Giugliano D, Ceriello A, Varrichio M, D'Onofrio F. Pharmacologic doses of vitamin E improve insulin action in healthy subjects and non-insulin-dependent diabetic patients. Am J Clin Nur 1993;57:650-6.
16. Caballero B. Vitamin E improves the action of insulin. Nutr Rev 1993;51:339-40. [Medline]
17. Salonen JT. Is there a continuing need for longitudinal epidemiologic research--the Kuopio Ischaemic Heart Disease Risk Factor Study. Annals of Clinical Research 1988;20:46-50. [Medline]
18. Lakka TA, Salonen JT. Intra-person variability of various physical activity assessments in the Kuopio Ischaemic Heart Disease Risk Factor Study. Int J Epidemiol 1992;21:467-72. [Abstract/Free Full Text]
19. Salonen JT, Salonen R, Seppanen K, Rauramaa R, Tuomilehto J. High density lipoprotein, high density lipoprotein(sub 2), and HDL(sub 3) subfractions, and the risk of acute myocardial infarction. A prospective population study in eastern Finnish men. Circulation 1991;84:129-39. [Abstract/Free Full Text]
20. World Health Organisation Study Group on Diabetes Mellitus. Report. World Health Organ Tech Rep Ser 1985; No 727.
21. De Leenheer AP, De Bevere VORC, De Ruyter MGM, Claeys AE. Simultaneous determination of retinol and (alpha)-tocopherol in human serum by high performance liquid chromatography. J Chromatogr 1979;162:408-13. [Medline]
22. Kauhanen J, Julkunen J, Salonen JT. Coping with inner feelings and stress: heavy alcohol use in the context of alexithymia. Behav Med 1992;18:121-6. [Medline]
23. Kaplan GA, Salonen JT. Socioeconomic conditions in childhood and ischaemic heart disease during middle age. BMJ 1990;301:1121-3.
24. Norusis M. SPSS for Unix. Advanced statistics, release 5.0. Chicago: SPSS Inc, 1993:1-30.
25. Tuomilehto J, Korhonen HJ, Kartovaara L, Salomaa V, Stengard JH, Pitkanen M, et al. Prevalence of diabetes mellitus and impaired glucose tolerance in the middle-aged population of three areas in Finland. Int J Epidemiol 1991;20:1010-7. [Abstract/Free Full Text]
26. Laakso M, Reunanen A, Klaukka T, Aromaa A, Maatela J, Pyorala K. Changes in the prevalence and incidence of diabetes mellitus in Finnish adults, 1970-87. Am J Epidemiol 1991;133:850-7. [Abstract/Free Full Text]
27. Salonen JT, Salonen R, Seppanen K, Kantola M, Parviainen M, Alfthan G, et al. Relationship of serum selenium and antioxidants to plasma lipoproteins, platelet aggregability and prevalent ischaemic heart disease in eastern Finnish men. Atherosclerosis 1988;70:155-60. [Medline]
28. Gey KF. Prospects for the prevention of free radical disease, regarding cancer and cardiovascular disease. Br Med Bull 1993;49:679-99. [Abstract/Free Full Text]
29. Subcommittee on the Tenth Edition of the RDAs, Food and Nutrition Board, Commission on Life Sciences, National Research Council. Recommended dietary allowances. 10th ed. Washington, DC: National Academy Press, 1989:103.
30. Golay A, Felber JP. Evolution from obesity to diabetes. Diabete Metab 1994;20:3-14. [Medline]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Liu, S., Lee, I-M., Song, Y., Van Denburgh, M., Cook, N. R., Manson, J. E., Buring, J. E. (2006). Vitamin E and Risk of Type 2 Diabetes in the Women's Health Study Randomized Controlled Trial.. Diabetes 55: 2856-2862 [Abstract] [Full text]  
• Czernichow, S., Couthouis, A., Bertrais, S., Vergnaud, A.-C., Dauchet, L., Galan, P., Hercberg, S. (2006). Antioxidant supplementation does not affect fasting plasma glucose in the Supplementation with Antioxidant Vitamins and Minerals (SU.VI.MAX) study in France: association with dietary intake and plasma concentrations.. Am. J. Clin. Nutr. 84: 395-399 [Abstract] [Full text]  
• Hartemink, N., Boshuizen, H. C., Nagelkerke, N. J. D., Jacobs, M. A. M., van Houwelingen, H. C. (2006). Combining Risk Estimates from Observational Studies with Different Exposure Cutpoints: A Meta-analysis on Body Mass Index and Diabetes Type 2. Am J Epidemiol 163: 1042-1052 [Abstract] [Full text]  
• Song, Y., Manson, J. E., Buring, J. E., Sesso, H. D., Liu, S. (2005). Associations of Dietary Flavonoids with Risk of Type 2 Diabetes, and Markers of Insulin Resistance and Systemic Inflammation in Women: A Prospective Study and Cross-Sectional Analysis. J. Am. Coll. Nutr. 24: 376-384 [Abstract] [Full text]  
• Pussinen, P. J., Nyyssonen, K., Alfthan, G., Salonen, R., Laukkanen, J. A., Salonen, J. T. (2005). Serum Antibody Levels to Actinobacillus actinomycetemcomitans Predict the Risk for Coronary Heart Disease. Arterioscler. Thromb. Vasc. Bio. 25: 833-838 [Abstract] [Full text]  
• Montonen, J., Knekt, P., Harkanen, T., Jarvinen, R., Heliovaara, M., Aromaa, A., Reunanen, A. (2005). Dietary Patterns and the Incidence of Type 2 Diabetes. Am J Epidemiol 161: 219-227 [Abstract] [Full text]  
• Karpansalo, M, Kauhanen, J, Lakka, T A, Manninen, P, Kaplan, G A, Salonen, J T (2005). Depression and early retirement: prospective population based study in middle aged men. J. Epidemiol. Community Health 59: 70-74 [Abstract] [Full text]  
• Asbun, J., Manso, A. M., Villarreal, F. J. (2005). Profibrotic influence of high glucose concentration on cardiac fibroblast functions: effects of losartan and vitamin E. Am. J. Physiol. Heart Circ. Physiol. 288: H227-H234 [Abstract] [Full text]  
• Tolmunen, T., Hintikka, J., Voutilainen, S., Ruusunen, A., Alfthan, G., Nyyssonen, K., Viinamaki, H., Kaplan, G. A, Salonen, J. T (2004). Association between depressive symptoms and serum concentrations of homocysteine in men: a population study. Am. J. Clin. Nutr. 80: 1574-1578 [Abstract] [Full text]  
• Voutilainen, S., Virtanen, J. K, Rissanen, T. H, Alfthan, G., Laukkanen, J., Nyyssonen, K., Mursu, J., Valkonen, V.-P., Tuomainen, T.-P., Kaplan, G. A, Salonen, J. T (2004). Serum folate and homocysteine and the incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. Am. J. Clin. Nutr. 80: 317-323 [Abstract] [Full text]  
• Montonen, J., Knekt, P., Jarvinen, R., Reunanen, A. (2004). Dietary Antioxidant Intake and Risk of Type 2 Diabetes. Diabetes Care 27: 362-366 [Abstract] [Full text]  
• Ford, E. S., Mokdad, A. H., Giles, W. H., Brown, D. W. (2003). The Metabolic Syndrome and Antioxidant Concentrations: Findings From the Third National Health and Nutrition Examination Survey. Diabetes 52: 2346-2352 [Abstract] [Full text]  
• Ylonen, K., Alfthan, G., Groop, L., Saloranta, C., Aro, A., Virtanen, S. M, the Botnia Research Group, (2003). Dietary intakes and plasma concentrations of carotenoids and tocopherols in relation to glucose metabolism in subjects at high risk of type 2 diabetes: the Botnia Dietary Study. Am. J. Clin. Nutr. 77: 1434-1441 [Abstract] [Full text]  
• Dhein, S., Kabat, A., Olbrich, A., Rosen, P., Schroder, H., Mohr, F.-W. (2003). Effect of Chronic Treatment with Vitamin E on Endothelial Dysfunction in a Type I in Vivo Diabetes Mellitus Model and in Vitro. J. Pharmacol. Exp. Ther. 305: 114-122 [Abstract] [Full text]  
• Montonen, J., Knekt, P., Jarvinen, R., Aromaa, A., Reunanen, A. (2003). Whole-grain and fiber intake and the incidence of type 2 diabetes. Am. J. Clin. Nutr. 77: 622-629 [Abstract] [Full text]  
• Salonen, R. M., Nyyssonen, K., Kaikkonen, J., Porkkala-Sarataho, E., Voutilainen, S., Rissanen, T. H., Tuomainen, T.-P., Valkonen, V.-P., Ristonmaa, U., Lakka, H.-M., Vanharanta, M., Salonen, J. T., Poulsen, H. E. (2003). Six-Year Effect of Combined Vitamin C and E Supplementation on Atherosclerotic Progression: The Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study. Circulation 107: 947-953 [Abstract] [Full text]  
• Mayer-Davis, E. J., Costacou, T., King, I., Zaccaro, D. J., Bell, R. A. (2002). Plasma and Dietary Vitamin E in Relation to Incidence of Type 2 Diabetes: The Insulin Resistance and Atherosclerosis Study (IRAS). Diabetes Care 25: 2172-2177 [Abstract] [Full text]  
• Lonn, E., Yusuf, S., Hoogwerf, B., Pogue, J., Yi, Q., Zinman, B., Bosch, J., Dagenais, G., Mann, J. F.E., Gerstein, H. C. (2002). Effects of Vitamin E on Cardiovascular and Microvascular Outcomes in High-Risk Patients With Diabetes: Results of the HOPE Study and MICRO-HOPE Substudy. Diabetes Care 25: 1919-1927 [Abstract] [Full text]  
• Evans, J. L., Goldfine, I. D., Maddux, B. A., Grodsky, G. M. (2002). Oxidative Stress and Stress-Activated Signaling Pathways: A Unifying Hypothesis of Type 2 Diabetes. Endocr. Rev. 23: 599-622 [Abstract] [Full text]  
• Fung, T. T, Hu, F. B, Pereira, M. A, Liu, S., Stampfer, M. J, Colditz, G. A, Willett, W. C (2002). Whole-grain intake and the risk of type 2 diabetes: a prospective study in men. Am. J. Clin. Nutr. 76: 535-540 [Abstract] [Full text]  
• Pereira, M. A, Jacobs, D. R Jr, Pins, J. J, Raatz, S. K, Gross, M. D, Slavin, J. L, Seaquist, E. R (2002). Effect of whole grains on insulin sensitivity in overweight hyperinsulinemic adults. Am. J. Clin. Nutr. 75: 848-855 [Abstract] [Full text]  
• Franz, M. J., Bantle, J. P., Beebe, C. A., Brunzell, J. D., Chiasson, J.-L., Garg, A., Holzmeister, L. A., Hoogwerf, B., Mayer-Davis, E., Mooradian, A. D., Purnell, J. Q., Wheeler, M. (2002). Evidence-Based Nutrition Principles and Recommendations for the Treatment and Prevention of Diabetes and Related Complications. Diabetes Care 25: 148-198 [Full text]  
• O'Connell, B. S. (2001). Select Vitamins and Minerals in the Management of Diabetes. Diabetes Spectr. 14: 133-148 [Abstract] [Full text]  
• Ford, E. S. (2001). Vitamin Supplement Use and Diabetes Mellitus Incidence among Adults in the United States. Am J Epidemiol 153: 892-897 [Abstract] [Full text]  
• Facchini, F. S, Humphreys, M. H, DoNascimento, C. A, Abbasi, F., Reaven, G. M (2000). Relation between insulin resistance and plasma concentrations of lipid hydroperoxides, carotenoids, and tocopherols. Am. J. Clin. Nutr. 72: 776-779 [Abstract] [Full text]  
• Porkkala-Sarataho, E., Salonen, J. T., Nyyssonen, K., Kaikkonen, J., Salonen, R., Ristonmaa, U., Diczfalusy, U., Brigelius-Flohe, R., Loft, S., Poulsen, H. E. (2000). Long-Term Effects of Vitamin E, Vitamin C, and Combined Supplementation on Urinary 7-Hydro-8-Oxo-2'-Deoxyguanosine, Serum Cholesterol Oxidation Products, and Oxidation Resistance of Lipids in Nondepleted Men. Arterioscler. Thromb. Vasc. Bio. 20: 2087-2093 [Abstract] [Full text]  
• Salonen, J. T, Tuomainen, T.-P., Kontula, K. (2000). Role of C282Y mutation in haemochromatosis gene in development of type 2 diabetes in healthy men: prospective cohort study. BMJ 320: 1706-1707 [Full text]  
• Boeing, H., Weisgerber, U. M, Jeckel, A., Rose, H.-J., Kroke, A. (2000). Association between glycated hemoglobin and diet and other lifestyle factors in a nondiabetic population: cross-sectional evaluation of data from the Potsdam cohort of the European Prospective Investigation into Cancer and Nutrition Study. Am. J. Clin. Nutr. 71: 1115-1122 [Abstract] [Full text]  
• Connolly, V, Unwin, N, Sherriff, P, Bilous, R, Kelly, W (2000). Diabetes prevalence and socioeconomic status: a population based study showing increased prevalence of type 2 diabetes mellitus in deprived areas. J. Epidemiol. Community Health 54: 173-177 [Abstract] [Full text]  
• Tuomainen, T.-P., Kontula, K., Nyyssonen, K., Lakka, T. A., Helio, T., Salonen, J. T. (1999). Increased Risk of Acute Myocardial Infarction in Carriers of the Hemochromatosis Gene Cys282Tyr Mutation : A Prospective Cohort Study in Men in Eastern Finland. Circulation 100: 1274-1279 [Abstract] [Full text]  
• Voutilainen, S., Morrow, J. D., Roberts, L. J. II, Alfthan, G., Alho, H., Nyyssonen, K., Salonen, J. T. (1999). Enhanced In Vivo Lipid Peroxidation at Elevated Plasma Total Homocysteine Levels. Arterioscler. Thromb. Vasc. Bio. 19: 1263-1266 [Abstract] [Full text]  
• Tirosh, A., Potashnik, R., Bashan, N., Rudich, A. (1999). Oxidative Stress Disrupts Insulin-induced Cellular Redistribution of Insulin Receptor Substrate-1 and Phosphatidylinositol 3-Kinase in 3T3-L1 Adipocytes. A PUTATIVE CELLULAR MECHANISM FOR IMPAIRED PROTEIN KINASE B ACTIVATION AND GLUT4 TRANSLOCATION. J. Biol. Chem. 274: 10595-10602 [Abstract] [Full text]  
• Salonen, J. T, Tuomainen, T.-P., Nyyssönen, K., Lakka, H.-M., Punnonen, K. (1998). Relation between iron stores and non-insulin dependent diabetes in men: case-control study. BMJ 317: 727-730 [Full text]