Carotenoids and the development of type 2 diabetes
Potential mechanisms for antioxidants and reduction in risk for type 2 diabetes
One major action of antioxidants in cells is to prevent damage resulting from the action of reactive oxygen species. Reactive oxygen species include hydrogen peroxide (H2O2), hypochlorous acid (HOCl), and free radicals such as the hydroxyl radical (OH) and the superoxide anion (O2-). Reactive oxygen species are highly reactive chemicals that attack molecules by capturing electrons and thus modifying chemical structures. Antioxidative effects have been observed for a number of plant compounds, among them polyphenols, vitamin C, tocopherols, and carotenoids. Carotenoids are a widely distributed group of naturally occurring pigments. Carotenoids with molecules containing oxygen, such as lutein and zeaxanthin, are known as xanthophylls. The unoxidized carotenoids such as alpha-carotene, beta-carotene and lycopene are known as carotenes. Although major sources of carotenoids in the diet are plant foods, carotenoids are used extensively as safe, natural colorants for food and also in animal feeding.
The development of type 2 diabetes is associated with a combination of pancreatic beta-cell dysfunction and insulin resistance. Normal betacells can compensate for insulin resistance by increasing insulin secretion or beta-cell mass. However, insufficient compensation leads to the onset of glucose intolerance. Once hyperglycemia becomes apparent beta-cell function gradually deteriorates and insulin resistance aggravates. Under conditions of chronic hyperglycemia and elevated free fatty acids oxidative stress is provoked in pancreatic beta-cells and the mechanisms for glucotoxicity and lipidoxicity seem, at least in part, to be mediated by overloads of reactive oxygen species1, 2. Beta-cells might be rather vulnerable to oxidative stress due to their relatively low expression of antioxidant enzymes such as catalase and glutathione peroxidase3. Thus, it is likely that oxidative stress is involved in beta-cell deterioration in type 2 diabetes. This is further supported by animal studies which suggest potential usefulness of antioxidants for diabetes prevention1, 2. The role of carotenoids in the development of type 2 diabetes has therefore received considerable scientific interest in recent years.
Carotenoid intake and risk for type 2 diabetes in observational studies
Montonen et al.4 observed a significant lower diabetes risk among participants with high total carotenoid intake in the Finnish Mobile Clinic Health Examination Survey. Among single carotenoids, beta-cryptoxanthin intake was significantly associated with a reduced risk of type 2 diabetes in this prospective cohort study. However, no adjustments for other dietary characteristics were made in this study. In the Women’s Health Study, there was no association between dietary intake of lycopene or lycopenecontaining foods and the risk of incident type 2 diabetes5.
Carotenoid concentrations and risk for type 2 diabetes in observational studies
Plasma beta-carotene levels were not significantly associated with the incidence of diabetes in a study by Reunanen et al. after adjustment for risk factors6. In the Women’s Health Study, there was no prospective association between baseline plasma carotenoids (total, lycopene, alpha-carotene, beta-carotene, beta-cryptoxanthin and lutein/zeaxanthin) and the risk of type 2 diabetes7. In contrast, serum carotenoids were associated with lower diabetes risk among nonsmokers in the CARDIA Study8. This association was evident for total carotenoids and beta-carotene, while alpha-carotene, lutein/zeaxanthin and lycopene were not significantly associated with risk. Interestingly, no association between carotenoids and diabetes was observed among smokers, suggesting an effect modification by smoking.
Carotenoid supplementation and risk for type 2 diabetes in intervention studies
The efficacy of beta-carotene supplements for primary prevention of type 2 diabetes among apparently healthy men was tested in the Physician’s Health Study, a randomized placebocontrolled trial9. Over 12 years of follow-up, there was no significant difference in diabetes incidence between the intervention group (receiving 50 mg on alternate days) and the placebo group. In the SU.VI.MAX trial, participants in the intervention group received 120 mg vitamin C, 30 mg vitamin E, 6 mg beta-carotene, 100 μg Se, and 20 mg Zn daily. There was no difference in glucose levels after follow-up between the intervention group and the placebo group10.
Although study findings are generally conflicting, the results of the Cardia Study suggest that a beneficial effect of beta-carotene may be present among non-smokers. However, most participants in the Physician’s Health Study randomized trial did not smoke at the time of the study9. The lack of effect observed in the trial speaks against a role of beta-carotene in the prevention of diabetes. There is also little evidence to suggest that other carotenoids may reduce the risk of type 2 diabetes. Although carotenoids are naturally occurring in plant foods, particularly fruits and vegetables, beta-carotene is also extensively used in many countries as a colorant and for fortification in food processing and animal feeding. Supplements are an additional source of beta-carotene, and blood levels may therefore be not a good indicator of fruit and vegetable intake11. Although studies of blood concentrations of beta-carotene consider the hypothesized antioxidative compound, the results of these studies cannot be interpreted as a lack of effect of fruit and vegetable intake. The same applies to the prevention trial which tested beta-carotene but not fruits and vegetables. These studies therefore leave the question as to whether fruit and vegetables consumption are important in diabetes prevention unanswered. Because fruit and vegetables contain not only carotenoids, but also fibers, polyphenols, vitamin C and other bioactive compounds, it seems straight forward to assume beneficial effects. Unfortunately, there is also only limited evidence supporting a role of fruit and vegetable consumption in diabetes prevention.
- 1Ceriello A, Motz E. Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler Thromb Vasc Biol. May 2004;24(5):816-823.
- Kaneto H, Nakatani Y, Kawamori D, et al. Role of oxidative stress, endoplasmic reticulum stress, and c-Jun N-terminal kinase in pancreatic beta-cell dysfunc tion and insulin resistance. Int J Biochem Cell Biol. Aug 2005;37(8):1595-1608.
- Tiedge M, Lortz S, Drinkgern J, Lenzen S. Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells. Diabetes. Nov 1997;46(11):1733-1742.
- Montonen J, Knekt P, Jarvinen R, Reunanen A. Dietary antioxidant intake and risk of type 2 diabetes. Diabetes Care. Feb 2004;27(2):362-366.
- Wang L, Liu S, Manson JE, Gaziano JM, Buring JE, Sesso HD. The consumption of lycopene and tomato-based food products is not associated with the risk of type 2 diabetes in women. J Nutr. Mar 2006;136(3):620-625.
- Reunanen A, Knekt P, Aaran RK, Aromaa A. Serum antioxidants and risk of noninsulin dependent diabetes mellitus. Eur J Clin Nutr. Feb 1998;52(2):89-93.
- Wang L, Liu S, Pradhan AD, et al. Plasma lycopene, other carotenoids, and the risk of type 2 diabetes in women. Am J Epidemiol. Sep 15 2006;164(6):576-585.
- Hozawa A, Jacobs DR, Jr., Steffes MW, Gross MD, Steffen LM, Lee DH.Associations of serum carotenoid concentrations with the development of diabetes and with insulin concentration: interaction with smoking: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Am J Epidemiol. May 15 2006;163(10):929-937.
- Liu S, Ajani U, Chae C, Hennekens C, Buring JE, Manson JE. Long-term betacarotene supplementation and risk of type 2 diabetes mellitus: a randomized controlled trial. Jama. Sep 15 1999;282(11):1073-1075.
- Czernichow S, Couthouis A, Bertrais S, et al. 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. Aug 2006;84(2):395-399.
- Al-Delaimy WK, Ferrari P, Slimani N, et al. Plasma carotenoids as biomarkers of intake of fruits and vegetables: individual-level correlations in the European Prospective Investigation into Cancer and Nutrition (EPIC). Eur J Clin Nutr. Dec 2005;59(12):1387-1396.