Circulating β-carotene levels are associated with type 2 diabetes, but the causal direction of this association is disputed. Recently, Ärnlöv et al
reported results of a longitudinal community-based study, Uppsala Longitudinal Study of Adult Men (ULSAM), assessing risk of serum and dietary β-carotene on the incidence of type 2 diabetes1
. The ULSAM study observed a strong association between increased baseline serum levels at age 50 years and reduced type 2 diabetes incidence during 27 years of follow up. For a 1 standard deviation (SD) increase in serum β-carotene, they observed a protective effect with an odds ratio (OR) of 0.68 (0.53–0.89). The authors also reported that a 1SD increase in β-carotene levels at age 50 years was associated with improved insulin sensitivity at aged 70 years, in non-diabetic individuals. Ärnlöv et al
argued that these associations support the importance of impaired antioxidant status for the development of insulin resistance and type 2 diabetes. They also suggested that antioxidants could be involved early in the pathological processes leading to diabetes and that it takes a long period of exposure to low antioxidant levels before metabolic factors are affected. These findings are consistent with some but not all observational epidemiological reports on the role of β-carotene levels in type 2 diabetes. Previous studies have provided evidence that β-carotene is not causally associated with type 2 diabetes2,3
. Notably three placebo controlled trials, the Physicians' Health Study4
, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study5
and the Women's Antioxidant Cardiovascular Study6
have all reported null effects of β-carotene supplementation on adverse metabolic effects including type 2 diabetes.
A caveat to observational epidemiological studies is that associations between risk factors and disease incidence many years later do not necessarily strengthen the case that the risk factor is causal. Disease processes can begin many years before disease diagnosis, and adverse metabolic effects have been reported as early as the first decade of life7
. Confounding factors may also result in a misleading association between anti-oxidant vitamins and adverse metabolic outcomes such as diabetes. We note that the association between β-carotene levels and type 2 diabetes in the ULSAM study was stronger before correcting for BMI, self reported physical activity and smoking status1
Genetics studies may be able to help dissect the causal directions of disease-biomarker associations. Genotypes cannot be influenced by disease status or any other trait, therefore making them much less likely to be confounded or the result of reverse causation than non-genetic factors. This principle of `Mendelian Randomization' (MR) has been applied before to indicate that C-Reactive Protein is unlikely to have a causal role in the development of various metabolic traits8
. More recently it has also been applied to examine the role between a range of inflammatory proteins and type 2 diabetes. Rafiq et al
found no evidence for a causal role of inflammatory or autoimmune factors on type 2 diabetes risk, including Interleukin 189
We have used a Mendelian Randomization approach to help dissect the causal role of β-carotene in type 2 diabetes risk (). To do this we used a) a common polymorphism (rs6564851) near the β-carotene 15,15'-Monooxygenase 1 (BCMO1) gene recently identified as strongly associated with circulating β-carotene levels; b) an estimate of the association between β-carotene levels and type 2 diabetes using two studies; c) an estimate of the expected effect of rs6564851 on type 2 diabetes risk given a) and b); and finally d) a large case control study to assess the observed effect of the β-carotene-associated SNP on type 2 diabetes.
Triangulation of β-carotene levels and risk of type 2 diabetes