It has been recognized that homocysteine (Hcy) degradation needs B vitamins to serve as a prerequisite substrate donor (folate) or essential coenzymes (vitamin B6 and B12), and increase of Hcy has emerged as a risk factor for type II diabetes due to its association with insulin resistance. Although studies from some other countries reported that dietary folate intake was inversely related to self-reported incident diabetes, none have examined the association of dietary folate and other B vitamin intake with diabetes risk among the US general population.

Addressing an Unmet Need

For a study published in Diabetes Cares, we and our colleagues sought to prospectively investigate intakes of folate and vitamins B6 and B12 in relation to diabetes risk in a large US cohort of African-American and Caucasian young adults with 30 years of follow-up, using data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study. The study included 4,704 CARDIA apparently healthy adults aged 18-30 at baseline (1985-86) who were followed until 2015-2016. Diabetes incidence was ascertained by clinical examinations and anti-diabetic medication records. The cumulative average intakes of folate, vitamin B6, and vitamin B12 were used, based on multiple dietary assessments conducted during the follow-up.

Results from this large longitudinal cohort study demonstrated that consumption of folate (including both dietary and supplemental resources; Table), but not vitamins B6 and B12, in young adulthood was inversely associated with incident diabetes in midlife. Notably, the null associations of vitamin B6 and B12 intake with diabetes risk might be explained by most of the participants having had adequate intakes of vitamin B6 and B12, unlike their intake of folate. Therefore, further intakes of these two B vitamins may not result in additional benefit with respect to diabetes development. Consistently, we found that higher folate intake was significantly related to lower blood levels of Hcy, insulin, and C-reactive protein, suggesting that the observed inverse association between folate intake and diabetes risk may be, at least in part, explained by mechanisms related to Hcy level, insulin sensitivity, and systemic inflammation.

Examining the Implications

The novel findings from this longitudinal study suggest that adequate intake of folate in young adulthood reduces the likelihood of developing diabetes later in life among the general US adult population. When clinicians see patients who are at high risk of diabetes (eg, family history of diabetes or increased Hcy and/or glucose levels), they should ensure that B vitamin status is optimal and encourage these patients to add foods rich in B vitamins in their diet as needed.

Although the possible effects of other lifestyle risk factors and diet quality were controlled in the study, any potentially residual confounders cannot be ruled out. Additionally, the B vitamin intakes in the study included both dietary and supplemental resources, and high B vitamin consumption may indicate a marker of healthy dietary pattern, suggesting that other nutrients in B vitamin-rich foods may also contribute to the observed association. Moreover, the results were based on the healthy cohort of African-American and Caucasian young adults in the US. Thus, the generalizability to the population with or at increased risk for chronic diseases or in other races was limited. Further research is warranted to establish the cause-and-effect relationship between folate intake and diabetes.

References

Zhu J, Chen C, Lu L,Yang K, Reis J,He K. Intakes of Folate, Vitamin B6, and Vitamin B12 in Relation to Diabetes Incidence among American Young Adults: A 30-year Follow-up  Study. Diabetes Care. 2020;43(10):2426-2434.
https://care.diabetesjournals.org/content/43/10/2426

Tsai MY, Loria CM, Cao J, Kim Y, Siscovick DS, Schreiner PJ, Hanson NQ. Polygenic association with total homocysteine in the post-folic acid fortification era: the CARDIA study. Mol Genet Metab 2009;98(1-2):181-186.

Looker HC, Fagot-Campagna A, Gunter EW, Pfeiffer CM, Sievers ML, Bennett PH, Nelson RG, Hanson RL, Knowler WC. Homocysteine and vitamin B(12) concentrations and mortality rates in type 2 diabetes. Diabetes Metab Res Rev 2007;23(3):193-201.

Huang T, Ren J, Huang J, Li D. Association of homocysteine with type 2 diabetes: a meta-analysis implementing Mendelian randomization approach. BMC Genomics 2013;14:867.

Hong SM, Woo HW, Kim MK, Kim SY, Lee YH, Shin DH, Shin MH, Chun BY, Choi BY. A prospective association between dietary folate intake and type 2 diabetes risk among Korean adults aged 40 years or older: the Korean Multi-Rural Communities Cohort (MRCohort) Study. Br J Nutr 2017;118(12):1078-1088

Eshak ES, Iso H, Muraki I, Tamakoshi A. Among the water-soluble vitamins, dietary intakes of vitamins C, B2 and folate are associated with the reduced risk of diabetes in Japanese women but not men. Br J Nutr 2019;121(12):1357-1364