Folate Supplementation Can Reduce Cardiac Events Associated with Diabetes

Folate Background:

Folic acid is sometimes referred to as vitamin B9. The terms folic acid and folate are sometimes used interchangeably but from a dietary perspective they are distinctly different. The term folate should be used to refer only to the bioactive forms of folic acid, namely dihydrofolate (DHF) and tetrahydrofolate (THF) and their derivatives.

Folic acid is a conjugated molecule consisting of a pteridine ring structure linked to para-aminobenzoic acid (PABA) that forms pteroic acid. Pteroic acid is then converted to folic acid through the N-esterification of glutamic acid to the carboxylic acid of the PABA portion of pteroic acid. This latter structure is the form of “folate” present in dietary supplements and when used to fortify manufactured food products.

Dietary folates (which are predominately the N⁵-methyl-THF form; 5-methyl-THF) are obtained primarily from yeasts and leafy vegetables as well as animal liver. Humans cannot synthesize PABA nor attach glutamate residues to pteroic acid, thus, requiring folic acid or folates (DHF or THF) in the diet.

Within cells (principally the liver where it is stored) the folic acid found in enriched food and in vitamin supplements is converted first to dihydrofolate (DHF) and then to tetrahydrofolate (THF) through the action of dihydrofolate reductase, DHFR. The level of DHFR activity in the human liver is relatively low such that high levels of folic acid intake (such as by megadosing vitamins) can lead to pathological consequences. Several studies have shown increased rates of colon cancer and prostate cancer associated with the intake of large doses of folic acid. However, the lack of folate in the diet, or the lack of folic acid supplementation, is directly correlated to neural tube defects occurring during fetal development.

The function of THF derivatives is to carry and transfer various forms of one carbon (1C) units during biosynthetic reactions. The one carbon units are either methyl, methylene, methenyl, formyl, or formimino groups.

Folate deficiency results in complications nearly identical to those described for vitamin B12 deficiency. The most pronounced effect of folate deficiency on cellular processes is upon DNA synthesis. This is due to an impairment in thymidine (dTMP) nucleotide synthesis which leads to cell cycle arrest in S-phase of rapidly proliferating cells, in particular hematopoietic cells. The inability to synthesize DNA during erythrocyte maturation leads to abnormally large erythrocytes termed macrocytic (megaloblastic) anemia.

Measurement of red blood cell size is termed mean corpuscular volume (MCV) and is determined in a typical blood test referred to as a complete blood count (CBC). Indeed, any time the MCV value is elevated above normal the initial suspected cause will be folate or B12 deficiency.

Both folate and B12 deficiencies are also associated with elevated levels of an amino acid, homocysteine, in the blood termed homocysteinemia. Homocysteinemia results in a significant increase in the risk for cardiovascular disease such as deep vein thrombosis (DVT) and atherosclerosis.

Diabetes and Cardiovascular Disease:

Type 2 diabetes is characterized by persistent hyperglycemia that results from reduced, or resistant, insulin effects. Type 2 diabetes rarely leads to ketoacidosis as is typical in type 1 diabetes. Type 2 diabetes generally manifests after age 40 and therefore has the obsolete name of adult onset-type diabetes. However, due to the rising rates of adolescent obesity in industrialized countries there is an increasing incidence of type 2 diabetes in pre- and postpubescent children. There is a strong correlation between obesity and the onset of type 2 diabetes with its associated insulin resistance. The metabolic syndrome (MetS) is a clustering of atherosclerotic cardiovascular disease risk factors, one of which involves insulin resistance characteristic in type 2 diabetes.

Several studies have suggested that folate supplementation could act as a modifiable factor for the prevention of diabetes. A new prospective cohort study, published in the journal, Nutrition Research, assessed US adults with diabetes, prediabetes, or insulin resistance to examine the association of daily folate consumption with all-cause, cardiovascular disease (CVD) and cancer mortality:

Daily folate consumption is associated with reduced all-cause and cardiovascular disease mortality among US adults with diabetes, prediabetes, or insulin resistance

The results presented in this publication represent a subset of the data that is being continuously collected through the National Health and Nutrition Examination Survey (NHANES). The study results were obtained from NHANES III and 10 cycles of NHANES 1999-2018 involving 9266, 12,601, and 16,025 US adults with diabetes, prediabetes, and IR, respectively.

Study participants included adults with age ranges from under 40 to greater than 60, various levels of education, smokers and non-smokers, drinkers and non-drinkers, various activity levels, and several ethnic groups.

The cardiometabolic biomarkers analyzed in this study included fasting plasm glucose (FPG), glycated hemoglobin A1c (HbA1c), fasting plasma insulin (FPI), serum C-reactive protein (CRP), serum total cholesterol, serum high-density lipoprotein (HDL), serum low-density lipoprotein (LDL), serum triglyceride, systolic pressure, serum thyroxine, and serum tri- iodothyronine.

Daily folate consumption was calculated as the sum of daily dietary folate intake and daily folate supplements.

Among the study participants there were 3356 (1053 CVD deaths and 672 cancer deaths), 3796 (1117 CVD deaths and 854 cancer deaths), and 4340 (1286 CVD deaths and 928 cancer deaths) deaths among participants with type 2 diabetes, prediabetes, and insulin resistance, respectively.

The results of this study demonstrated a significant inverse association of daily folate consumption with all-cause and CVD mortality among all participants. Daily folate consumption was significantly and inversely associated with HbA1c, FPI, and insulin resistance in dose-response manners among all participants. Higher daily folate consumption was also significantly and dose-dependently associated with lower FPG and CRP among participants with diabetes or prediabetes. Increased daily folate consumption was significantly associated with increased total cholesterol and triglyceride levels among participants with insulin resistance, and with increased high-density lipoprotein (HDL) among participants with type 2 diabetes.

The authors point out that folate supplementation improves carbohydrate (glucose) metabolism and suppresses inflammation. Folate may indirectly contribute to glycemic control  by stimulating thyroid function since they found a positive relationship between folate consumption and thyroxine (thyroid hormone) levels. Although all of the underlying mechanisms by which folate is beneficial relative to this study design, it is known that folate exerts beneficial effects on digestive, neurological, and cardiovascular health, and these effects are likely to aid in the prevention of the complications of diabetes.