Folate helps reduce the risk for development of insulin resistance

Introduction

Folate is a water-soluble B vitamin. Folate is also known as folic acid and vitamin B9. 12 Folate is

an essential micronutrient because the body cannot make its’ own supply. Folate can come from diet and

diet alone. Folate supplements are available over-the-counter, but it is also naturally occurring in many

foods. Kale, spinach, avocado, beets, and liver contain the highest amount of folate. 4 Folate is also added

to processed grains. 5 No side effects from high folate have been reported, but its recommended to have at

least 0.4 mg of folate per day for the average adult. 9 Your body contains 10 to 30 mg of folate at a time

and half of that is usually stored in the liver. 9 Folate has many functions in the body that make it

important, but some of the most recognized functions are making DNA, RNA and metabolizing amino

acids for cell division. Not as recognized, folate and other B vitamins, have been shown to lower

homocysteine levels. 1 Homocysteine is an amino acid commonly found in the blood. 10 Homocysteine

comes from consuming meat. 10 High levels of homocysteine are associated with increased risk of heart

disease and heart related issues. 5 Usually when high levels of homocysteine are discovered, it is

accompanied by low levels of certain B vitamins. 11 Folate lowers homocysteine levels by recycling it into

methionine. 1 High levels of homocysteine have also been associated with high glucose and insulin

resistance. 1 If one were to lower homocysteine levels with a healthy amount of folate, would one also

lower risk of insulin resistance? With an increase in folate, there is a correlation of decreased risk for

insulin resistance. A high intake of folate is associated with a decreased risk for insulin resistance. In

addition, low intake of folate is associated with an increased risk for insulin resistance.

Methods

To collect data and research, online sources were the most utilized. Databases with peer-reviewed

articles were the main sources of the research found. Websites like UNF library and google scholar

contributed to the articles used. Terms such as, “folate” and “insulin resistance” were used frequently
throughout the database search. All types of studies were found and used. The majority of the studies

were clinical trials. The first two studies mentioned were performed as clinical trials. These also provide

the most evidence of a correlation between folate and lack of insulin resistance. The third study

mentioned is an animal study. While not as strong of a study due to it being an animal based study, this

study also provided a correlation between folate and insulin resistance, but instead suggest low folate

causes insulin resistance. Animal studies tend to be the least reliable, but still contain very useful

information for future studies. The fourth study mention was a clinical trial. Unlike the other studies, the

results of this study were an increase in insulin resistance with increased folate. This study had to do with

mother and offspring, not an individual like the other studies, so that must be taken into consideration.

Other clinical trials, case control, longitudinal, and cross-sectional studies have been evaluated and added

to the paper for additional support.

Studies

The first clinical trial evaluated the relationship between folate and B12 supplementation with

decreasing homocysteine levels, as well as whether homocysteine levels effected insulin resistance.1

Several case-control studies before this one has shown the relationship between homocysteine levels and

insulin levels, as well as few others show the correlation between insulin levels and insulin resistance. 5-12

The aim of this study became to further study this relationship by testing homocysteine levels after

treatment with folate and B12. 1 In addition, they tested if decreased homocysteine levels decrease insulin

resistance. 1 The clinical trial was a double-blind, parallel, identical placebo, randomized study. 1 They

needed patients with metabolic syndrome and hyperinsulinemia. 1 50 patients, adult men and woman,

were enrolled and preformed the 2-month study. 1 The patients were divided into two groups. 1 Both

groups were treated with diet and a placebo pill for the two months, but in the second month, group 2

unknowingly starting taking folate and B12 in place of the placebo pill. 1 The patients received 5 mg of

folic acid and 500 um of B12, per day. 1 The study included B12 because previous published data suggested

it was more effective than folate alone in decreasing homocysteine levels. 7 Every 14 days the patients
were evaluated by a dietician and at the end of each month, they were evaluated by the Metabolic Unit. 1

Throughout, they measured body weight, BMI, systolic/diastolic pressure, fasting glucose levels, fasting

insulin, HOMA, and fasting triglycerides. 1 HOMA levels indicate the level insulin resistance in the body.
1
The results showed a 28% decrease in homocysteine levels, a 26% decrease in insulin levels, and a 27%

decrease in HOMA levels in group 2. 1 Not much change was indicated in group 1 from the first to second

month. 1 The trial was also able to indicate that, “homocysteine levels were positively correlated with

insulin, HOMA, and triglycerides.” 1 These results indicate a true hypothesis, and more evidence folate

(with B12) improve insulin resistance.

The second clinical trial was very similar to the first in that they were both measuring insulin

resistance with folate treatment. Their focus subjects were nondiabetic, nonobese overweight adults. 2 6

patients between ages 29-61 enrolled for the 3-month study. 2 The purpose of this trial was to test effects

of insulin levels and some inflammatory markers after the dietary supplementation of folate. 2 The

subjects were put on a “modest hypocaloric” diet and randomly received either a placebo or folate pill. 2

These patients received 2.5 mg of folic acid, which is half the amount that was assigned to the patients in

the first clinical study. 1-2 BMI, fat mass, systolic/diastolic pressure, fasting glucose, fasting insulin,

HOMA index, cholesterols, and triglycerides were measured at the beginning and end of the study period.
2
The results of the second clinical study also showed a decrease in insulin levels and HOMA index in the

folate-treated group. 2 The study concluded the reduction of these levels indicate a decrease in insulin

resistance. 2 They also believe folate supplementation reduces inflammatory markers circulating in the

body. 2

Folate may be important enough for maintaining your body’s insulin levels, that a deficiency in it could

lead to insulin resistance. This was investigated in my third article, an animal study on folate deficiency. 3

They were seeking to connect the role of folate deficiency with oxidative stress, high blood pressure, and

insulin resistance. 3 For this study they specifically wanted to use spontaneously hypertensive rats because

they easily compare with the characteristics of metabolic syndrome. 3 The SHR are the most widely
studied animal for hypertension model studies. 3 The rats are prone to a disturbance in lipid and glucose

metabolism when fed a high fructose diet. 3 The SHR weren’t necessarily fed that high fructose diet

during this experiment, but they were all aloud free access to their food and water during the duration of

the experiment. 3 The rats were broken into two groups, folate-deficient diet rats and the control diet rats.
3
The folate-deficient rats were fed less than 0.1 mg of folate per kg of food, while the control group was

fed 2 mg of folate per kg of food. 3 This diet lasted 4-weeks. 3 Many of the same measurements were

evaluated like they were in the previous studies, insulin levels, glucose levels, folate levels, homocysteine

levels, body weight, triglyceride levels, etc. 3 The results indicate a definite reduction in overall folate

levels. 3 This also came with an increase in homocysteine levels. 3 Increased blood pressure, and increased

liver weight. 3 Ectopic fat accumulation in the liver is a known determinate of insulin resistance. 3

Strangely enough, the folate-deficient rats had an increase in glucose and insulin levels after glucose

loading. 3 This glucose loading and lack of metabolism should indicate a glucose intolerance which as is a

known determinate of insulin resistance. 3 Their conclusion was that the SHR model is susceptible to

glucose intolerance, fatty liver, insulin resistance, high BP, and oxidative tissue damage with a low-folate

diet. 3

The fourth study evaluated insulin resistance in children. India is home to the largest number of diabetic

patients in the world. 4 They have determined that low birth rates in India also predict insulin resistance in

children. 4 They hypothesize that B12 and folate deficiency in mothers during pregnancy predicts this

greater chance for insulin resistance in her offspring. 4 The study starts with non-pregnant mothers living

in 6 different villages near Pune, India. 4 Woman were given iron (60 mg per day) and folate (5 mg per

day) tablets during pregnancy. 4 Once the child was born, it received a detailed anthropometry

measurement, and continued to have an updated one every 6 months. 4 Finally, at the age of 6, they were

measured for body composition, glucose intolerance, insulin resistance, blood pressure, B12, lipids, and

anthropometry. 4 In their analysis, they included the results of the maternal pre-pregnant size, maternal

macronutrient intake, maternal micronutrient intake, newborn size, and the 6-year body composition. 4
The mother were between the ages of 19-23, they had low pre-pregnant weight, and were on the shorter

side, but interestingly they had a high body fat percentage. 4 The results of insulin resistance with folate

proved much different in this study than in the previous studies mentioned. 1-4 The more folate a mother

would consume, the higher her risk for producing an offspring that develops insulin resistance. 4

Oppositely, the more B12 a mother would consume, the lower her risks are for producing an offspring that

develops insulin resistance. 4 The study concluded that mother with the highest folate status and lowest

B12 status had the most insulin resistance children. 4 More studies need to be conducted to conclude why

these levels of high folate and low B12 predict insulin resistance offspring. In addition, it would be helpful

to have a comparison study with mother who receive high folate and high B12 to determine if the high

folate, or lack of B12 is the issue.

Conclusion

By increasing the rate of recycling homocysteine to methionine, homocysteine levels lower with the help

of folate. 1 Indirectly this negatively affects insulin resistance. Most of the studies today indicate that is

correct and with increase folate, one can reduce the risk for developing insulin resistance. Not all have

this conclusion and more research needs to be done. There is lack of information on if folate has a direct

correlation on insulin resistance. The first two studies conclude increased folate did reduce insulin

resistance. The third study backed up the first two by showing how a lack of folate can create insulin

resistance. The fourth study did not indicate a reduce in risk of insulin resistance, but in fact an increase in

risk of insulin resistance with higher folate intake. This study different from the others in that it involved

a mother and child, not just an individual. It also said the most insulin resistance children were that of

mother who not only had high folate intake, but low B12. Follow up studies need to evaluate B12 and

folate’s relationship more closely. High B12 and high folate seem to work better together at lowering

insulin resistance in individual adults, especially ones with metabolic syndrome. The data concludes a

relationship with decreased homocysteine levels, decreased insulin resistance with an increase in folate

intake.
References

1. E. Setola, et al. Insulin resistance and endothelial function are improved after folate and vitamin B12

therapy in patients with metabolic syndrome: relationship between homocysteine levels and

hyperinsulinemia. European Journal of Endocrinology. 2004; 151:483-489.

2. 1. A. Solini, et al. Effect of short-term folic acid supplementation on insulin sensitivity and

inflammatory markers in overweight subjects. International Journal of Obesity. 2006; 30:1197-1202.

3. M. Pravnec, et al. Folate Deficiency Is Associated With Oxidative Stress, Increased Blood Pressure,

and Insulin Resistance in Spontaneously Hypertensive Rats. American Journal of Hypertension. 2013;

26:1.

4. C. S. Yajnik, et al. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in

the offspring: the Pune Maternal Nutrition Study. Diabetologia. 2007; 51:29-38.

5. Giltay EJ, et al. Insulin resistance is associated with elevated plasma total homocysteine levels in

healthy, non-obese subjects. Atherosclerosis. 1998; 139:197–198.

6. Emoto M, et al. Impact of insulin resistance and nephropathy on homocysteine in type 2 diabetes.

Diabetes Care. 2001; 24:533–538.

7. Fonseca VA, Fink LM & Kern PA. Insulin sensitivity and plasma homocysteine concentrations in non

diabetic obese and normal weight subjects. Atherosclerosis. 2003; 167: 105–109.

8. Oron-Herman M, Rosenthal T & Sela BA. Hyperhomocysteinemia as a component of syndrome X.

Metabolism. 2003; 52:1491–1495.

9. Schachter M, et al. Insulin resistance in patients with polycystic ovary syndrome is associated with

elevated plasma homocysteine. Human Reproduction. 2003; 18:721–727.

10 Laivuori H, et al. Plasma homocysteine levels elevated and inversely related to insulin sensitivity in

preeclampsia. Obstetrics and Gynecology. 1999; 93:489–493.

11. Meigs JB, et al. Fasting plasma homocysteine levels in the insulin resistance syndrome. Diabetes

Care. 2001; 24:1403–1410.

12. Gillum R. Distribution of serum total homocysteine and its association with diabetes and

cardiovascular risk factors of the insulin resistance syndrome in Mexican American men: the Third

National Health and Nutrition Examination Survey. Nutrition Journal. 2003; 2:6–13.