The present study demonstrated that vitamin D and omega-3 co-supplementation for eight weeks in women of reproductive age with pre-diabetes and hypovitaminosis have positive effects on fasting blood insulin, glucose and HDL-C levels, HOMA-B, waist circumference and weight. Research has shown that an increased fasting glucose in pre-diabetic individuals can lead to diabetes type 2 in the long term (35). Therefore, Vitamin D and omega-3 co-supplementation can be considered for preventing diabetes type 2 because of their positive effects on fasting blood glucose and insulin.
Various studies have shown that vitamin D has a role in the metabolism of carbohydrates (36)and fats(37–39). Several mechanisms have been proposed for this process. Vitamin D affects Parathyroid Hormone (PTH) secretion and its deficiency results in an increase in PTH. A rise in this hormone is associated with an increase in insulin resistance and a reduction in lipolysis(38).
This vitamin can activate the Insulin Receptor (INSR) synthesis gene by binding to the nuclear receptor, thus enhancing the synthesis of these receptors and increasing the presence of insulin-regulated glucose transporter type-4 (GLUT4) in the cell membrane (40). Vitamin D increases the expression of the peroxisome proliferator-activated receptor gamma (PPAR-γ) gene, which improves fatty acid metabolism and increases insulin sensitivity. These vitamin receptors are present in the pancreatic beta cells and the immune system. Therefore, vitamin D deficiency affects insulin secretion, peripheral responses to insulin, and immune system function, which can result in insulin resistance and other inflammatory processes contributing to glucose and fat metabolism disorders (40). Vitamin D modulates the function of the renin-angiotensin system by decreasing the renin gene expression and inhibiting angiotensin-1 receptors. The increased activity of this system causes insulin resistance, inflammation and hypertension (40).
A number of studies have suggested that high doses of vitamin D do not have beneficial effects on glycemic indices and other cardiovascular risk factors in pre-diabetic individuals (35, 41–43).
The findings of present study in the vitamin D group were similar to the results reported by Solids(35). Although a significant reduction was found in fasting blood glucose, total cholesterol and LDL-C levels, no statistically significant differences were observed in other lipids and insulin metabolism markers. Also, in a meta-analysis of ten clinical trials in persons with pre-diabetic, Poolsup et al. showed that vitamin D intake reduced fasting glucose significantly but did not affect insulin resistance(44).
Moreover, some studies have shown that unsaturated fatty acids are effective in a number of chronic diseases including cardiovascular diseases, type 2 diabetes, and the metabolic syndrome (45, 46).
Animal model studies reported the mechanism of effect of omega-3 on glycemic indices and serum lipids in three main areas: (1) Some adipokines such as adiponectin and leptin, stimulate AMP-activated protein kinase (AMPK) in the tissues. AMPK reduces lipogenesis and increases the oxidation of fatty acids. It stimulates glucose transport into the cell independent of insulin. Omega-3 can activate AMPK in white adipose tissues, muscles and the liver. (2) Omega-3 reduces glucose synthesis and lipogenesis in the liver. (3) Omega-3 increases anti-inflammatory synthesis, such as resolvin E1, resolvin D1 and protectin D1, thus reducing oxidative stress and the cell damage caused by them. Omega-3 with anti-inflammatory effects, increased insulin sensitivity and reduced adipocyte proliferation and hence reduces the body lipid content, thus resulting in decreased insulin and serum lipids (47).
Different results have been reported from clinical trials on omega-3 in pre-diabetic individuals. Some studies have reported beneficial effects for omega-3 in improving fasting glucose, insulin resistance, triglyceride levels, and waist circumference (48, 49). A number of studies have found that omega-3 has little or no effect on fat and glucose metabolism but has significant effects on triglyceride levels (47, 50).
In the present study, at the end of the intervention, the omega 3 group showed a significant improvement in glycemic indices and serum lipids compared to the beginning of the study. This disparity in results may be due to the differences in sample size (50), gender and age of the participants (48, 49) and doses administered (48, 50). Furthermore, a study have shown that omega-3 can activate vitamin D (51). Various studies have therefore been carried out on vitamin D and omega-3 co-supplementation on glycemic indices.
Jamilian et al. investigated the effects of the intake of 50,000 IU of vitamin D every two weeks and 1000 mg of omega-3 twice daily in women with gestational diabetes for six weeks. This co-supplementation was reported to have positive effects on glycemic control, triglyceride and VLDL-c level, but had no effects on other serum lipids (24). These results were consistent with the present findings in terms of the effects of vitamin D and omega-3 co-supplementation on fasting insulin and glucose, but inconsistent in terms of serum lipids, perhaps due to the differences in study participants. The sample studied by Jamilian included pregnant women with gestational diabetes while the sample in the present study consisted of women of reproductive age with pre-diabetes. Hormonal changes during pregnancy cause hyperlipidemia and increase insulin resistance, resulting the lipids to be used as an energy source in pregnant women, which it does not exist healthy non-pregnant women (7). Therefore, vitamin D and omega-3 co-supplementation had more significant effect on glycemic status and serum lipids in pregnant women with gestational diabetes.
In line with the present findings, Gurol et al. also observed the synergistic effects of vitamin D and omega-3 co-supplementation in rats undergoing islet transplantation, the glycemic level decreased in the co-supplementation group (52).
Baidal et al investigated the effects of high doses of omega-3 (two 1-g capsules of omega-3, three times daily) and high doses of vitamin D (25,000 IU of vitamin D weekly) in a 14-year-old adolescent with diabetes type 1 (25). Fasting glucose was found to be lower in the first-year follow-up compared to the baseline, and the researchers suggested that this co-supplementation could be effective in beta cell function. The results were similar to findings of the present study.
Davis et al. also studied the effects of the daily intake of four to ten grams of fish oil and 2,000 IU of vitamin D daily on serum lipids in 45 men and women with subclinical arteriosclerosis over 18 months (53). They reported a reduction in cholesterol, triglyceride and LDL-C and an increase in HDL-C in the subjects. The difference between the results of this study and the present study might be due to the higher dose of omega-3 administered and the longer intervention period.
Effectiveness of This co-supplementation on glycemic control and lipid profiles was previously shown in patients with gestational diabetes, diabetes type 1, and atherosclerosis (24, 25, 53). To the best of our knowledge, the present study is the first on the effect of vitamin D and omega-3 co-supplementation on glycemic index and lipid profiles in pre-diabetic women. The results suggest that this co-supplementation can improve fasting serum glucose, insulin and HDL-C and beta cell function in reproductive-aged women with pre-diabetes and hypovitaminosis D.