Insulin Resistance & Association between Vitamin D & Magnesium
Dietary Magnesium Intake Level Modifies the Association Between Vitamin D and Insulin Resistance: A Large Cross-Sectional Analysis of American Adults
Insulin resistance (IR) refers to an efficiency decline in the performance of insulin to promote glucose uptake and utilization in tissues or cells. It can be caused by a variety of reasons and pushes the body to compensate by producing too much insulin to keep the blood sugar within a normal range. IR is a core component of metabolic syndrome and type 2 diabetes. It may precede other cardiometabolic risk factors, as mentioned in the study of Gong et al. Yin et al. also conducted a meta-analysis considering IR and the risk of thyroid cancer in 2018 and found that people with IR had a significantly greater chance of developing thyroid cancer. IR is also associated with the incidence of colorectal cancer and lung cancer. In 2021, the International Diabetes Federation published guidelines stating that 629 million people aged 20–79 years are expected to develop type 2 diabetes by 2045 all over the world, for which one of the main causes is IR. In summary, understanding the risk factors underlying the development of health care is significant for the health of the World’s people.
Vitamin D (Vit D) is a lipid-soluble vitamin whose main function is to maintain the balance between calcium metabolism and bone formation in the human body. Vit D is activated in the body to acquire the biological activity of a hormone, with 1, 25-bishydroxyvitamin D3 acting as its main active form. According to related studies, Vit D level may be a protective factor against the development of IR. However, this conclusion is considered controversial at present. A cross-sectional analysis by Schleu et al. found that lower Vit D levels were strongly associated with increased IR in obese women. Szymczak-Pajor and Śliwińska suggested that Vit D deficiency is one of the factors that accelerates the development of IR. In contrast, a randomized controlled trial by Gulseth et al. found that Vit D levels and IR were not correlated with one another, and similar findings were also reported by Margaret and Lansang. The reason for these variations may be that the adjustment strategies were not consistent across studies. Among them, we are particularly concerned about the absence of a certain factor in most of these studies: dietary magnesium intake.
Magnesium is the second most abundant divalent ion in cells following potassium ions, and it has been recognized as a cofactor in > 300 enzymatic reactions. It is essential for the modulation of blood pressure, insulin metabolism, and other physiological functions. Meanwhile, magnesium is closely related to Vit D synthesis, and previous studies have shown that magnesium is necessary for the movement and activation of Vit D in the blood. A randomized clinical trial published in 2018 by Dai et al. showed that magnesium optimizes Vit D status in the body with a bidirectional regulatory effect; in other words, magnesium can be optimized according to the body’s original Vit D level so that Vit D levels are maintained in the normal range. Further, all enzymes used for the metabolism of Vit D seem to require magnesium, which acts as a co-factor in the enzymatic reactions of the liver and kidneys. Magnesium intake alone or its interaction with Vit D intake may contribute to Vit D status. The enzymatic activation of 25-hydroxylase in the liver and 1α-hydroxylase in the kidneys is a process that requires magnesium. Magnesium is also needed to deactivate Vit D when levels are too high. Previous studies presented that concentrations of cytochrome P450 (CYP) enzymes are modified by magnesium level. Cytochrome P450 enzymes include not only the Vit D–activating enzymes [i.e., 25-hydroxylase (e.g., CYP2R1) and 1α-hydroxylase (i.e., CYP27B1)] but also Vit D–deactivating enzymes [i.e., 24-hydroxylase (i.e., CYP24A1 and CYP3A4)]. 25-Hydroxylase synthesizes 25 (OH)D from Vit D3 or Vit D2 in the liver, and then 1α-hydroxylase synthesizes active 1, 25 (OH) 2D from 25 (OH)D in the kidney. 24-Hydroxylase metabolizes both 25 (OH)D and 1, 25 (OH) 2D to inactive forms: 24, 25-dihydroxyVit D and 1, 24, 25-trihydroxyVit D, respectively. Finally, CYP3A4 degrades 24, 25-dihydroxyVit D and 1, 24, 25-trihydroxyVit D. Other studies have shown that Vit D is transported through the body in combination with a carrier protein, i.e., Vit D-binding protein, and the activity of this protein is also dependent on magnesium. Thus, magnesium is a co-factor for Vit D biosynthesis, transport, and activation.
As we know magnesium is an activator of Vit D and also modulates IR, the question of whether magnesium can influence the link between Vit D and IR deserves consideration. To date, however, there has been little research on this issue. Therefore, we conducted a clinical study of the effect of magnesium intake on the relationship between Vit D and IR. In the present study, we hypothesized that magnesium ingestion could affect the association between Vit D and IR. The aim of this investigation was to explore the effect of magnesium intake on the relationship between Vit D and IR using a nationally representative public database in the United States in an effort to provide some reference for the subsequent revelation of its mechanism of action.
In this study, Vit D levels were found to be independently associated with the HOMA-IR index and IR among American adults after adjusting for potential confounders, and magnesium intake strengthened this association. The results of this study provide new clinical insights. However, because this was a cross-sectional analysis that could not determine the role of magnesium in the association of Vit D levels with IR and HOMA-IR index, more randomized controlled studies or cohort studies are required to provide evidence in the future.
Background
Previous clinical studies and randomized controlled trials have revealed that low serum vitamin D levels are associated with the risk of developing insulin resistance. Magnesium has been reported to be a protective factor for insulin resistance, and magnesium has been considered an important co-factor for vitamin D activation. However, the effect of dietary magnesium intake on the relationship between vitamin D and the risk of developing insulin resistance has not been comprehensively investigated. Therefore, we designed this cross-sectional analysis to assess whether dietary magnesium intake modifies the association between vitamin D and insulin resistance.
Methods
A total of 4,878 participants (male: 48.2%) from 4 consecutive cycles of the National Health and Nutrition Examination Survey (2007–2014) were included in this study after a rigorous screening process. Participants were stratified by their dietary magnesium intake into low-intake (<267 mg/day) and high-intake (≥267 mg/day) groups. We assessed differences between serum vitamin D levels and the risk of developing insulin resistance (interaction test), using a weighted multivariate logistic regression to analyze differences between participants with low and high magnesium intake levels.
Results
There was a negative association between vitamin D and insulin resistance in the US adult population [OR: 0.93 (0.88–0.98)], P < 0.001. Dietary magnesium intake strengthened the association (P for interaction < 0.001). In the low dietary magnesium intake group, vitamin D was negatively associated with insulin resistance [OR: 0.94 (0.90–0.98)]; in the high dietary magnesium intake group, vitamin D was negatively associated with insulin resistance [OR: 0.92 (0.88–0.96)].
Conclusion
Among adults in the United States, we found an independent association between vitamin D level and insulin resistance, and this association was modified according to different levels of magnesium intake.