calcium or magnesium

 

Summary

 

INTRODUCTION

Magnesium, the second most considerable intracellular cation within the physique, performs an important position in >300 organic actions (1). Rising proof from research performed in Western societies has linked a low consumption of magnesium to insulin resistance (2) and systemic irritation (3) and, thus, to the chance of illnesses frequent in Western international locations, reminiscent of colorectal most cancers (4–6), kind 2 diabetes (7, 8), and coronary coronary heart illness (9, 10). In line with information from the Nationwide Well being and Vitamin Examination Survey (NHANES), 1999–2000, 79% of US adults don’t meet the Beneficial Dietary Allowance of magnesium (11).

Migration research discovered that the incidence of the abovementioned illnesses in East Asians, a bunch that historically has low dangers for these illnesses (12), rose after their immigration to Western societies to strategy the incidence in whites (13). This discovering implicates a important position of environmental elements, notably dietary elements. We discovered, nevertheless, that the imply consumption of magnesium within the US inhabitants (11) doesn’t differ considerably from and isn’t even barely increased than that within the East Asian inhabitants (14, 15). This implies that low consumption of magnesium per se is probably not the main motive for the incidence distinction. As an alternative, the ratio of calcium to magnesium (Ca:Mg) consumption is way increased within the US inhabitants (2.8) than within the East Asian inhabitants (1.6) (14, 16). Ionized magnesium (Mg2+) counters the motion of ionized calcium (Ca2+) in lots of physiologic actions (17). Research discovered that Mg2+, the physiologic antagonist of Ca2+, has the identical damaging suggestions system—together with vitamin D—as does Ca2+ (18, 19). Research additionally discovered that calcium straight or not directly competes with magnesium for intestinal absorption and transport (20). A low focus of calcium and a excessive focus of magnesium (thus, a low Ca:Mg) within the lumen prompts the transport of magnesium (20). In a examine utilizing the multitracer stable-isotope approach, kids who consumed even the Beneficial Dietary Allowance of magnesium had been in damaging magnesium stability if their calcium consumption was excessive (21). An animal examine discovered that calcium deficiency considerably lowered the elevated inflammatory responses attributable to magnesium deficiency (22), which suggests the significance of the calcium-magnesium stability. Subsequently, we hypothesized {that a} excessive Ca:Mg consumption might exaggerate magnesium deficiency and, in flip, result in threat of colorectal most cancers.

It was not till lately that Mg2+ was thought to share ion channels with Ca2+ (18). Genetic research discovered that the transient receptor potential melastatin 7 (TRPM7), a ubiquitously expressed constitutive ion channel with a better affinity for Mg2+ than for Ca2+ (18), performs a central position in Mg2+ homeostasis as an Mg2+ uptake pathway (23). In a latest examine, a missense variant [Thr-1482 to isoleucine (Ile)] within the TRPM7 gene was not recognized in controls, however was recognized solely in circumstances of Guamanian amyotrophic lateral sclerosis and parkinsonism dementia, each of which circumstances have been linked to extreme environmental deficiency of calcium and magnesium (24). Subsequently, we postulated that individuals who carry the variant Ile allele could also be at a excessive threat of magnesium deficiency and, in flip, of colorectal neoplasia and different power illnesses frequent within the Western populations, notably if the Ca:Mg consumption is excessive.

To check these hypotheses, we used information from the Tennessee Colorectal Polyp Examine to analyze whether or not the affiliation of colorectal adenomatous and hyperplastic polyps with the intakes of calcium and magnesium or with the Thr1482Ile polymorphism within the TRPM7 gene could also be modified by the Ca:Mg consumption.

 

SUBJECTS AND METHODS

 

RESULTS

Chosen demographic traits and doubtlessly confounding elements had been in contrast between circumstances and controls, as proven in Desk 1. In contrast with controls, adenomatous and hyperplastic polyp circumstances had been extra more likely to be male, people who smoke, and alcohol drinkers and to have decrease academic attainment, a better day by day dietary intakes of complete vitality and saturated fats, and a decrease consumption of complete calcium. Adenomatous circumstances had been older and extra more likely to have decrease intakes of complete magnesium, dietary vitamin D, folate, and fiber; to be bodily inactive; and to have a better BMI. As well as, hyperplastic polyp circumstances had been considerably extra more likely to smoke than had been adenoma circumstances.

The most important single contributor to magnesium consumption is supplemental magnesium (51.1 mg/d, which accounts for 16.3% of complete common consumption). The remainder of the ten essential contributors had been bran or high-fiber cereals (20.6 mg); peanuts and different nuts (16.3 mg); caffeinated espresso (16.2 mg); darkish or whole-grain breads (15.5 mg); low-fat milk (10.0 mg); oatmeal, cream of wheat, and different sizzling cereals (8.4 mg); 100% orange juice or grapefruit juice (8.3 mg); and skim milk and buttermilk (8.1 mg). The highest 20 contributors to magnesium consumption, together with supplementation, account for 69.3% of common magnesium consumption.

The general associations, in addition to the stratified associations by the median of the Ca:Mg consumption, between intakes of complete magnesium and calcium and the chance of colorectal adenoma are proven in Desk 2. The danger of colorectal adenoma decreased with an growing complete consumption of magnesium in all 3 fashions. In contrast with the age-adjusted mannequin, the chance was decrease after adjustment for different potential confounding elements and complete consumption of calcium, with an OR of 0.54 (95% CI: 0.36, 0.82) in topics who consumed complete magnesium on the highest tertile versus these with the bottom consumption (P for development < 0.01). The affiliation with the dietary consumption of magnesium was weaker. Whole consumption of calcium was strongly related to a decrease threat within the age-adjusted mannequin. After changes for different confounding elements, the inverse affiliation was nonetheless of borderline significance (P for development = 0.06) with an OR of 0.75 (95% CI: 0.55, 1.02). This inverse affiliation fully disappeared, nevertheless, after extra adjustment for complete magnesium consumption. Dietary calcium consumption was not considerably related to colorectal adenoma threat in any mannequin.

We performed stratified analyses of complete magnesium and calcium by the median Ca:Mg consumption. We discovered that the inverse affiliation of magnesium and calcium primarily appeared amongst these with a low Ca:Mg consumption. Amongst these with a excessive Ca:Mg consumption, complete consumption of magnesium was not associated to threat, whereas complete consumption of calcium confirmed a development towards affiliation with a better threat. The inverse affiliation of magnesium with adenoma threat didn't differ considerably between women and men or between proximal and distal colorectal adenoma (information not proven). We now have additionally performed analyses stratified by dietary consumption of vitamin D (information not proven). Whole magnesium consumption was linked to a considerably decrease adenoma threat in topics who consumed excessive quantities of vitamin D and have a low Ca:Mg consumption, with an OR of 0.32 (95% CI: 0.13, 0.80) evaluating the best tertile of magnesium consumption with the bottom (P for development < 0.01). Whole calcium consumption, nevertheless, could also be related to a decrease threat of adenoma solely when the Ca:Mg consumption is low and dietary vitamin D consumption is excessive. The outcomes for the affiliation between the Thr1482Ile polymorphism within the TRPM7 gene and colorectal adenoma (Desk 3) had been obtained solely from non-African American topics as a result of African Individuals weren't polymorphic at this loci. The distribution of genotypes for the polymorphisms is in keeping with Hardy-Weinberg equilibrium for both circumstances or controls. We discovered that the 1482Ile allele is related to a 20% elevated threat of adenoma, though the consequence was of borderline significance (Desk 3). In contrast with those that had been homozygous for 1482Thr, individuals who carry ≥1 1482Ile allele had been discovered to have a considerably (60%) better threat of colorectal adenoma (OR: 1.60; 95% CI: 1.12, 2.29) if additionally they consumed diets with a excessive Ca:Mg consumption. The interplay between the Thr1482Ile polymorphism and the Ca:Mg consumption was statistically important (P for interplay = 0.03). The general affiliation between consumption of magnesium or calcium and the chance of adenoma in non-African American topics (Desk 4) was in keeping with that in all topics (Desk 2). In topics with ≥1 1482Ile allele, the inverse affiliation with magnesium consumption was additional lowered, whereas excessive calcium consumption tended to be associated to an elevated threat of adenoma, though the checks for interactions weren't important. We discovered that the whole magnesium consumption could also be associated to a decrease threat of hyperplastic polyps, as proven in Desk 5, which doesn't differ from the findings for adenoma. The inverse affiliation development nonetheless existed after adjustment for complete calcium consumption, though the affiliation was not important. Once more, calcium consumption was considerably related to the chance. Nevertheless, there was no affiliation within the absolutely adjusted mannequin. In stratified evaluation, we discovered that complete calcium consumption tended to be related to a better threat if the Ca:Mg consumption was excessive (information not proven). Likewise, we discovered, as proven in Desk 6, that, in contrast with those that had been homozygous for 1482Thr, topics with ≥1 1482Ile allele tended to be at a better threat (OR: 1.41; 95% CI: 0.99, 2.01) of hyperplastic polyps, and the distinction in threat was even better for these topics who consumed diets with excessive Ca:Mg consumption (OR: 1.85; 95% CI: 1.09, 3.14).  

DISCUSSION – “calcium or magnesium”

We discovered on this massive colonoscopy-based case-control examine that, in keeping with our hypotheses, the whole magnesium consumption is linked to a considerably decrease threat of colorectal adenoma in each women and men and notably in these with a low Ca:Mg consumption and a excessive vitamin D consumption. Likewise, complete calcium consumption could also be related to a decrease threat of adenoma solely when vitamin D consumption is excessive and the Ca:Mg consumption is low. Moreover, an inverse affiliation development, though nonsignificant, was additionally discovered for hyperplastic polyps. We discovered that Thr1482Ile polymorphism considerably interacted with the Ca:Mg consumption in relation to the chance of both adenomatous or hyperplastic polyps. Individuals who carried ≥1 1482Ile allele had been at better threat of adenoma or hyperplastic polyps, notably in the event that they consumed diets with a excessive Ca:Mg consumption. Amongst individuals who carried ≥1 1482Ile allele, the inverse affiliation with magnesium consumption was additional lowered, whereas excessive calcium consumption tended to be associated to a better threat of adenoma.

Rising proof has highlighted a doubtlessly vital position in colorectal carcinogenesis of the serrated pathway comprising hyperplastic polyps and serrated adenomas (26, 27). Till lately, these polyps had been largely assumed to don’t have any malignant potential, and, thus, few research have evaluated threat elements for these polyps (28). Our discovering of an inverse affiliation of magnesium with colorectal adenomas or hyperplastic polyps is in keeping with 2 latest cohort research, additionally performed in Western societies, by which the consumption of magnesium was related to a decrease threat of colorectal most cancers (4, 5). The diploma of discount within the threat of adenoma or hyperplastic polyps related to magnesium within the present examine is just like that discovered for colorectal most cancers in 2 earlier research (12, 13), which signifies that magnesium might shield towards colorectal carcinogenesis at an early stage. Very lately, findings from the Netherlands Cohort Examine recommend that the consumption of magnesium could also be related to a decrease threat of colon most cancers solely in chubby topics (6), whereas one other follow-up examine of individuals concerned in an interventional trial of aspirin and vitamin E discovered a null affiliation (29). One attainable clarification for the inconsistency in these earlier research is that the Ca:Mg consumption just isn’t thought-about.

We discovered that, as was in keeping with our speculation, the consumption of magnesium or calcium could also be related to a decrease threat of adenoma solely when the Ca:Mg consumption is low and dietary vitamin D is excessive. Intakes of calcium and vitamin D have been inconsistently related to the chance of colorectal most cancers and adenoma in remark research. One pooled evaluation of 10 cohort research (30) and intervention trials (31–34) urged that prime consumption of complete calcium could also be related to a decrease threat of adenoma and colorectal most cancers, primarily in individuals with a excessive consumption of vitamin D. It’s disappointing {that a} latest, large-scale, randomized scientific trial discovered that calcium plus vitamin D supplementation for 7 y had no impact on the incidence of colorectal most cancers (31). One attainable clarification for that damaging discovering is that calcium might stop colorectal most cancers improvement solely at its earliest stage. For instance, very lately, Baron et al (35) discovered within the observational part of a scientific trial that the protecting impact of calcium supplementation on colorectal adenoma recurrence price extends as much as 5 y after cessation of energetic therapy. Moreover, in these earlier research, the potential impact modification of Ca:Mg consumption was not evaluated, and which may be one other attainable clarification for the inconsistency of the affiliation between calcium and colorectal most cancers or adenoma (29–34, 36–41). Our discovering can be supported by the outcomes from analyses utilizing information from each the Nurses’ Well being Examine and the Well being Professionals Observe-up Examine. In these 2 research, the best discount within the dangers related to calcium consumption was achieved by intakes of 700–800 mg/d, however no extra discount in threat was noticed at increased calcium intakes (42). A calcium consumption of >700–800 mg/d, which might most likely be as a result of ingestion of calcium dietary supplements, may very well be linked to a better Ca:Mg consumption, which might result in or improve magnesium deficiency if the consumption of magnesium and the bioavailability of vitamin D are also low.

Though no examine has investigated the potential interplay of magnesium with calcium or vitamin D in relation to colorectal most cancers or adenoma, in vitro, in vivo, and human research point out that calcium might straight or not directly have an effect on the absorption of magnesium (20, 21). Moreover, in contrast to calcium absorption, magnesium absorption just isn’t fully vitamin D dependent, though a excessive vitamin D focus does help magnesium absorption (20). Subsequently, absorption of magnesium could also be considerably elevated when the vitamin D consumption is excessive and the Ca:Mg consumption is low. As a result of calcium is extra delicate to vitamin D than is magnesium, when each Ca:Mg consumption and vitamin D consumption are excessive, the absorption of magnesium is suppressed, however calcium absorption is considerably elevated. Furthermore, though the adjustments in blood or colon lumen concentrations of ionized calcium and magnesium are monitored by the identical mechanism—the calcium-sensing receptor—the efficiency of ionized magnesium in binding to the receptor is simply one-half to one-third that of calcium (43). Subsequently, as soon as the calcium focus is excessive, magnesium absorption may very well be considerably depressed. Furthermore, it’s a well-known paradoxical phenomenon {that a} very low or a really excessive focus of ionized magnesium might inhibit parathyroid hormone secretion and, in flip, scale back the focus of the bioactive metabolite of vitamin D (43, 44), which means that magnesium deficiency might subsequently trigger calcium deficiency. Accordingly, when the Ca:Mg consumption is excessive and the vitamin D consumption is low, absorption of each calcium and magnesium may very well be suppressed concurrently.

Many in vitro and in vivo research discovered that, along with magnesium’s potential interplay with calcium within the absorption and focus censoring system, a excessive focus of magnesium will inhibit and a deficiency of magnesium will potentiate the motion of calcium in lots of physiologic processes (17). An imbalance of the Ca:Mg consumption might also result in irregularities in lots of organic actions, reminiscent of irritation, DNA restore, cell proliferation, differentiation, angiogenesis and apoptosis, insulin resistance, and carcinogenesis (22, 45). Few in vitro and in vivo research have evaluated the position of magnesium in carcinogenesis, and the outcomes are inconsistent (45, 46). The Ca:Mg consumption was not thought-about in any of those animal research.

TRPM7 was discovered to type a useful ion channel advanced with TRPM6, contributing basically to epithelial magnesium (re)absorption (47). Mutations within the TRPM6 gene had been linked to major hypomagnesemia and secondary hypocalcemia that was resulting from defects in magnesium absorption (48). Moreover, TRPM7 deficiency in cells results in Mg2+ deficiency, whereas mobile viability and proliferation may be rescued by extracellular Mg2+ however can’t be rescued by Ca2+ (23). Nevertheless, in zebra fish, a developmental defect attributable to a mutation within the TRPM7 gene was partially rescued not solely by Mg2+, but additionally by Ca2+ (48), which means that TRPM7 might also be concerned in regulating the stability of Mg2+ and Ca2+. In vitro research discovered that heterologously expressed Thr1482Ile results in an elevated sensitivity to inhibition by intracellular Mg2+ (24), which means that (re)absorption of magnesium is extra topic to inhibition amongst topics with the Ile allele. Within the current examine, we discovered that the Thr1482Ile polymorphism considerably interacts with Ca:Mg consumption, whereas the associations of magnesium and calcium intakes with the chance of adenoma might differ in individuals with ≥1 1482Ile allele. These findings are biologically believable and in keeping with earlier research, which means that TRPM7 not solely possesses a better affinity for Mg2+ than Ca2+ (18) but additionally is concerned in magnesium and calcium stability. Furthermore, these findings additionally point out that, along with magnesium or calcium alone, the Ca:Mg consumption might present extra indications for magnesium or calcium standing within the physique.

The current examine has a number of strengths. Not like sigmoidoscopy-based research, the current examine included solely controls who underwent a full colonoscopy, and, thus, potential contamination of circumstances within the management group just isn’t a significant concern. Furthermore, just about all individuals offered a DNA pattern. Nevertheless, the current examine additionally has a number of limitations. As with all case-control research, differential recall bias might exist. But most individuals had been recruited earlier than the colonoscopy, and only some circumstances had been recognized as having a malignant lesion; thus, nondifferential recall bias could also be minimized. Choice bias is one other concern for this case-control examine. We now have discovered, nevertheless, that age, intercourse, and the rationale for the colonoscopy don’t differ between individuals who consented and those that didn’t consent to take part within the examine. Moreover, most individuals are recruited earlier than the colonoscopy that defines their case or management standing, and, thus, controls are usually not any much less more likely to take part than circumstances. In our examine, 55% of all circumstances underwent colonoscopy as a real screening measure with no indication for the examination apart from age. We now have performed analyses of those topics solely and located outcomes that don’t differ considerably. Regardless of this, cautious interpretation of our outcomes is warranted, notably concerning generalization of our findings. We now have used the most typical calcium or magnesium components within the calcium and multivitamin dietary supplements to calculate the whole intakes of calcium and magnesium. The magnesium content material of consuming water couldn’t be included within the calculation of magnesium consumption. This will likely result in nondifferential misclassification of calcium and magnesium intakes, which often biases associations towards the null. We now have adjusted for a lot of potential confounding elements, however that will not eradicate the likelihood that different residual confounding elements, or a associated dietary sample, might clarify our outcomes. Nevertheless, that’s unlikely, as a result of, within the current examine, the affiliation of magnesium and gene-nutrient interactions was discovered persistently in each adenomatous and hyperplastic-only circumstances. Furthermore, the affiliation between the useful polymorphism, Thr1482Ile, and the chance of polyps might mimic the hyperlink between a low consumption of magnesium, a excessive Ca:Mg consumption, or each and polyps. As well as, the affiliation with the polymorphism just isn’t inclined to confounding in accordance with the Mendelian randomization concept (49), and analyses utilizing genotyping information had been performed amongst non-African American topics solely. Of these included within the analyses, 97.4% are white, and Wacholder et al (50) confirmed that inhabitants stratification just isn’t more likely to be a significant issue within the white inhabitants.

Future research, together with intervention trials, are crucial to substantiate our findings. These outcomes, if confirmed, might present a brand new avenue for the prevention of magnesium deficiency and, thus, colorectal most cancers, notably in Western populations with a excessive Ca:Mg consumption.

 

Acknowledgments

 

Footnotes