논문) Magnesium in Obesity, Metabolic Syndrome, and Type 2 Diabetes

[gaho91]

안녕하세요. 요새 근육경련과 관련하여 마그네슘 관련 자료들을 찾아보다가 다른 내용이지만 만성질환에 있어서 마그네슘의 역할에 관한 논문이 있어서 읽고 부분부분 번역해보았습니다. !

※정리해보겠습니다.

마그네슘의 적절한 섭취는 인체 정상 생리활동에 있어서 매우 중요합니다.

또한 마그네슘 결핍이 있는 비만, 대사증후군, 제 2형 당뇨병, 심혈관질환 환자에 있어서 마그네슘의 섭취는 증상, 지표, 위험성 개선에 많은 도움이 됩니다.

다만, 현재 널리쓰이고 있는 방법인 혈액 내 마그네슘 농도 측정은 실제 체내의 마그네슘 충분 정도와 괴리가 있습니다. 왜냐하면 인체내 마그네슘의 대부분은 뼈(60%)와 연부조직(40%)에 들어 있으며 혈액 내 있는 비중은 1% 미만이므로, 혈액 내 농도가 실제 정도를 반영하지 못하여, 어떤 사람이 실제로는 무증상성(Subclinical) 마그네슘 결핍이지만 혈액검사상 정상으로 측정될 수 있습니다.

논문에서는 서구화된 식단으로 식사를 통한 마그네슘 섭취량 감소, 위장관 흡수장애, 과음, 신장기능 장애 등으로 인하여 현대인들이 생각보다 마그네슘 결핍이 심각하고, 많다고 보고 있습니다.

따라서 혈액검사상 마그네슘 농도 (magnesemia)가 결핍되어있거나 혹은 정상이더라도 위와 같은 S/H 사회력이 있는

비만(Obesity), 대사증후군(Metabolic syndrome), 제 2형 당뇨병(Type 2 diabetes; T2D) 그리고 심혈관질환 환자에게 여러 치료법과 더불어 식단교정과 마그네슘 보충제 투여를 병행한다면 좋은 효과가 있을 것이라 합니다.

마그네슘 보충제 : 시판중인 보충제의 마그네슘염 형태는 다양하다. 어떤 형태가 가장 좋을지는 연구가 부족하다. citrate, sulfate, chelate 등등

복용 용량 : 250-600mg/day 복용기간 : 7일 ~ 6개월.

=> 300~400mg 정도 용량으로 꾸준히 복용 ?

비만, 대사증후군, 제 2형 당뇨병에서 마그네슘의 중요성

Magnesium in Obesity, Metabolic Syndrome, and Type 2 Diabetes

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912442/

Magnesium in Obesity, Metabolic Syndrome, and Type 2 Diabetes

Magnesium (Mg[2+] ) deficiency is probably the most underestimated electrolyte imbalance in Western countries. It is frequent in obese patients, subjects with type-2 diabetes and metabolic syndrome, both in adulthood and in childhood. This narrative review ...

www.ncbi.nlm.nih.gov

Piuri G, Zocchi M, Della Porta M, Ficara V, Manoni M, Zuccotti GV, Pinotti L, Maier JA, Cazzola R. Magnesium in Obesity, Metabolic Syndrome, and Type 2 Diabetes. Nutrients. 2021 Jan 22;13(2):320. doi: 10.3390/nu13020320. PMID: 33499378; PMCID: PMC7912442.

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1. Introduction

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Magnesium (Mg2+) is the second most abundant intracellular cation and the fourth most abundant cation of the human body. Almost all the body Mg2+ is found in the bones (about 60%) and soft tissues (about 40%), while <1% is in the blood. It is a cofactor of hundreds of enzymatic reactions, acting both on the enzymes as a structural or catalytic component and on the substrates. An example of Mg2+ bioactive activity is given by the reactions involving the complex Mg-ATP, which is an essential cofactor of kinases. For this reason, Mg2+ is a rate-limiting factor for many enzymes involved in carbohydrate and energy metabolism. Furthermore, Mg2+ is essential in the intermediary metabolism for the synthesis of the macromolecules [1]. Other vital Mg2+-dependent functions are muscle contraction and relaxation, normal neurological function, and release of neurotransmitters [2].

At the cellular level, Mg2+ homeostasis is fine-tuned by the coordinated activity of membrane channels and transporters. Some of them are ubiquitously expressed, such as transient receptor potential melastatin (TRPM) 7, Mg2+ transporter 1 (MagT1) and solute carrier family 41 member 1 (SLC41A1). Others are tissue-specific, such as TRPM6, expressed in the kidney and the colon, cyclin and CBS domain divalent metal cation transport mediator cyclin M2 (CNNM2), expressed in the kidney, and CNNM4, expressed in the colon [3].

Obesity, metabolic syndrome, and type 2 diabetes mellitus are three interrelated conditions that share a series of pathophysiological mechanisms attributable to “low-grade” systemic inflammation [4]. Mg2+ deficit is frequent in obese subjects [3] and is a highly preval‎ent condition in patients with diabetes or metabolic syndrome. Moreover, it increases the risk of developing type-2 diabetes [5]. Besides, Mg2+ depletion can promote chronic inflammation both directly [6,7,8] and indirectly by modifying the intestinal microbiota [9].

This review aims to offer insights into the pathophysiological mechanisms linking Mg2+ deficiency with obesity and the risk of developing metabolic syndrome and type 2 diabetes (Figure 1).

마그네슘은 우리몸에 풍부한 양이온이다. 대부분의 마그네슘이온은 뼈(60%)와 근육,인대 등의 연부조직(40%)에 있고 1% 미만의 마그네슘이 혈액속에 있다. 마그네슘은 수백가지 효소반응의 보조인자이다. 마그네슘 이온은 탄수화물 대사를 비롯한 에너지 대사의 rate-limiting 요소이며 체내 고분자 물질 합성에 필수적인 요소이다.

비만, 대사증후군, 제 2형 당뇨병 이 세가지는 "낮은 단계"의 전신적인 염증 상태를 만드는 병태생리적 메카니즘을 공유하는 상호연관된 질환들이다. Mg이온의 결핍은 비만인에게서 빈번하며 당뇨병, 대사증후군 환자들에서도 널리 퍼져 있다. 더욱이 마그네슘 결핍은 제 2형 당뇨병을 악화시킬 가능성을 증가시킨다. 게다가 마그네슘의 결핍은 장내 미생물총에 영향을 끼쳐서 직간접적으로 체내 만성 염증을 촉진시킬 수 있다.

이 리뷰논문에서는 Mg2+ 결핍과 비만, 대사증후군 및 제2형 당뇨병의 발병 위험과 관련된 병태생리학적 메카니즘에 대한 insight를 제공하고자 한다.

Figure 1
Physio-pathological mechanisms of magnesium deficiency in obesity, metabolic syndrome, and type 2 diabetes.

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2. Mg2+ Deficiency

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Among all the lab tests most frequently used to eval‎uate Mg2+ status in routine clinical practice is magnesemia because it is feasible and inexpensive [1,10]. However, magnesemia does not correlate with tissue pools because serum Mg2+ is just a tiny percentage of the intracellular/total body Mg2+ content [2]. This is one of the reasons why Mg2+ deficiency is the most underestimated electrolyte imbalance in Western countries, where a significantly high risk of latent hypomagnesemia occurs [11,12]. Based on distribution patterns of Mg2+ in the blood, the reference range for serum Mg2+ concentration is 0.75–0.95 mmol/L [13,14,15,16] and hypomagnesemia is generally defined as serum Mg2+ level lower than 0.7 mmol/L [3,17]. Recently, a panel of experts proposed that urinary Mg2+ secretion should also be considered. Specifically, a magnesemia lower than 0.82 mmol/L with Mg2 urinary excretion of 40–80 mg/die should be considered indicative of Mg2 deficiency [13]. Since serum Mg2+ content is only 1% of total Mg2+ in the body and is not representative for global intracellular Mg2+ status, Mg2+ deficiency may be underestimated and persist latently for years [16]. Subclinical hypomagnesemia is responsible for a variety of clinical manifestations that are non-specific and can overlap with symptoms of other electrolyte imbalances [18]. Some of these symptoms are depression, fatigue, muscle spasms and arrhythmias. Furthermore, a chronic low-Mg2+ status has been associated with an increased risk of chronic non-transmissible diseases, among which osteoporosis and sarcopenia [19,20,21]. Severe Mg2+ depletion, defined by serum Mg2+ concentration below 0.3–0.4 mmol/L, may lead to cardiac arrhythmias, tetany and seizures [3].

There are several causes of hypomagnesemia and one of the most relevant is an insufficient dietary intake. In fact, several studies show that the majority of the population in Europe and North America consumes less than the recommended daily allowance (RDA) of Mg2+, i.e., approximately 420 Mg2+ for adult males and 320 Mg2+ for adult females [22,23,24]. This deficit mainly derives from the Western-style diet (WD) that often contains only 30–50% of Mg2+ RDA. Indeed, the WD is based on massive consumption of processed foods, demineralized water and low amounts of vegetables and legumes, often grown in Mg2+-poor soil [18]. Hypomagnesemia may also be a consequence of pre-existing pathological conditions. For example, Mg2+ depletion is frequent in subjects affected by impaired gastrointestinal absorption caused by celiac disease [25], inflammatory bowel diseases [26,27,28] or in the presence of colon cancer, gastric bypass and other minor gastrointestinal disorders [29]. Additional causes of Mg2+ deficit are type 1 diabetes mellitus, renal disorders and hydro-electrolyte imbalances [30]. Hypomagnesemia is also associated, through different molecular mechanisms, with the frequent use of several medications such as diuretics (furosemide, thiazide), epidermal growth factor receptor inhibitors (cetuximab), calcineurin inhibitors (cyclosporine A), cisplatin and some antimicrobials (rapamycin, aminoglycosides antibiotics, pentamidine, foscaret, amphotericin B). It is also interesting to highlight that the wide use of proton pump inhibitors (PPI–omeprazole, pantoprazole, esomeprazole), which is generally considered safe, induces hypomagnesemia in 13% of the cases but the underlying mechanism is still unknown [31]. Moreover, ethanol abuse results in Mg2+ deficiency [32,33].

A low-Mg2+ status may also have genetic origins and derive from mutations of genes such as TRPM6, CLDN16-19 (claudin 16 and 19), KCNA1 (potassium voltage-gated channel subfamily A member 1), CNNM2 [34]. These mutations result in a severe hypomagnesemia accompanied by calcium wasting, renal failure, seizures and mental retardation [3]. Finally, from a physiological point of view, Mg2+ deficit may be observed after intensive sport activities with an increase in sweating, in healthy postmenopausal women [35] or during lactation [30]. Moreover, Mg2+ status is generally impaired in older people [36].

Considering the focus of this work, it is important to underline that a moderate or subclinical Mg2+ deficiency induces a chronic low-grade inflammation sustained by the release of inflammatory cytokines and production of free radicals, which exacerbate a pre-existing inflammatory status [7]. For this reason Mg2+ depletion is considered a risk factor for pathological conditions characterized by chronic inflammation, such as hypertension and cardiovascular disorders but also metabolic syndrome and diabetes [29,37,38].

체내 마그네슘정도를 측정하는 용도로 혈중 마그네슘 농도(Magnesemia) 테스트가 가장 널리 사용되고 있다. 하지만 혈중내 마그네슘이온은 세포내 또는 전체 체내 마그네슘 양에 비하면 정말 작은 퍼센트라 실제 체내 마그네슘의 정도를 정확히 나타내지는 못하고 있다. 이 때문에 마그네슘 결핍은 과소평과 되고 있는 상황이다.

무증상의 저마그네슘혈증은 다양한 임상적 증후들의 원인이 될 수 있다. 그러한 증상들로는 우울증, 피로, 근육경련, 부정맥이 있다. 또한 만성적인 저마그네슘 상태는 골다공증, 근감소증을 포함한 만성적인 비전염성 질환의 위험증가와 관련이 있으며 심각한 마그네슘 결핍은 심부정맥, 근육의 수축경련, 발작을 유발할 수 있다.

저마그네슘혈증의 주요한 원인은 마그네슘 섭취량 부족이다. 서구화된 식단은 일일 권장 섭취량보다 부족한 양의 마그네슘을 섭취하게 된다. 서구화된 식단은 가공식품, 미네랄이 부족한 식수를 많이 먹게 되며 야채와 콩류 섭취는 부족하게 된다. 또한 저마그네슘혈증의 원인이 되는 질환으로 위장관 흡수장애 (셀리악병,IBS,IBD,대장암..), 신장기능장애가 있다.

특정약물의 빈번한 사용도 원인이 된다. 이뇨제(furosemide, thiazide), EGFRi항암제(cetuximab), 칼시뉴린억제제=면역억제제(cyclosporine A), cisplatin(항암제), 항균제(rapamycin, aminoglycosides antibiotics, pentamidine, foscaret, amphotericin B).

위산억제제(PPI) 복용자의 13%에서도 저마그네슘혈증이 관찰되었다. 음주,과음이나 노화,고령도 마그네슘 결핍의 원인이 된다.

결론적으로 저마그네슘혈증은 염증성 사이토카인 분비와 활성산소 생성에 의한 만성적인 low-grade inflammation 상태를 유발하며 기존에 존재하던 염증질환들을 악화시킨다. 이러한 이유로 마그네슘 결핍은 고혈압, 심혈관질환, 대사증후군, 당뇨병 등 만성 염증을 특징으로 하는 질환에서 위험인자(risk factor)로 고려된다.

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3. Mg2+ and Obesity

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Obesity and its comorbidities, including metabolic syndrome and type 2 diabetes, are a relevant medical problem worldwide. Obesity is the result of unhealthy diets, high in calories, but poor in essential nutrients. As a consequence, obese subjects are often Mg2+ deficient [39]. Indeed, the National Health and Nutrition Examination Survey (NHANES) 3 study underlines that Mg2+ deficit is more preval‎ent in subjects with body mass index (BMI) in the obese range than in the normal American population [40,41]. Analogously, Mg2+ intake is impaired in 35% of French individuals with BMI > 35 kg/m2 [42]. The 30-year longitudinal CARDIA study, performed on more than 5000 subjects, indicates that Mg2+ intake is inversely associated with the incidence of obesity and with the levels of C reactive protein [43]. Besides, in animal models of diet-induced obesity Mg2+ supplementation prevents the accumulation of adipose tissue [44] and human studies report an inverse association between Mg2+ intake and markers of adiposity, such as BMI and waist circumference [45,46,47].

비만률과 CRP수치는 마그네슘 섭취량과 상반된 관련성이 있다.

In obese subjects, most of the energy of the diet derives from refined grains and simple sugars and, consequently, their hepatic glucose catabolism is very active. Several key enzymes of glucose oxidation pathways are Mg2+-dependent and Mg2+ is necessary also for the activation of vitamin B1 into thiamine diphosphate (TDP) that is another critical coenzyme of oxidative metabolism. Importantly, TDP-dependent enzymes require Mg2+ to reach optimal activation [48]. Therefore, low intracellular concentrations of Mg2+ and/or TDP may alter the oxidative metabolism of glucose. In the liver, a decrease of the activity of the Mg2+- and TDP-dependent enzyme pyruvate dehydrogenase may divert glucose metabolism into the oxidative phase of the pentose phosphate pathway, thus generating an excess of NADPH [48]. NADPH provides essential redox potential for synthetic pathways, including fatty acid biosynthesis, thus promoting an increased synthesis of triglycerides and very low-density lipoprotein and, consequently, a higher triglyceride storage in adipocytes that increases the extent of obesity and the risk of obesity co-morbidities such as dyslipidemia, metabolic syndrome and type 2 diabetes [49,50,51].

비만한 사람의 경우 탄수화물 등 칼로리 섭취량이 많으며 이에 따라 glucose 에너지 대사가 과도하게 일어난다. glucose 대사에서 마그네슘은 필수적인데, 결과적으로 마그네슘이 많이 쓰이게 되면서 부족해지고 glucose대사가 원활하게 이루어지지 않으면서 NADPH가 과잉 생성된다. NADPH는 중성지방과 LDL의 생성을 촉진하여 결과적으로 체내 지방축적이 증가시킨다. 이에 따라 비만의 정도가 고지혈증, 대사증후군, 제 2형 당뇨병 같은 합병증이 생길 위험을 높이게 된다.

Moreover, obese subjects are often deficient also in vitamin D [49,52] both in the presence and in the absence of type 2 diabetes [53], and Mg2+ is essential also for vitamin D synthesis and activation [54]. A randomized controlled trial suggests that optimal Mg2+ status may be fundamental for optimizing vitamin D status [55]. Because of its role in the renin-angiotensin system and its immunomodulatory properties, vitamin D deficiency is identified as a potential risk factor in cardiometabolic disorders, including insulin resistance, metabolic syndrome and cardiovascular diseases [56]. Moreover, chronic latent Mg2+ deficiency and/or Vitamin D deficiency predispose non-diabetic obese subjects to an increased risk of cardiometabolic diseases. Meanwhile, maintaining a normal Mg2+ status improves the beneficial effect of Vitamin D on cardiometabolic risk indicators [57]. Interestingly, an interventional study performed on healthy women showed a significant increase in serum concentration of Mg2+ in obese but not in non-obese subjects after vitamin D intramuscular injection, probably caused by increased Mg2+ renal retention induced by vitamin D and emphasized by baseline Mg2+ deficiency of the obese subjects [58].

비만인 사람들에게서는 당뇨병의 유무와 상관없이 비타민D 결핍이 자주 관찰된다. RCT연구에 따르면 체내 최적의 마그네슘 상태를 유지하는 것이 체내 비타민 D 최적화 하는데 필수적이다.

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4. Mg2+ in Metabolic Syndrome

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Obesity and metabolic syndrome (MetS) are both characterized by excessive accumulation of body fat. However, while obesity only implies the accumulation of excess body fat, metabolic syndrome is a disorder of accumulation and use of energy, promoted by low-grade systemic inflammation, and resulting in central adiposity, hypertension, dyslipidemia, or insulin resistance. Many studies have found a positive correlation between low dietary Mg2+ intake and MetS risk independently from other risk factors such as age, gender, BMI, race, educational attainment, marital status, smoking, alcohol intake, exercise, energy intake, percentage of calories from saturated fat, use of an antihypertensive or lipid medication [59,60,61,62,63,64]. Dibaba et al. showed in the last meta-analysis available that the dietary Mg2+ intake is inversely associated with the preval‎ence of MetS [63]. A recent cross-sectional analysis performed in a large Chinese population reports an inverse correlation between dietary Mg2+ intake and the preval‎ence of MetS [65]. In more than 11.000 middle-aged and older women high dietary Mg2+ intake lowers systemic inflammation and the risk of the MetS [59]. An interesting Serbian study shows a positive association between chronic exposure to insufficient Mg2+ in drinking municipalities water and the preval‎ence of hypertension and MetS [66].

MetS exponentially increases the risk of developing type 2 diabetes, cardiovascular disease and, in general, morbidity and mortality. Proper Mg2+ intake reduces cardiometabolic risk and is associated with a reduced hazard of cardiovascular disease, diabetes, and all-cause mortality [67,68,69,70]. Likewise, higher levels of circulating Mg2+ are associated with a lower risk of cardiovascular disease, mainly coronary artery disease [71].

Low chronic Mg2+ dietary intake leads to serum and intracellular Mg2+ deficiency. This is particularly evident in obese people with MetS, in elderly subjects and non-white people with insulin resistance [72,73,74].

Mg2+ is a natural calcium (Ca2+) antagonist, and its metabolic effect needs to be discussed according to Ca2+ concentration. A recent meta-analysis suggests that high Ca2+ dietary intake reduces the risk of MetS [75]. Other experimental data suggest that a higher Ca2+/Mg2+ intracellular ratio, induced by a diet high in Ca2+ and low in Mg2+, may lead to hypertension, insulin resistance, and MetS [76]. Accordingly, subjects who meet the recommended daily allowance for both Mg2+ and Ca2+ have reduced risk of MetS [76]. Mg2+ and Ca2+ work together to regulate the metabolic response of overweight and obese subjects, and an unbalanced Ca2+/Mg2+ ratio maximizes the effect of their single deficiency. The optimal Ca2+/Mg2+ ratio leads to the best-decreased risk of MetS [77,78].

마그네슘을 잘 섭취하는 것은 대사증후군의 유병률과 위험성을 낮추는데 도움이 된다. 적절한 마그네슘의 섭취는 전신적인 염증 반응을 억제하고 심혈관대사의 위험성을 낮추는데 이는 심혈관 질환, 당뇨병, 관상동맥 질환의 위험성을 낮춰준다.

마그네슘이온은 체내에서 칼슘이온의 길항제로 작용한다. 따라서 적절한 마그네슘과 칼슘의 섭취로 두 이온간의 비율을 잘 맞추어야 하며 적절한 Ca2+/Mg2+ 비율은 대사증후군의 위험성을 줄이는데 아주 중요하다.

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5. Mg2+ in Type 2 Diabetes

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Type 2 diabetes (T2D) is often associated with altered Mg2+ homeostasis and Mg2+ intake is inversely associated with the risk of T2D in a dose-response manner [79,80]. Epidemiologic studies have shown a high preval‎ence of hypomagnesemia in subjects with T2D [81,82]. Mg2+ depletion in patients with T2D is mainly caused by a low intake and an increased urinary loss of Mg2+, probably resulting from impaired renal function [82].

제 2형 당뇨병 환자들에게서 저마그네슘혈증이 높은 비율로 나타난다. 이러한 마그네슘 결핍은 섭취 부족과 신장 기능 장애에 의한 소변을 통한 마그네슘 유실에 의한다.

Moreover, recent findings demonstrate that hypomagnesemia is strongly associated with the progression of T2D [83]. In particular, if it is true that insulin regulates Mg2+ homeostasis, at the same time Mg2+ is also a significant determinant of post-receptor insulin signaling. The influence of Mg2+ on glucose metabolism, insulin sensitivity, and insulin action could explain the negative association between Mg2+ intake and T2D incidence [82,84,85,86,87] (Figure 2). To better understand this issue, it is worth recalling that insulin secretion is started by a Ca2+ influx that is competitively inhibited by extracellular Mg2+ and, consequently, insulinemia is inversely correlated with magnesemia. Circulating glucose is easily taken from cells β through the glucose transporter 2 (GLUT2), and then converted in glucose-6-phosphate (G6P) by glucokinase (GK). The oxidation of G6P in glycolysis determines an increase in the ATP/ADP ratio leading to the closure of ATP-sensitive K+ channels (KATP channels) and, consequently, to the depolarization of the membrane, followed by the opening of voltage-dependent Ca2+ channels [88]. The increase in intracellular concentrations of Ca2+ triggers the fusion of insulin-containing granules with the membrane and the subsequent release of their content. The molecular mechanisms by which Mg2+ contributes to insulin resistance are mostly unrevealed. However, it is accepted that Mg2+ deficiency has a significant impact on insulin secretion and may contribute to dysfunction of pancreatic beta cells in T2D [89]. This depends on the key roles played by Mg2+ in the glucose-dependent signaling inducing insulin release. The activities of GK and many glycolytic enzymes depend on Mg-ATP complex, thus, a low intracellular Mg2+ concentration results in decreased ATP level in the cells. In addition, the closure of KATP channels depends on ATP binding to the Kir6.2 subunit, while the opening of these channels depends on Mg-ATP binding to the SUR1 subunit. The reduction in the intracellular levels of both ATP and Mg-ATP deranges the fine regulation of KATP channels. This leads to an increase in the basal secretion of insulin and induces hyperinsulinemia, thus contributing to a chronic exposure of cells to insulin and to the development of insulin resistance fostered also by the concomitant low grade inflammation [89]. Moreover, the prolonged hyperinsulinemia typical of insulin resistance induces an increase in renal excretion of Mg2+, thus perpetuating a vicious cycle [90]. In addition, we recall that physiological concentrations of insulin and glucose stimulate Mg2+ transport, thus increasing intracellular Mg2+ content. It is noteworthy that low intracellular Mg2+ impairs cell responsiveness to insulin, because low intracellular Mg2+ alters the tyrosine-kinase activity of the insulin receptor (INSR), leading to the development of post-receptor insulin resistance and decreased cellular glucose utilization [89,91]. In particular, Mg2+ and Mg-ATP complex are key regulators of the PI3K/Akt kinase pathway downstream to the INSR. This pathway starts with INSR auto-phosphorylation, which triggers the downstream kinase cascade. Insulin receptor substrate (IRS) mainly activates phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K), which generates the second messenger phosphatidylinositol-3,4,5-triphosphate (PIP3). PIP3 activates 3-phosphoinositide dependent protein kinase-1 (PDK1), which activates Akt. Akt regulates the metabolic actions of insulin, including glucose uptake by GLUT4 mobilization in skeletal muscle and adipose tissue, glycogen and protein synthesis and lipogenesis. For this reason, the lower is the basal intracellular Mg2+ concentration, the higher is the amount of insulin required to metabolize the same glucose load, indicating decreased insulin sensitivity [89,91]. All these data underline that insulin action is strictly dependent on the intracellular Mg2+ concentration.

위와 같은 이유로 세포 내 마그네슘 이온의 농도가 낮을 수록 같은 양의 glucose를 대사하기 위해서 더 많은 양의 인슐린이 필요하게 된다. 이는 즉, 인슐린 민감성이 감소하는 것이다. 이러한 모든 데이터들은 인슐린 호르몬의 작용이 세포 내 마그네슘이온 농도에 철저히 의존한다는 것을 나타낸다. 마그네슘이 부족하면 인슐린이 제대로 작용하지 못하고, 마그네슘이 충분히 있어야 적절히 잘 작용한다.

Figure 2
Links between Mg2+ and insulin signaling. For details, please see the text.

Mg2+ deficiency can also contribute to T2D through the modulation of Na+/K+-ATPase that is crucial for maintaining the membrane potential and low cytoplasmic sodium concentration. Mg2+ ions drive the conformational change of the sodium pump whose dysfunction has been correlated to T2D [92,93]. Moreover, some single nucleotide polymorphisms in the TRPM6 gene are associated with an increased risk of developing T2D because TRPM6 cannot be activated by insulin in the presence of these mutations [94].

The observation that several pharmacological treatments for diabetes, such as metformin, appear to increase Mg2+ levels further supports this assumption and suggests a substantial interdependence between Mg2+ deficiency and the development of insulin resistance and T2D. Mg2+ deficiency may not be a secondary consequence of T2D, but it may contribute to insulin resistance and altered glucose tolerance, thereby leading to T2D [82].

Few studies have discussed the relationship between hypomagnesemia and metabolic disorders in childhood and adolescence. Mg2+ deficiency in obese children may be secondary to decreased dietary Mg2+ intake. Obese children show lower serum Mg2+ levels than the normal-weight control group. In obese children and adolescents, Mg2+ blood concentration is inversely correlated with the degree of obesity and is related to an unfavorable serum lipid profile and higher systemic blood pressure than healthy controls [95,96]. The association between Mg2+ deficiency and insulin resistance has been described also in childhood [97]. Mg2+ supplementation or increased intake of Mg2+-rich foods to correct its deficiency may represent an essential and inexpensive tool in preventing T2D in obese children.

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6. Mg2+ and Gut Microbiota

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The gut microbiota is a complex microbial ecosystem, symbiotic with humans, that plays a crucial role in a series of pathophysiological processes. In healthy subjects the gut microbiota is rich in microbial species and, through its genes and metabolites (i.e., short-chain fatty acids, amino acid derivatives, secondary bile acid), it acts as an immunologic and metabolic organ [98,99]. By contrast, obesity and related metabolic disorders, such as MetS and T2D, determine profound functional and compositional alterations in the intestinal microbiota, collectively referred to as dysbiosis [100].

비만이나 관련 대사장애 환자들은 장내세균총이 망가져 있는 경우가 많았다.

Little is known about Mg2+ deficiency and gut microbiota in humans, while some data are available in animal models. A 6-week Mg2+-deficient diet in rodents altered the gut microbiota and was associated with anxiety-like behavior [101]. In particular, Mg2+ deficiency may mediate an imbalance of the microbiota–gut–brain axis, which contributes to the development of depressive-like behavior [102]. It should be pointed out that obesity increases the risk of depression and depression was found to be predictive of developing obesity [103].

마그네슘 결핍이 장내세균총에 끼치는 영향에 대해서 정확한 사실이 다 알려진 건 아니지만,

몇몇 동물실험 연구들에서는, 마그네슘 결핍이 미생물-장-뇌 축의 불균형을 초래하여 우울증 유사 행동을 발전시키는데 기여할지도 모른다고 추측하고 있다.

Moreover, epidemiological data have demonstrated that obesity is an important risk factor for the development of gastroesophageal reflux disease [104] and PPI used for the treatment of such disease, may lead to Mg2+ deficiency also through the involvement of the gut microbiome [105]. As previously mentioned, Mg2+ deficiency is a nutritional disorder connected to a low-grade, latent chronic inflammatory state. Interestingly, in Mg2+-deficient mice, changes in intestinal bifidobacteria levels are associated with an inflammatory response, thus creating an effective link between Mg2+ status, gut microbiota and inflammation [106].

역학데이터에 따르면 비만은 위식도역류 질환 발병의 중요한 위험인자중의 하나이다. 그리고 PPI(위산 분비 억제제)는 이 질환의 치료법으로서 사용되고 있는데, 문제는 PPI가 장내 미생물총에 영향을 끼쳐 결과적으로 마그네슘 결핍을 유발할 수 있다.

It is now widely accepted that an altered gut microbiota composition participates in systemic low-grade inflammation [107,108,109,110]. An analysis of patients with different glucose tolerance suggests that both structure and diversity of gut microbiota are altered in the presence of impaired glucose regulation and T2D [111,112]. However, Thingholm et al. compared the microbiota composition of obese versus lean subjects and obese versus obese with T2D. The authors observed that microbiome diversity and functionality were significantly reduced in obese compared to lean subjects, while only modest differences emerged when comparing the microbiome of obese versus obese with T2D [113]. Therefore, the development of obesity-associated T2D could be related to a progressive disruption of the gut microbiome. Gut microbiota manipulation through dietary adjustment has become an important research direction in T2D prevention and therapy. In this perspective, Mg2+ supplementation might help in remodeling the microbiota. Indeed, Mg2+ supplementation in obese subjects with and without T2D affects microbial composition and functional potential [113]. Moreover, dietary supplementation with a multi-mineral functional food derived from seaweed and seawater, rich in bioactive Mg2+ and other trace elements, significantly enhances the gut microbial diversity in adult male rats [114].

To conclude, an adequate Mg2+ dietary intake could positively affect the composition of the intestinal microbiota and, consequently, the host metabolism, thus helping in preventing metabolic alterations associated with the development of MetS and TD2. However, the path for clarifying the impact of Mg2+ in this emerging field of research is still long.

결론적으로 적절한 식단을 통한 마그네슘 섭취는 장내 미생물총 구성에 긍정적인 영향을 준다.

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7. Dietary Mg2+

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The intakes of food rich in Mg2+, including whole grains, nuts and seeds, legumes, and dark-green vegetables, were associated with a lower incidence of obesity, T2D and MetS [43]. Therefore, correcting unhealthy diets is a priority to meet the daily-recommended requirement for Mg2+. However, because of agronomic and environmental factors as well as food processing, Mg2+ content in fruits and vegetables dropped in the last 50 years [115] and it might be necessary to supplement it.

일일 마그네슘 권장량을 잘 챙겨먹는 것이 좋은데, 요새는 건강치 못한 식습관과 농업,환경 변화에 따라 과일이나 야채에 들어있는 마그네슘 양 자체도 줄어들어서 이를 만족하기가 어려워졌다. 따라서 마그네슘 보충제를 챙겨 먹어야 할 필요가 있다.

This is an approach that has been proven beneficial in T2D and MetS (Figure 2). The daily administration of 250 mg of elemental Mg2+ for three months improves glycemic control in T2D subjects as demonstrated by the significant reduction of glycated hemoglobin, insulin levels, C-peptide, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) [116]. This effect is probably due to the correction of an underlying latent Mg2+ deficiency. Indeed, the supplementation with 360 mg of Mg2+ for the same period does not improve insulin sensitivity in normomagnesemic T2D patients [117]. The administration of 250 mg of elemental Mg2+ for 12 weeks improved the wound healing of diabetic foot ulcers, decreasing the lesion size, and ameliorating glucose metabolism [118]. Mg2+ could also affect glucose metabolism by modulating the concentration of inflammatory cytokines, such as IL-6. Although these data need to be confirmed, in prediabetic subjects, the supplementation with 380 mg of Mg2+ provides a trend of reduction in IL-6 plasmatic levels while there are no differences in the levels of C-reactive protein (CRP), Tumor Necrosis Factor-alpha (TNF-alpha), and Interleukin 10 (IL-10) [119]. It is noteworthy that, in apparently healthy runners fed a low Mg2+ diet, the administration of 500 mg of Mg2+ lowers IL-6 levels, reduces muscle soreness and increases post-exercise blood glucose [120].

마그네슘 결핍이 있는 제 2형 당뇨병 환자에게서만 관련 증상, 지표들의 개선이 있다. 결핍이 없는 사람의 경우 별다른 개선효과가 안나타남

Mg2+ supplementation seems to improve blood pressure control and vascular resistance in patients with essential hypertension [121]. The administration of 300 mg of Mg2+ for one month decreases systolic and diastolic pressures, systemic vascular resistance, and left cardiac work [122]. The oral Mg2+ supplementation with 600 mg for 12 weeks is associated with moderate but consistent ambulatory blood pressure reduction in patients with mild hypertension [123]. This result can be explained by the evidence that Mg2+ is a Ca2+ antagonist, increases the synthesis of vasodilators such as prostacyclin and nitric oxide, and inhibits vascular calcifications through the modulation of TRPM7 [123,124]. An increase in the transcription of the Mg2+ channel TRPM6 could explain the antihypertensive effects of Mg2+ supplementation. The increase of TRPM6 mRNA expression‎ is obtained with the administration of 360 mg of Mg2+ for four months [124]. The positive effect of Mg2+ supplementation on blood pressure is also reported in patients already undergoing drug treatment for hypertension. In thiazide-treated women, the administration of 600 mg of Mg2+ improves endothelial function and subclinical atherosclerosis [125]. In hemodialysis patients, the administration of 440 mg of Mg2+ for six months decreases carotid intimate-media thickness, which is a marker of cardiovascular disease. This effect is not associated with an improvement of endothelial function measured by brachial artery flow-mediated dilatation and might be explained by the modulation of calcification through the regulation of calcium and phosphorus concentration in blood [126]. In disagreement with the aforementioned results, a randomized controlled trial on overweight and obese middle-aged and elderly adults did not report any improvement of endothelial function and cardiometabolic risk markers after supplementing 350 mg Mg2+ daily for 24 weeks [126,127].

마그네슘 보충하는 것은 본태성 고혈압 환자의 혈압 조절과 혈관 저항성을 개선하는데 도움이 되는 것으로 보인다.

마그네슘 이온은 칼슘이온의 길항제로서 혈관확장 성분(prostacyclin, NO 등)의 합성을 증가시키고 TRPM7을 조절하여

혈관의 석회화(calcification)를 억제한다.

이러한 혈압조절에 관한 마그네슘 보충의 긍정적인 효과는 이미 고혈압 약물 치료를 받고 있는 환자에게서도 보고 되었다.

(이미 이뇨제 thiazide치료를 받고 있는 고혈압 여성환자에게 하루 600mg씩 마그네슘을 보충해준 결과 혈관내피세포 기능과 무증상 죽상동맥경화증이 개선되었음)

이러한 효과는 마그네슘이 혈중 칼슘과 인의 농도를 조절하여 석회화를 억제, 조절해주는 것으로 보인다.

Since correcting Mg2+ status lowers blood pressure, corrects lipid profile and ameliorates the control of glycemia, it is not surprising that Mg2+ supplementation has positive effects in MetS. The supplementation of 380 mg of Mg2+ for 16 weeks improves MetS by reducing blood pressure, hyperglycemia, and hypertriglyceridemia [128], because the correction of hypomagnesemia leads to changes in gene expression‎ and proteomic profiling consistent with favorable effects on several metabolic pathways [85]. The effect of Mg2+ on the lipid profile is still debated and appears to be mediated by the improvement of insulin resistance and appears to be present only if Mg2+ supplementation corrects a previous deficiency [129]. The administration of 370 mg of Mg2+ in healthy normomagnesemic young men with a family history of MetS does not show beneficial effects on blood pressure, vascular function, and glycolipid profile [130]. For MetS, as well as for T2D, the positive effect of Mg2+ administration is only registered if the supplementation corrects a condition of hypomagnesemia.

마그네슘 투여는 혈압, 혈당, 중성지방을 낮추어 대사증후군을 개선시켰다.

하지만 마그네슘이 정상(Normomagnesemic)일 경우 혈압, 혈관기능, 당지질을 개선하는데 별다른 효과가 없었다.

따라서 대사증후군과 제 2형 당뇨병에서 마그네슘 보충제가 긍정적인 개선효과를 보이는 경우는

오직 환자가 마그네슘 결핍이 있을 경우로 제한된다.

Some critical issues emerge from the analysis of the literature and complicate the interpretation of the data (Table 1). First, there is no agreement on the dosages and timing of Mg2+ supplementation in the treatment of MetS, T2D, and hypertension. Considering the literature just discussed [109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124], the dosage of Mg2+ varies from 250 mg to 600 mg, with a median of 380 mg (95% confidence interval (CI) 300–500 mg). The time of Mg2+ supplementation ranges between 7 days and six months, with a median of about three months (95% CI 4–24 weeks). Besides, there is no consensus on the type of Mg2+ salt to use. The bioavailability of different Mg2+ salts has been investigated in depth [131,132,133,134]. Magnesium sulfate, oxide, carbonate, chloride, citrate, malate, acetate, gluconate, lactate, aspartate, fumarate, acetyl taurate, bis-glycinate, and pidolate are all employed in Mg2+ supplementation. In part, the differences in the bioavailability of Mg2+ salt is due to their different solubility [135]. Although organic Mg2+ salts were slightly more bioavailable than inorganic Mg2+ salts, inorganic Mg2+ salts have been administered to patients with interesting clinical outcomes. The choice of the type of Mg2+ salt based on its bioavailability conditions its dosage and the possible side effects, especially as intestinal symptoms of osmotic dysentery [136] (Figure 3).

여러 논문들의 마그네슘 투여량 중앙값은 380mg per day / 3개월이다.

Figure 3
Beneficial effects of magnesium supplementation in hypomagnesemic patients with metabolic syndrome and type 2 diabetes.

여러 논문들의 결과를 종합해보면

저마그네슘 혈증이 있는 제 2형 당뇨병환자나 대사증후군 환자에게

매일 마그네슘 250~600mg 씩 7일에서 6개월까지 투여하였을때 여러가지 긍정적인 지표개선이 보였다.

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Table 1

A quick recap of the last and most relevant clinical trials describing the effects of Mg2+ supplementation on obesity, metabolic syndrome (MetS), and type 2 diabetes (T2D).

Author(s)	Year	Dosage of Mg2+ Supplementation	Type of Salt	Timing of Mg2+ Supplementation	Effects of Mg2+ Supplementation	Ref.
Elderawi WA et al.	2018	250 mg/day	Oxide, gluconate, lactate	3 months	Improves glycemic control in T2D subjects with a reduction of glycated hemoglobin, insulin levels, C-peptide, and HOMA-IR.	[116]
Navarrete-Cortes A et al.	2014	360 mg/day	Lactate	3 months	No effects on insulin sensitivity.	[117]
Razzaghi R et al.	2018	250 mg/day	Oxide	12 weeks	Improves wound healing of diabetic foot ulcers, decreasing the lesion size, and ameliorating glucose metabolism.	[118]
Simental-Mendía LE et al.	2012	380 mg/day	Chloride	3 months	Reduces IL-6 plasmatic levels.	[119]
Steward CJ et al.	2019	500 mg/day	Oxide, stearate	7 days	Lowers IL-6 levels, reduces muscle soreness and increases post-exercise blood glucose.	[120]
Banjanin N et al.	2018	300 mg/day	Oxide	1 month	Decreases systolic and diastolic pressures, systemic vascular resistance, and left cardiac work.	[122]
Hatzistavri LS et al.	2009	600 mg/day	Pidolate	12 weeks	Reduces ambulatory blood pressure.	[123]
Rodríguez-Ramírez M et al.	2017	360 mg/day	Lactate	4 months	Increases TRPM6 mRNA relative expression‎.	[124]
Cunha AR et al.	2017	600 mg twice a day	Chelate (not better specified)	6 months	Improves endothelial function and subclinical atherosclerosis.	[125]
Mortazavi M et al.	2013	440 mg 3 times per week	Oxide	6 months	Decreases carotid intimate-media thickness, which is a marker of cardiovascular disease.	[126]
Joris PJ et al.	2017	350 mg/day	Citrate	24 weeks	No effect on endothelial function.	[127]
Rodríguez-Morán M et al.	2018	380 mg/day	Chloride	16 weeks	Improves MetS by reducing blood pressure, hyperglycemia, and hypertriglyceridemia.	[128]
Cosaro E et al.	2014	370 mg twice a day	Pidolate	8 weeks	Effects on blood pressure, vascular function, and glycolipid profile.	[130]

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HOMA-IR: Homeostasis Model Assessment-estimated for Insulin Resistance; IL-6: Interleukin-6; TRPM6: Transient Receptor Potential Melastatin 6.

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8. Conclusions

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Obesity, type 2 diabetes, and metabolic syndrome are intertwined conditions characterized by chronic low-grade inflammation partly attributable to Mg2+ deficiency. In metabolic diseases, a low Mg2+ status mainly due to unhealthy diets contributes to generate a pro-inflammatory environment that exacerbates metabolic derangement.

비만, 제 2형 당뇨병, 대사증후군은 낮은 정도의 염증이라는 특징을 공유하며 서로 얽혀 있다. 이러한 염증상태는 부분적으로 마그네슘 결핍에서 기인한다.

Mg2+ supplementation seems to foment the correction of this vicious loop, but at the moment it is hard to interpret whether Mg2+ beneficial effects occur through a direct effect on metabolic pathways or an indirect action on inflammation, or both.

마그네슘 보충제는 이런 질환들의 악순환의 고리를 고치는데 도움이 되는 것으로 보이지만 아직 모든 기전이 다 밝혀지진 않았다.

Several important points need to be clarified. At the clinical level, more studies are necessary to define which Mg2+ salt and which dosage guarantee better outcomes. In addition, the investigation of microbiota in hypomagnesemic subjects might provide interesting hints and suggest targeted dietary approaches aimed at harmonizing the gut microbial ecosystem. In addition, biomarkers that grant the possibility of eval‎uating Mg2+ homeostasis should be identified. At the cellular and molecular level, it is important to focus on the role of intracellular Mg2+ in modulating cell function, from the regulation of metabolism to the release of inflammatory mediators.

Considering the worldwide preval‎ence of obesity, type 2 diabetes and metabolic syndrome, the correction of bad dietary habits and, eventually, the supplementation of Mg2+ might represent an inexpensive but valuable tool to contain the occurrence and the progression of these conditions.

비만, 제 2형 당뇨병, 대사증후군의 전세계적 유병률을 고려했을때,

나쁜 식습관의 교정과 마그네슘 보충제의 섭취는 이러한 질환들의 발병과 진행을 억제하는 가성비 좋은 방법이 될 것이다.

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Acknowledgments

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The authors acknowledge support from the University of Milan through the APC initiative. Moreover, this work was developed as part of the PhD program in Nutrition Sciences, University of Milan.

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