JCED Journal

1.       Abbreviations 

IR                           :               Insulin resistance

PD                          :               Pre-diabetes

T2D                        :               Type 2 diabetes

Mg                          :               Magnesium

HOMA-IR            :               The homeostatic model assessment for insulin resistance

HbA1c                   :               Glycated hemoglobin 

2.       Introduction 

The natural progression to diabetes, going through IR to a PD state, escalates through a progressive deterioration of beta cell function accompanied by insulin resistance leading ultimately to a collapse of the metabolic loops and development of frank T2D. The distinction between PD and IR relies on the methods of detection but the two conditions likely share common pathogenesis and precede the status of full blown diabetes. PD definition relies on higher than normal glucose levels but less than the diabetic levels. IR relies on the detection of higher than normal insulin levels in response to glucose stimulation. 

Ions and micronutrients may play an important role in this process and may potentially be exploited for the diagnosis or possibly treatment of diabetes. Hypomagnesaemia has been implicated in the development of hyperglycemia [1,2]. The hypothesis we propose to test is whether the serum Mg concentration is a potential biomarker that changes through the different phases of T2D development [3]. 

Several heavy metals like cadmium, magnesium, gold and mercury were associated with autoimmune diseases. Autoimmune thrombocytopenia, glomerulonephritis and arthritis have been shown to result from heavy metal exposures in humans and animals. The final judgment remains undetermined as more data is necessary [4-6]. 

Insulin resistance has been shown to alter the transport of magnesium into the cells [7]. Serum magnesium levels were reported to be lower than normal in people with PD compared to those with normal glucose levels. T2D is often accompanied by an alteration of Mg status especially in people whose glycemic profile is poorly controlled [8-9]. 

To our knowledge, there are no published data on magnesium levels and its association with IR, PD and T2D in the lebanese population. Therefore, in our study of 120 individuals aged over 18 years and recruited from private clinics in Beirut, Metn and Kesrouan, we aim to study this association.

Our main objectives are to check if there is an association between magnesium levels on one end and IR, PD, and T2D on the other. Our secondary objectives are to study the influence of risk factors such as family history of T2D on serum magnesium levels and the potential association with sugar control.

Furthermore, it is import to understand the progression of hypomagnesaemia with the stages of glucose intolerance leading to T2D. We hope that understanding the association between Mg level and glucose metabolism may play a vital role in developing strategies to prevent and control the growing burden of diabetes.

3.       Material and Methods

A cross sectional study was conducted to examine the association between magnesium levels and IR, PD and T2D. The design of the study was approved by the Ethics Committee in the Department of Human Nutrition and Dietetics of the Faculty of Agricultural and Food Sciences - Holy Spirit University. One hundred and twenty Lebanese subjects were randomly recruited for this study, from four private endocrine clinics in Keserwan, Metn and Beirut. Subjects had to be over 18 years of age. The patients were excluded if they were diagnosed with type 1 diabetes, gestational diabetes, any endocrine diseases, gastrointestinal diseases, renal or hepatic abnormalities, chronic obstructive pulmonary disease, uncontrolled hypertension (SBP ≥ 180 mm Hg and / or DBP ≥ 90 mm Hg), congestive heart failure, bariatric surgery, angina pectoris, acute myocardial infarction or stroke within six months of the study, taking magnesium supplements, laxatives containing Mg, diuretics or antibiotic

Patients were classified to have IR, PD, T2D or normal glycemic profile by their physician. An audit of their medical records identified HbA1c, fasting glucose and insulin, serum magnesium, weight, height, body mass index, and family history of the first degree relative with T2DM.

An evaluation of serum magnesium levels in these different groups was performed and the subjects were considered to have normal magnesium levels if the Mg is between 1.9 and 2.5 mg / dl, Hypomagnesaemia if Mg is < 1.5 mg / dl and Preclinical hypomagnesaemia for levels of 1.5-1.8 mg / dl.

4.       Statistical Analysis

Data collection and statistical analysis were performed using the Statistical Package for Social Science (SPSS) version 20.0. Continuous variables were expressed as averages with their standard deviations and categorical variables as counts and percentages. The results were considered significant for a value of p <0.05.

The Spearman correlation test was used to study the relationship between two continuous variables of non-normal distribution (magnesium level on the one hand and HOMA-IR, HbA1c, and glycemia on the other). The Chi-square test was used to study the relationship between two qualitative variables (diabetes and hypomagnesaemia). The non-parametric Mann-Whitney test was used to determine the difference in HbA1c and fasting glucose levels between diabetic individuals and normal individuals. In the same way, this test was used to determine the difference of BMI between normal and low magnesium individuals. The age difference between the 3 levels of Mg was compared using the Kruskal-Wallis test.

5.       Results

Among the individuals with IR, 57% had a preclinical hypomagnesaemia (Mg: 1.5-1.8 mg / dl), 17% had a frank hypomagnesaemia (Mg: < 1.5 mg / dl) and 26% had a normal magnesium (Mg: 1.9-2.5 mg / dl).

Among pre-diabetics, 70% had preclinical hypomagnesaemia, 3% hypomagnesaemia and 27% normal magnesium. Among individuals with T2D, 50% had preclinical hypomagnesaemia, 33% hypomagnesaemia and 17% normal magnesium. In the control group, the preclinical hypomagnesaemia was seen only in 13% of individuals, the normal magnesium was found in 87% of normal individuals and no frank hypomagnesaemia was seen in this group. In the IR group, using the Chi-square test, 73.3% of individuals with hyper-insulinemia have hypomagnesaemia compared to 13.3% of normal patients who had hypomagnesaemia in the pre-clinical range. The difference was significant (p <0.001). The Spearman correlation test showed a negative mean correlation between HOMA-IR and Mg in insulin-resistant individuals, with a correlation coefficient of -0.57. The higher HOMA-IR was, the lower the serum magnesium was (p = 0.001).

Among individuals with PD, 73.3% have hypomagnesaemia compared to 13.3% of normal participants (p <0.001). In individuals with T2D, hypomagnesaemia was found in 83.3% of the individuals compared to 13.3% only in normal participants (p <0.001).(Figure 1).

These results show a clear and significant trend for a higher risk of hypomagnesaemia as the metabolism progresses from pre-diabetes to insulin resistance and into T2D. The low levels (Mg <1.5) also progress with those stages.

The Pearson Chi-Square Test showed that Mg levels did not correlate with gender (P = 0.45). Kruskal-Wallis Test was performed to compare the age difference 

between the three levels of Mg and no significant difference was found (p = 0.74).

The Mann-Whitney test used to compare BMI between the groups showed a significant difference (p = 0.007). Individuals with Hypomagnesaemia have an average 

BMI of 27.5 kg / m2 ± 3.5 while those with normal Mg have an average BMI of 25.8 kg / m2 ± 3.4.

6.       Discussion 

Preclinical hypomagnesaemia was highest in PD, while frank hypomagnesaemia was highest in the group with T2D. We found no difference between genders regarding hypomagnesaemia while others reported the serum Mg was lower in women than in men. Hypomagnsemia also correlated with glucose, HbA1C, BMI, and insulin resistance acting as a clear marker of pre-diabetes and diabetes progression. There is a clear relationship between the levels of Mg fall and insulin resistance and glucose intolerance as the situation progresses from PD to IR to T2D. We did not find in our cohort a change of this phenomenon with age as was reported by Barbagallo et al. [3,9]. 

Our study showed an inverse correlation between BMI and Mg similar to other studies as the fact that it is a risk factor for T2D and IR. Several risk factors may affect Mg status by altering glucose metabolism and insulin action [3,11,12].

Hypomagnesaemia is more common in people with a first degree family history of T2DM. There is a significant and independent inverse relationship between serum Mg ion and glycemic indices: the lower the Mg ion, the higher the fasting glucose and HbA1c (p <0.001) with a correlation coefficient of -0.70. By the same token, the association between fasting blood glucose and Mg was negative and significant (p <0.001) with a correlation coefficient of

-0.63.

These results are similar to studies that found insulin resistance is significantly associated with low serum Mg and this condition may progress to T2D specifically in individuals with a first degree family history of T2D [13,14]. 

According to Lima et al. insulin resistance can alter the transport of magnesium into the cells, and may regulate magnesium homeostasis. Insulin can induce excessive Mg excretion and lead to hypomagnesaemia in patients with hyperinsulinemia as demonstrated in our study [15]. 

Compared to the literature, we found a similarity with a study conducted by Guerrero et al..Low levels of serum magnesium in people with PD and are significantly lower than those with normal glucose tolerance test [16]. 

According to Rotter et al. the serum Mg concentration of T2D was lower compared to non-diabetic men, which was demonstrated in our study. In addition, this result was similar to studies that found many endocrine diseases have associations with magnesium deficiency. Among these T2D patients, it was shown that the low Mg levels declined as the disease evolves. Compared with the literature, other studies also showed that diabetic patients are subject to hypomagnesaemia with a strong correlation with glycated hemoglobin [3,17-19]. 

Similar to our findings, Barbagallo et al., found the fasting blood glucose to be inversely proportional to serum Mg levels and attributed this finding to the effects of hyperglycemia increasing urinary excretion of Mg [9]. Glucose homeostasis studies were also similar to our results that documented the negative and significant association between HbA1c and Mg [20-22].

The mechanism of how heavy metals may cause or contribute to diabetogenesis is not all clear but some mechanisms that have been elucidated include accumulation and injury to the islet cells by the metals, or induction of autoimmune processes against the pancreatic islet cells [4-6].

7.       Conclusion

Although our study has some limitations including the relatively small cohort sample size and the lack of information on the Mg-rich food consumption, we can clearly conclude that Mg level correlates negatively with PD, IR and the progression to T2D. The level of Mg also correlates with BMI, glucose and HbA1C.

Hypomagnesaemia is a simple, readily obtainable test that seems to correlate significantly with the development of insulin resistance, glucose intolerance and diabetes. Whether it is an innocent byproduct, a cause or a result of the progressive malfunction that culminates in diabetes is unclear.

Hypomagnesaemia was highest in PD while frank hypomagnesaemia was found most commonlyin the diabetic group implicating a progression with the disease progression.There is an inversely proportional correlation between serum magnesium levels and the three states: IR, PD, and T2D. This correlation may be explainable by the fact that Insulin can induce excessive Mg excretion and lead to hypomagnesaemia in patients with hyperinsulinemia.

Type 2 diabetes was accompanied by an alteration of Mg status especially in people whose glycemic profile was poorly controlled. This hypomagnesaemia is likely a consequence of polyuria, osmotic diuresis causing high renal excretion of magnesium, and reduction of tubular re-absorption due to insulin resistance.

The high body mass index indicating overweight and the presence of first-degree type 2 family history of diabetes increase the risk of hypomagnesaemia.

Our study was the first survey in Lebanon to assess the level of magnesium and its association with IR, PD, T2D. The importance of this research is to understand that the association between Mg level and glucose metabolism may play a vital role in developing strategies to prevent and control the growing burden of diabetes. It might also be used as an indicator reflecting the progressive insulin resistance and its effects on different organs.

Further studies will be needed to elaborate on this association, monitoring diets and physical activity in a larger population. It also remains to be proven whether there are any benefits if magnesium supplementations are given in T2D and its predecessor conditions.

Figure 1: Percentage of preclinical hypomagnesaemia, frank hypomagnesaemia and normal magnesium among the groups of normal individuals, diabetics, those with prediabetes and those with insulin resistance.

Table 1: The relationship between Mg levels and the different risk factors: HbA1c and blood glucose were significantly higher among individuals with hypomagnesaemia (p = 0.008 for HbA1C, and 0.01 for glucose).

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