1. Introduction
Diabetes is characterized by dysglycemia and is a major contributor to the development of stroke, heart attacks, and blindness. Considering the rapidly increasing global incidence of diabetes, the International Diabetes Federation predicts an alarming global health situation owing to diabetes and its associated complications in the 21st century [
1].
The pre-diabetic stage is characterized by insulin metabolism abnormalities, pancreatic dysfunction, and intermediate hyperglycemia [
2]. Approximately 70% of people with pre-diabetes develop diabetes [
3]. Given that pre-diabetes increases the risk of microvascular and macrovascular complications [
4,
5], individuals with pre-diabetes risk should be identified early, and lifestyle changes, such as diet control, regular physical exercise, and pharmacological intervention to prevent further progression and associated complications, should be implemented [
6,
7].
Insulin resistance (IR) is a major cause of type 2 diabetes (T2D) that increases the risk of subsequent retinopathy, renal dysfunction, and cardiovascular diseases. Within patients with pre-diabetes, the insulin level is elevated to help maintain normal glucose levels. However, this can lead to chronic hyperinsulinemia, hyperglycemia-induced pancreatic beta-cell dysfunction, and ultimately T2D. Obesity, increased visceral adipose tissue, family history of T2D, and fatty liver are associated with IR. Although the mechanisms underlying IR are not completely understood, ectopic lipid accumulation, endoplasmic reticulum stress, and inflammation of the liver and skeletal muscles are suggested as major contributors [
8].
Various compounds have been tested for blood glucose regulation in patients with diabetes or individuals with pre-diabetes [
9,
10,
11]. Oral magnesium (Mg
2+) supplements can improve blood glucose control in individuals with pre-diabetes and patients with diabetes [
12,
13,
14]. Mg
2+ is vital in glucose metabolism, fat, protein, and nucleic acid synthesis, and muscle contraction and is a key factor influencing dyslipidemia, hypertension, metabolic abnormalities, and bone health [
15]. Additionally, interactions between Mg
2+ and calcium (Ca
2+) affect IR at the cellular level [
16]. Several clinical studies have reported that dietary supplementation of Mg
2+ alleviates IR and reduces blood glucose levels [
17,
18,
19]. Low Mg
2+ levels are common in patients with T2D; this is associated with reduced metabolic rate and chronic complications [
20,
21]. Therefore, Mg
2+ supplementation is suggested as an adjuvant therapy for managing diabetes [
13,
14].
Seawater at depths of 200–2300 m is referred to as deep seawater, where almost no organic matter or pathogens exist and a temperature of <3 °C is maintained. Deep seawater is rich in minerals vital for the growth of marine organisms, including sodium (Na
+), Mg
2+, Ca
2+, and potassium (K
+) [
22], making it a useful marine resource for the food, medical, cosmetic, and agriculture industries.
Preliminary animal studies have shown that deep seawater can restore pancreatic function in obese diabetic mice fed a high-fat diet [
23]. Additionally, deep seawater lowers blood glucose levels by downregulating the expression of glucose production-associated genes and upregulating the expression of glucose uptake- and fatty acid degradation-associated genes [
23,
24,
25]. In a previous eight-week clinical trial involving patients with impaired fasting glucose or impaired glucose tolerance (IGT), homeostatic model assessment for IR (HOMA-IR), total cholesterol, and low-density lipoprotein cholesterol levels improved following administration of a deep seawater formulation containing Mg
2+ as a functional ingredient [
26]. These findings demonstrate the positive effects of Mg
2+ content in deep seawater on blood glucose metabolism, including IR alleviation.
In this study, we aim to confirm the IR-alleviating effect of Mg2+-containing deep seawater by measuring changes in various indicators associated with insulin metabolism. Further, we evaluate the levels of glucose and blood glucose-related indicators in patients with IGT following the administration of Mg2+-containing deep seawater mineral extracts for 12 weeks.
4. Discussion
This study explored the efficacy of deep seawater mineral extracts on indicators associated with blood glucose level and insulin sensitivity following daily consumption for three months by patients with IGT. After three months of intake, the fasting insulin, C-peptide, HOMA-IR, HOMA-β, QUICKI, and ISI
stumvoll levels in the deep seawater mineral extract group were considerably improved compared with those in the placebo group. However, no significant difference was observed in fasting blood glucose, postprandial blood glucose, iAUC, or HbA1c levels. Based on the changes in the test group, three months of Mg
2+ supplementation may not be sufficient; therefore, longer supplementation periods may be required. A meta-analysis of clinical trials revealed that oral supplementation of Mg
2+ markedly improves the HOMA-IR index without impacting blood glucose, insulin, or HbA1c levels in patients with diabetes and individuals without diabetes. However, oral Mg
2+ supplementation in the study subgroup with a supplementary period of four months or more shows notable improvement in fasting blood glucose concentration and HOMA-IR index compared to the subgroup with a supplementary period of under four months [
18].
There was no positive effect on the HbA1c level following Mg
2+ supplementation in this study, possibly because the HbA1c level is an index of total blood glucose concentration for the preceding 3–4 months [
34]. Therefore, the HbA1c level may not apply to blood glucose control effects in short-period trials. Song et al. [
35] presumed that 1769 participants were required per treatment group and that elemental Mg
2+ should be administered at least 360 mg per day for at least four months to confirm the effects on HbA1c value.
The current study findings provide evidence that Mg
2+ supplementation alleviates IR in individuals with pre-diabetes. Indices designed to assess insulin sensitivity using fasting specimens (HOMA-IR, QUICKI, and HOMA-β) and the OGTT-derived index (ISI
stumvoll) improved after Mg
2+ supplementation for three months. ISI
Stumvoll showed a marked improvement, whereas ISI
0,120 did not. There may be several reasons for the heterogeneous response of the IR index. The ISI
0,120 may be insensitive to detect insulin concentration changes, and longer durations of Mg
2+ supplementation may be required to achieve remarkable results. It was hypothesized that Mg
2+ primarily affects liver function rather than peripheral IR. Similarly, an index designed to assess insulin sensitivity using fasting samples that primarily reflects the fasting blood glucose level in the post-absorptive state and hepatic IR is an indicator of hepatic glucose production that is markedly improved by Mg
2+ supplementation [
36].
C-peptide is the cleavage product of proinsulin, the first molecule in the insulin synthesis pathway. C-peptide is stored in the secretory granules of the Golgi complex of pancreatic beta cells, removed from proinsulin, and secreted with insulin. Although C-peptide and insulin are secreted in the same molar quantity, the former has a longer half-life in blood and, thus, serves as an indicator of the pancreas’ insulin secretory function [
37]. Additionally, unlike insulin, the liver cannot metabolize C-peptide secreted into the portal vein. Hence, measuring blood C-peptide levels can accurately measure portal vein insulin secretion and serve as an indicator of beta cell function [
38]. In this study, insulin resistance was improved (
Table 8), and C-peptide levels decreased (
Table 7) in the Mg
2+ intake group. This further confirms that Mg
2+ intake improves insulin resistance and is expected to further improve the protective function of pancreatic beta cells.
Mg
2+ is a critical component of glucose metabolism in pancreatic beta cells [
39]; higher Mg
2+ concentrations are associated with greater insulin sensitivity [
40]. The influence of Mg
2+ on insulin activity was proposed at the start of the 1980s [
39]; subsequently, several clinical studies have observed the critical role of Mg
2+ in insulin-related metabolism, suggesting that Mg
2+ can be used to prevent T2D by alleviating IR [
41].
Similar to the observations of this study, previous studies have shown the efficacy of Mg
2+ in alleviating IR in individuals with pre-diabetes. Mg
2+ supplementation in patients with hypomagnesemia improves insulin sensitivity and the function of beta cells of pancreatic islets of Langerhans [
17,
39,
40]. The present study results are consistent with those of a previous clinical trial, demonstrating that treatment with 365 mg/day of Mg
2+ for six months remarkably improved fasting insulin and IR in individuals without diabetes [
42]. A study on American adults assessed the long-term effects of Mg
2+ supplementation on insulin metabolism, reporting that increased Mg
2+ intake lowers long-term IR when HOMA-IR is measured repeatedly over 20 years [
43].
The results of this study confirmed a previously reported association between increased Mg
2+ ingestion and reduced incidence of T2D [
44,
45]. The observation that ingesting high Mg
2+ concentrations lowers the incidence of T2D is in line with previous findings [
17,
39,
40]. Furthermore, previous clinical trials on Mg
2+ supplementation in patients with diabetes and individuals without diabetes showed that Mg
2+ supplements can improve blood glucose levels, insulin-related metabolism, and the function of beta cells of pancreatic islets of Langerhans [
41,
46,
47].
Interestingly, the present study findings suggest that the link between Mg
2+-related metabolic disorders is stronger when hyperinsulinemia and IR are included in the definition of metabolic disorders than when hyperglycemia or impaired blood glucose responses are included. Mg
2+ ingestion is valuable for maintaining insulin metabolism and overall health since insulin levels and IR elevation are precursors of chronically high fasting glucose levels [
48].
Hypomagnesemia is thought to have detrimental effects on beta-cell proliferation and mass, affecting insulin production and secretion [
39,
49]. High circulating insulin levels over a long period in IR can increase Mg
2+ excretion in the kidney [
38]. Conversely, Mg
2+ substitution does not alleviate IR or improve metabolic regulation in patients with metabolic syndromes [
50]. These results can be attributed to Mg
2+ formulation, dose, and duration of administration. The supplement was administered for three months in the present study, whereas Mg
2+ supplementation periods ranged from one to six months in previous studies [
12,
42,
47,
50,
51], and better results were obtained in trials with prolonged supplementation periods.
However, a few studies show that Mg
2+ does not affect glucose metabolism [
52,
53,
54,
55]. This may be because most studies have measured total magnesium in the bloodstream as free or bioavailable magnesium is not easy to measure. Ultimately, it is the amount of magnesium that is absorbed and utilized that is relevant.
Mg
2+ occurs in various forms. Cooperman [
56] suggested that more water-soluble magnesium is superior as it is relatively well absorbed, inexpensive, chemically stable, and does not cause diarrhea when taken in appropriate amounts. Magnesium oxide is used in most Mg
2+ supplements and is cheaper than other forms; however, it is poorly absorbed and is more likely to cause diarrhea. However, magnesium chloride, the main ingredient in the clinical trial product in this study, can be absorbed better as it is in a more water-soluble form when ingested. In particular, magnesium chloride is less likely to cause diarrhea and is recommended at high doses, suggesting that the aqueous state is optimal for ingestion.
Mg
2+ can alleviate IR through multiple mechanisms. First, Mg
2+ can improve insulin secretion by pancreatic beta cells [
39]. These findings on IR have been verified by previous studies demonstrating that Mg
2+ can reduce oxidative stress [
57], pro-inflammatory cytokine levels [
58], and acute-phase protein content [
59,
60]. Second, Mg
2+ directly affects tyrosine kinase activity and the autophosphorylation of the beta subunits of the insulin receptor and its downstream pathways [
61,
62,
63]. Finally, Mg
2+ plays a key role in muscle metabolism and mitigates IR in muscles [
64]. Similarly, Mg
2+ deficiency is involved in impaired glucose metabolism since it blocks the insulin pathway, reduces kinase dependence, and induces an acute-phase response related to a decrease in insulin sensitivity and subsequent glucose metabolism disorder [
65].
Potassium (K
+) is an essential mineral that plays a key role in determining the intracellular osmotic pressure and acid–base balance. K
+ intake exhibits a blood pressure-lowering effect via the renin–angiotensin system-mediated sodium (Na
+) excretion, in which renin secretion inhibition results in reduced Na
+ reabsorption, more K
+ is discharged, and blood pressure is lowered. In addition, as the K
+ concentration increases, the activation of Na
+–K
+–ATPase pumps causes vascular expansion via hyperpolarization of vascular endothelial cells [
66]. Epidemiologic studies suggest that increased K
+ and Mg
2+ intake and consumption of fruits and vegetables rich in antioxidant nutrients help lower the blood pressure [
67,
68]. Although the intervention used in this study contains K
+ and Na
+, it is unlikely that these mineral components are potential confounders. However, after improving the methods for mineral extraction from deep seawater, we will conduct clinical trials using Mg
2+ alone as an intervention.
In this study, Mg2+ was set as a functional component in deep seawater mineral extract, and its ability to improve insulin resistance was verified. However, it is necessary to improve the current deep seawater mineral extraction method further and develop a separate extraction method for each mineral for mass production. Each component of the minerals extracted through this method as well as combinations of minerals related to medical efficacy must be evaluated to clearly establish the relationships between the mineral components and efficacy. Additionally, it is necessary to identify differences in medical efficacy through comparative verification between deep seawater minerals and general minerals.
This study has certain limitations. First, given the patient-directed nature of this study, it was not possible to ensure the prescribed amount of Mg2+ was consumed, impacting the accuracy of the results. Second, any change in the blood glucose and HbA1c levels could not be measured as the Mg2+ intake period was short (3 months). Accordingly, more meaningful results may be obtained if a longer Mg2+ intake period is employed in future clinical trials with more patients and changes in intake route and product formulations assessed. When preparing products for future clinical trials, we plan to analyze the minor components in the clinical trial product to interpret its effects and include a control group that receives Mg2+ supplementation alone.