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MINIREVIEWS

Magnesium and type 2 diabetes

Mario Barbagallo, Ligia J Dominguez

Mario Barbagallo, Ligia J Dominguez, Geriatric Unit, Depart­ and glucose are important regulators of Mg metabolism.
ment of Internal Medicine and Medical Specialties, University of Intracellular Mg plays a key role in regulating insulin
Palermo, 90127 Palermo, Italy action, insulin-mediated-glucose-uptake and vascular
tone. Reduced intracellular Mg concentrations result
Author contributions: Barbagallo M and Dominguez LJ were in a defective tyrosine-kinase activity, postreceptorial
responsible for the initial plan, study design, conducting the impairment in insulin action and worsening of insulin
review, interpretation, manuscript drafting, critical revision of
resistance in diabetic patients. A low Mg intake and an
intellectual content, and approval of the version to be published.
increased Mg urinary loss appear the most important
Conflict-of-interest statement: None of the authors has a conflict mechanisms that may favor Mg depletion in patients
of interest to report. with type 2 diabetes. Low dietary Mg intake has been
related to the development of type 2 diabetes and
Open-Access: This article is an open-access article which was metabolic syndrome. Benefits of Mg supplementation
selected by an in-house editor and fully peer-reviewed by external on metabolic profiles in diabetic patients have been
reviewers. It is distributed in accordance with the Creative found in most, but not all clinical studies and larger
Commons Attribution Non Commercial (CC BY-NC 4.0) license, prospective studies are needed to support the potential
which permits others to distribute, remix, adapt, build upon this role of dietary Mg supplementation as a possible public
work non-commercially, and license their derivative works on health strategy in diabetes risk. The aim of this review
different terms, provided the original work is properly cited and is to revise current evidence on the mechanisms of Mg
the use is non-commercial. See: http://creativecommons.org/ deficiency in diabetes and on the possible role of Mg
licenses/by-nc/4.0/ supplementation in the prevention and management of
the disease.
Correspondence to: Mario Barbagallo, MD, PhD, Geriatric
Unit, Department of Internal Medicine and Medical Specialties,
University of Palermo, Via del Vespro 129, 90127 Palermo, Key words: Magnesium; Type 2 diabetes; Metabolic
Italy. mario.barbagallo@unipa.it syndrome; Inflammation; Aging; Hypertension; Insulin
Telephone: +39-91-6552885 resistance; Endothelium
Fax: +39-91-6552952
© The Author(s) 2015. Published by Baishideng Publishing
Received: April 15, 2015 Group Inc. All rights reserved.
Peer-review started: April 18, 2015
First decision: May 13, 2015 Core tip: Diabetes is frequently associated with Mg
Revised: June 29, 2015 deficit. The fact that most but not all diabetic subjects
Accepted: August 16, 2015 have low magnesium (Mg) and that no large rand­
Article in press: August 17, 2015 omised controlled trial (RCT) has been specifically
Published online: August 25, 2015 focused on subjects with Mg deficit, diagnosed with a
reliable technique, may help explain discrepancies of the
role of supplemental Mg on glycemic control, and the
impact on diabetes risk in prospective epidemiological
Abstract studies. Different baseline Mg, metabolic control, and
age are other potential factors that may contribute.
Type 2 diabetes is frequently associated with both extrace­
Future prospective RCTs are needed to support the
llular and intracellular magnesium (Mg) deficits. A chronic
potential role of dietary Mg supplementation as a
latent Mg deficit or an overt clinical hypomagnesemia
possible public health strategy to reduce diabetes risk in
is common in patients with type 2 diabetes, especially
the population.
in those with poorly controlled glycemic profiles. Insulin

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 Barbagallo M et al . Mg and type 2 diabetes

Barbagallo M, Dominguez LJ. Magnesium and type 2 diabetes. on the mechanisms of Mg deficiency in DM2. The evidence
World J Diabetes 2015; 6(10): 1152-1157 Available from: URL: on the role of Mg supplementation in the man­agement
http://www.wjgnet.com/1948-9358/full/v6/i10/1152.htm DOI: of DM2 will also discussed.
http://dx.doi.org/10.4239/wjd.v6.i10.1152

MECHANISMS OF MG DEFICIENCY IN
DM2
INTRODUCTION Reduced Mg intake and/or augmented Mg urinary loss
Magnesium (Mg) is an electrolyte of chief physiological are among the most important causes of Mg deficits in
importance in the body, being the most abundant DM2, while Mg absorption and retention seems to be
[16-18]
divalent intracellular cation in the cells, the second maintained .
most abundant cellular ion next to potassium and the A relationship between Mg levels in the plasma and
[1]
fourth cation in general in the human body . the development of DM2 in the general population has
[19]
Type 2 diabetes mellitus (DM2) is often accompanied been suggested . DM2 is frequently accompanied by
[20,21]
by alteration of Mg status. An increased prevalence of Mg renal calcium and Mg loss , but the mechanism(s) of
[22]
deficits have been identified in DM2 patients, especially this wasting is still not completely elucidated .
in those with poorly controlled glycemic profiles, with Both hyperglycemia and hyperinsulinemia may
longer duration of the disease and with the presence of increase urinary Mg excretion. Urinary Mg excretion and
[2-6]
micro- and macrovascular chronic complications . fasting blood glucose have been found to be inversely
Laboratory tests with a high sensitivity and specificity related to serum Mg levels. Thus, hyperglycemia
[20]
and easy to perform to allow an accurate clinical assess­ decreases Mg tubular reabsorption . A good metabolic
ment of Mg status are missing. Patients are considered control is associated with a reduction of the urinary Mg
[3]
frankly hypomagnesemic with serum Mg concentrations wasting .
≤ 0.61 mmol/L or 1.5 mg/dL[7-9]. Mg concentrations In streptozotocin-induced diabetic rats, Lee et
[22]
≤ 0.75 mmol/L or 1.8 mg/dL may be considered as al found an increase in renal Mg transporters. The
[10,11]
preclinical hypomagnesemia . alteration was corrected by insulin administration. Insulin
Mg deficiency can be present without hypoma­ resistance and hyperinsulinemia may also affect Mg
[21]
gnesemia. However, hypomagnesemia, when present, transport .
is usually indicative of an important systemic Mg deficit.
A depletion in intracellular and/or ionized plasma Mg can
be found in individuals with normal total serum Mg .
[12] MG AND INSULIN SENSITIVITY
However, most of the studies in the literature have Hypomagnesemia in DM2 is present only in severe
measured total serum Mg instead of the free, ionized (and generally long lasting) Mg deficits. A chronic latent
(bioactive) or the intracellular Mg concentrations, which Mg deficiency without alteration in serum total Mg is
[12]
make it a challenge to correlate Mg deficits to diseases. more commonly observed . These often undetected
We have recently confirmed that diabetic older Mg insufficiencies have clinical importance, since Mg is
patients are more prone to hypomagnesemia; this a main co-factor in numerous enzymatic reactions (>
condition being closely related to metabolic control as 300 enzymatic reactions including all the enzymes of
measured by glycated hemoglobin even after adjustment glycolysis). Mg also is deeply involved in the regulation
for relevant confounders. Ionized Mg may help to identify of insulin signaling, in the phosphorylation of insulin
diabetic older adults with low concentrations of blood Mg receptor kinase, in the post receptorial action of insulin,
[17,23]
that are not evident with the only measurement of total and in insulin-mediated cellular glucose uptake .
[12]
Mg . The clinical consequence of a chronic Mg deficit
Intracellular free Mg levels are consistently reduced is post-receptorial insulin resistance and consequent
in subjects with DM2, when compared with nondiabetic reduced glucose utilization in the cells, worsening the
[1,13,14] [18]
subjects . Although the mechanism has not been reduced insulin sensitivity present in DM2 .
fully elucidated, an alteration in the mechanism(s) of Another possible link between Mg deficiency and
the Mg uptake in the cells, and/or a deficit of ATP, may reduced insulin sensitivity is the presence of oxidative
help to understand the cellular Mg deficit observed in stress and/or inflammation. Thus, free radicals are
[15]
DM2 . The relationship between intracellular Mg and often increased in DM2, hypertension, metabolic
ATP concentration is rather complex. The decrease syndrome and aging, conditions also associated with
[24,25]
in cellular ATP might partially explain the decrease in Mg deficits . In particular, we demonstrated an
cellular Mg. Otherwise, a decrease in cellular ATP leads age-dependent deficit of cellular Mg in persons aged
to a decreased binding of Mg to ATP in the formation 65 years and over, as well as in patients with essential
[14,25]
of MgATP, which might increase the intracellular Mg hypertension or DM2, independently of age .
concentration. Nevertheless, independently of the mechanisms
The aim of this review is to revise current evidence of Mg deficits in DM2, metabolic syndrome, essential

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 Barbagallo M et al . Mg and type 2 diabetes

[34,48]
hypertension and aging, it is apparent that this Mg syndrome has been linked to dietary Mg content .
deficiency may contribute to enhance the insulin resi­ Hypomagnesemia itself in a 10-year follow-up study
[17,18] [49]
stance status of these conditions . Mg deficit could was associated with glucose tolerance impairment .
precede and cause post-receptorial resistance of insulin Conversely, higher Mg intake was associated with
[50]
and alter glucose tolerance. increased insulin sensitivity and with decreased risk
of incident DM2, with a decreased risk of 0.68 in the
[51,52]
higher compared with the lower quintiles .
MG DEFICIENCY AND CARDIO- Similar findings were obtained in the CARDIA study,
METABOLIC DISEASES during a 20-year follow-up, which also confirmed the
reverse relationship of dietary Mg with inflammation
Mg deficiency may be also a factor implicated in DM2 [53]
markers .
complications. We found a relation between ionic
[26]
changes and echocardiographic indices alterations .
We observed an significant association of reduced
[26]
POSSIBLE USE OF MG SUPPLEMENTS IN
cellular Mg with cardiac hypertrophy in DM2 patients .
Cellular Mg measured in vivo in skeletal muscle and THE MANAGEMENT OF DM2
31
in the brain with P-NMR, was directly related to aortic The detection and correction of altered Mg status in
[27]
distensibility . diabetic patients is clinically appropriate, although many
Reduced Mg levels were also associated with an physicians tend to ignore Mg status. The increased
increased prevalence of arrhythmias in DM2 obese risk of developing impaired glucose tolerance and/or
[6]
subjects , and with a more rapid decline of renal func­ frank DM2 in persons with dietary or serum Mg deficits
tion. Thus, hypomagnesemia is currently considered have suggested a potential benefit of Mg supplements
an accurate predictor of progression of diabetic nephro­ in patients with DM2 or in the presence of risk factors
[28-30]
pathy . Mg deficits have also been associated with for DM2. Mg supplements have been proposed as a
[31] [32] [25,33]
cognitive decline , multimorbidity and agin . complementary tool for the prevention of DM2 and its
[54,55]
metabolic control . Some benefits of Mg supplements
on glycemic profiles have been found in most but not all
DIETARY MG DEFICIENCY MAY studies.
PREDISPOSE TO DM2 Regrettably, results from clinical trials are still
[56]
Dietary Mg deficiency may cause insulin resistance as limited . Thus, the clinical evidence of a clear effect
shown by several studies both in humans and in exp­ of Mg supplementation on metabolic indices in persons
erimental animals
[34-40]
. In sheeps, Mg-deficient diet with DM2 are controversial. Some benefit has been
[8,54,57,58] [59]
caused a significant impairment of insulin-mediated found in several , but not in all clinical studies .
[35]
glucose uptake . In rats, Mg supplements were The hypothesis of a role of supplemental Mg in the
[36]
able to postpone the onset of diabetes . In healthy control of DM2 still needs to be ascertained by large
[60,61]
women (without DM2), the higher was the intake of randomized clinical trials . Mg supplementation
[37]
Mg, the lower were fasting levels of insulin . In young, may improve glycemic concentrations in fasting and
nondiabetic African Americans, low dietary Mg was postprandial states, and insulin sensitivity. We found a
associated with insulin resistance and insulin responses significant relationship between the increase in serum
[62]
[38]
to an oral glucose tolerance test . A low Mg diet in rats and cellular Mg and insulin sensitivity . We also showed
produced an increase in triglyceride and plasma glucose that Mg supplementation is able to improve an altered
[63]
[39]
levels . In rats, a maternal restriction of dietary Mg was endothelial function in DM2 older adults . Barragán-
[64]
[40]
able to cause insulin resistance in pups . Suárez et al
[41] Rodríguez et al suggested a positive effect in the
suggested that the worsening of glucose metabolism treatment of depression in older persons with DM2
induced by Mg dietary restriction in experimental rats and hypomagnesemia. Presumably, the main problem
is due to an impairment of both, insulin secretion and is that all RCTs were underpowered, partially through
insulin action. overestimation of the treatment effect. Differences
Deficiencies of Mg status including both hypoma­ may be related to the fact that most of the existing
gnesemia and/or reduced dietary Mg intake have been studies have included a small number of subjects, using
linked to an enhanced risk to develop DM2 or glucose different Mg doses and different Mg salts.
intolerance
[19,42-44]
. Higher Mg intakes were conversely Several studies have linked high Mg content present
associated with a reduced incidence of DM2 .
[45]
in fiber with the positive action of whole grains to
[65-68]
Several studies have shown a clear association of Mg improve insulin sensitivity . Oral Mg supplements
intake with DM2 and with cardio-metabolic syndrome, have been shown to improve fasting and postprandial
suggesting that a higher Mg consumption is related to glucose levels and insulin sensitivity in hypomagnesemic
[57]
a reduction of the incidence of these conditions. Two DM2 patients , to improve insulin sensitivity in non-
[8]
meta-analyses of prospective studies concluded that Mg diabetic subjects with insulin resistance , and to
[46,47]
intake is inversely associated with the onset of DM2 . decrease C-reactive protein levels in hypomagnesemic
[69]
In addition, the development of the cardio-metabolic patients with prediabetes .

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 Barbagallo M et al . Mg and type 2 diabetes

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P- Reviewer: Das UN, Sriraman R, Tomkin GH

S- Editor: Tian YL L- Editor: A E- Editor: Jiao XK

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