European Review for Medical and Pharmacological Sciences 2023; 27: 5784-5794

Effects of water-sodium balance and regulation

of electrolytes associated with antidiabetic drugs
J. ZHANG1,2, M.-N. LI1,2, G.-M. YANG1,2, X.-T. HOU1,2, D. YANG1,2, M.-M. HAN1,2,
Y. ZHANG3, Y.-F. LIU1,2

1
Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi
Province, China
2
First Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi Province, China
3
Department of Pharmacology, Shanxi Medical University, Taiyuan, Shanxi Province, China

Abstract. – As the prevalence of diabetes Introduction

rises, the use of antidiabetic drugs becomes
more frequent. Thus, focusing on the effects of
these drugs on water-sodium balance and elec-
trolyte regulation is necessary. This review dis-
cusses the effects and the mechanisms behind
them. Several sulfonylureas, such as chlor-
propamide, methanesulfonamide, and tolbut-
amide, exhibit water-retaining properties. Other
sulfonylureas, such as glipizide, glibenclamide,
acetohexamide, and tolazamide, are not antidi-
uretic or even diuretic. Numerous clinical stud-
ies showed that metformin can reduce serum
magnesium concentrations and may have an
effect on the cardiovascular system, but the
specific mechanism remains to be discussed.
Different opinions exist about the mechanisms
of thiazolidinedione-induced fluid retention.
Sodium-glucose cotransporter 2 inhibitors can
cause osmotic diuresis and natriuresis and el-
evated serum potassium and magnesium con-
centrations. Glucagon-like peptide-1 receptor
agonists and dipeptidyl peptidase-4 inhibitors
can enhance urine sodium excretion. At the
same time, increased urinary sodium caused
by sodium-glucose cotransporter 2 inhibitors,
glucagon-like peptide-1 agonists and dipepti-
dyl peptidase-4 inhibitors reduce blood pres-
sure and plasma volume, thereby protecting
the heart. Insulin has a sodium-retaining effect
and is also associated with hypokalemia, hy-
pomagnesemia, and hypophosphatemia. Sev-
eral of the aforementioned pathophysiologi-
cal changes and mechanisms have been dis-
cussed, and conclusions have been drawn.
However, further investigation and discussion
are still warranted.
Key Words:
Antidiabetic drugs, Electrolyte, Water-sodium bal-
ance, Insulin, Hypokalemia.
Type 2 diabetes mellitus (T2DM) has become
a major medical issue due to its growing global
prevalence, but many anti-diabetic drugs, once
sanctioned, have been withdrawn from use by
the U.S. Food and Drug Administration1. Sulfo-
nylureas achieve hypoglycemia by stimulating
insulin release from pancreatic islet cells. They
also reduce hepatic insulin clearance, decrease
glucagon secretion, and improve insulin sensiti-
zation in peripheral tissues of patients with type
2 diabetes2. Thiazolidinediones (TZDs) act as a
peroxisome proliferator-activated receptor γ sub-
type (PPAR-γ) activator and can directly reduce
insulin resistance3. Sodium-glucose cotransporter
2 inhibitors (SGLT2i) inhibit glucose absorption
from the kidney’s proximal tubule (PT) and hence
cause glycosuria4. Glucagon-like peptide-1 (GLP-
1) is a substance secreted by the intestines that
promotes insulin secretion. It promotes insulin
secretion by pancreatic β cells in a glucose-de-
pendent manner, which is less likely to induce
hypoglycemia and inhibits glucagon secretion by
pancreatic α cells. Glucagon-like peptide-1 re-
ceptor agonists (GLP-1RAs) enhance the action
of GLP-1 by activating the GLP-1 receptor. Di-
peptidyl peptidase-4 inhibitors (DPP-4i) increase
the level of GLP-1 by inhibiting the inactivation
of GLP-1. GLP-1RAs and DPP-4i thus lower glu-
cose levels, while being widely used in recent
years due to their minimal side effects5,6. All of
these drugs lower blood sugar while altering the
water-sodium balance and electrolyte levels to a
greater or lesser extent. Maintaining water and
electrolyte levels within standard ranges is of

Corresponding Authors: Yunfeng Liu, MD, Ph.D; e-mail: nectarliu@163.com

5784 Yi Zhang, Ph.D; e-mail: yizhang313@163.com
 Water-sodium balance and electrolyte regulation

great importance for cellular activity, biological
function and survival7,8. Abnormalities in water
and electrolytes not only cause sodium retention,
hypomagnesemia, hypokalemia, and hypophos-
phatemia but also further increase the risk of dis-
ease in vital organs such as the heart and kidneys.
In this narrative review of the literature, we pres-
ent and discuss the mechanisms of the effects of
antidiabetic drugs on water-sodium balance and
electrolyte regulation.
The key role of the kidneys in water-sodium
balance and electrolyte homeostasis9 are briefly
outlined below. Figure 1 shows a partial display
of renal tubular reabsorption processes and pos-
sible sites of action of antidiabetic drugs. Most of
the Na and water is reabsorbed at the PT. In the
first half of the PT, the Na+-K+-ATPase at the ba-
solateral membranes of the epithelia reduces the
intracellular Na+ concentration. The Na+-H+ ex-
changer-3 (NHE3), sodium-glucose/amino acid/
phosphate/Cl- cotransporter at the apical mem-
brane then convert Na+ from the tubular fluid into
the epithelia. The Na+-K+-ATPase, in turn, trans-
fers it to the interstitial fluid, where Na+ enters the
blood due to the increased hydrostatic pressure of
the interstitial fluid. SGLT-2 and GLP-1R are both
found in the PT10. In the second half of the PT,
the Cl--HCO3- exchanger at the apical membrane
allows Cl- to enter the epithelia and the K+-Cl-
cotransporter at the basolateral membrane trans-
fers it to the interstitial fluid. The Cl- in the tu-
bular fluid can be reabsorbed by the paracellular
pathway due to the concentration difference, and
then Na+ can be reabsorbed along the potential
gradient by the paracellular shunt. In the PT and
thin descending limbs, aquaporin-1 is abundantly

Figure 1. Partial display of renal tubular reabsorption processes and possible sites of action of antidiabetic drugs. PT, proxi-
mal tubule; tDL, thin descending limb; tAL, thin ascending limb; TAL, thick ascending limb; DCT, distal convoluted tubule;
ADH, Antidiuretic hormone; ANP, Atrial natriuretic peptide.

5785
 J. Zhang, M.-N. Li, G.-M. Yang, X.-T. Hou, D. Yang , M.-M. Han, Y. Zhang, Y.-F. Liu
present in the apical and basolateral membranes11.
Electrolyte reabsorption causes the osmotic pres-
sure of the intercellular fluid to increase; thus,
water is reabsorbed through aquaporin-1 and
paracellular pathways under the action of osmot-
ic pressure. Compared with the thin descending
limb, the thin ascending limb is more permeable
to NaCl and has a 100-fold lower water permea-
bility; thus, NaCl can enter the interstitial fluid via
facilitated diffusion. Approximately 25-30% of
net sodium recovery is done at the thick ascend-
ing limb. Na+-K+-2Cl- cotransporter (NKCC2) at
the apical membrane transports Na+, K+, and Cl-
along a concentration gradient. Na+ and Cl- enter
the interstitial fluid via the Na+-K+-ATPase and
Cl- channel, but K+ goes back into the tubular flu-
id along the concentration. Positive ions, such as
Na+K+Ca2+, are passively reabsorbed by the para-
cellular pathway, resulting in potential differenc-
es caused by K+. In the distal convoluted tubule,
Na+-Cl- cotransporter mainly transfers Na+ and
Cl-. The collecting duct is classified into the inner
medullary collecting duct (IMCD), outer medul-
lary collecting duct and cortical collecting duct.
Here, Na+ uses the concentration difference gen-
erated by Na+-K+-ATPase to cross into the epithe-
lial cells via the epithelial Na channel (ENaC)12.
Water is reabsorbed through aquaporin-2 (AQP2)
in the apical membrane and subapical vesicles in
the principal cells and aquaporin-3.4 in the baso-
lateral membrane. Antidiuretic hormone (ADH)
regulates water reabsorption by controlling the
amount of AQP213. The renin-angiotensin-aldo-
sterone system (RAAS) plays an essential role in
maintaining the water–sodium balance of the hu-
man body14. Aldosterone ultimately acts on ENaC
and Na+-K+-ATPase in the epithelia to increase
Na+ and water reabsorption and K+ excretion15.
Atrial natriuretic peptide (ANP) exerts natriuretic
and diuretic effects by inducing a signaling cas-
cade expressed along the glomerulus and neph-
ron. ANP mainly decreases Na reabsorption by
suppressing ENaC and cyclic nucleotide-gated
cation channels in the epithelial cells of the med-
ullary collecting ducts16. ANP also inhibits the se-
cretion of renin, aldosterone, and ADH17.
Sulfonylureas
Sulfonylureas have been commercially avail-
able since the 1950s, but their use remains con-
troversial18. The effect of sulfonylureas on water
balance is either diuretic or antidiuretic19. Sev-
5786
eral sulfonylureas, such as chlorpropamide and
methanesulfonamide, can cause water retention20.
Some studies21 reported that pharmacological
doses of chlorpropamide can directly increase the
permeability of terminal IMCD to water without
ADH. However, chlorpropamide can induce hy-
ponatremia in approximately 4-6% of patients by
potentiating the ADH effect. The risk of hypona-
tremia development is greater in older patients
who concomitantly use diuretics. Hyponatremia
can be induced by lowering renal clearance of
free water (CH2O) with the addition of Tolbut-
amide22. Other sulfonylureas, such as glipizide,
glibenclamide, acetohexamide, and tolazamide,
are neither diuretic or antidiuretic. The ingestion
of sulfonylureas that lack antidiuretic properties
can increase CH2O by enhancing Na+, K+, and Cl-
reabsorption at the thin ascending limb (tAL)
and thick ascending limb (TAL)20. Additionally,
increased adrenaline secretion caused by sulfo-
nylurea-induced hypoglycemia may be associated
with hypokalemia, hypomagnesemia, and hypo-
phosphatemia in some cases23.
Metformin
Hypomagnesemia often occurs in patients with
untreated diabetes. Hyperglycemia can cause uri-
nary magnesium excretion. Hypomagnesemia is
associated with insulin resistance and the devel-
opment of chronic complications of diabetes mel-
litus24. Meanwhile, the majority of the studies25-28
showed that the use of metformin leads to a de-
crease in serum magnesium concentrations. A co-
hort study25 that included 395 patients with T2DM
reported that plasma magnesium concentrations
were reduced in patients using metformin. A lon-
gitudinally observed Fremantle Diabetes Study26
Phase I that enrolled 940 non-insulin-treated pa-
tients, showed that 19% of patients had serum mag-
nesium <0.70 mmol/L. Serum magnesium con-
centrations were lower in patients on metformin
alone or in combination with sulfonylurea than in
those on diet alone. Gastrointestinal losses due to
increased duration of metformin treatment may be
responsible for hypomagnesemia. A case report27
described a patient who presented with severe and
symptomatic hypokalemia, hypomagnesemia, hy-
pocalcemia, and hypophosphatemia secondary to
metformin-induced diarrhea. In a previous study28,
patients using metformin showed decreased mag-
nesium excretion but remained to have hypomag-
nesemia and hypercalciuria. Although metformin
 Water-sodium balance and electrolyte regulation
treatment does not correct hypomagnesemia, it pre-
vents excessive urinary loss of magnesium. Other
studies29 suggested that serum magnesium levels
are hypothesized not to reflect the original chang-
es caused by metformin treatment, because 99%
of the total body magnesium ions were considered
to be intracellular. Considering that magnesium
plays a key role in regulating vascular tone, intra-
cardiac conduction and myocardial contraction30,
it is reasonable to suspect that metformin-induced
hypomagnesemia may have a detrimental effect on
the heart. However, a study by Peters et al26 found
that metformin treatment was not a significant in-
fluence on cardiovascular disease. So, metformin
resulting hypomagnesemia did not increase cardio-
vascular risk in diabetic patients, possibly because
intracellular magnesium was not reduced. The
mechanism by which metformin causes a decrease
in serum magnesium levels is unclear. Metformin
can directly increase basal and insulin-stimulated
glucose metabolism in various cells, ultimately
leading to an increase in total intracellular mag-
nesium in the peripheral blood mononuclear cells
(PBMC) in diabetic patients31. However, a study32
on the metabolic effects of drugs on the total intra-
cellular calcium and magnesium contents of cul-
tured PBMC found that metformin did not affect
intracellular calcium and magnesium.
Thiazolidinediones
Fluid Retention
As the most common and serious side effect of
TZDs, the incidence of fluid retention ranges from
7% with TZDs monotherapy to 15% in combina-
tion with insulin33. Some studies33,34 suggest that
TZD-induced fluid retention is due to increased
sodium and water reabsorption in the kidneys.
However, mechanisms of renal sodium retention
are controversial. In a recent study34, mRNA
expression of α, β, and γ isoforms of ENaC and
AQP2, and aquaporin 3 (AQP3) in the renal me-
dulla was significantly increased (by 1.5 to 2-fold)
in response to pioglitazone. The increased expres-
sion of these channels caused higher reabsorption
of sodium and water in the kidney. In addition,
rosiglitazone increased AQP2, alpha epithelial
Na+ channel (αENaC), and AQP3 expression in
mouse IMCD, human embryo kidney, and the re-
nal medulla of type 2 diabetic rats. In the study by
Tahara34, pioglitazone caused a decrease in uri-
nary sodium excretion, which supports the theo-
ry that increased ENaC gene expression leads to
increased Na+ reabsorption. By contrast, the level
of sodium in the plasma is reduced. Moreover, the
urine volume markedly decreased and urinary
osmolality increased. The above water retention
phenomenon may be due to the increased expres-
sion of AQP which increases water reabsorption.
ENaC, a regulator of body fluid volume, is neces-
sary for the kidney to absorb sodium and plays a
role in edema formation35. In view that TZDs are
PPAR-γ activators, a study36 found that TZDS-in-
duced fluid retention due to enhanced expression
of ENAC-γ by PPAR-γ. Another study37 found
that PPAR-γ enhances ENaC by upregulating se-
rum glucocorticoid regulated kinase-1 in collect-
ing duct cells. However, several studies38-40 have
refuted the inference that TZD enhances sodium
transport by activating ENaC, as follows: (1) based
on some observations, PT may be another target
for TZD action38. (2) Vallon et al39 demonstrated
that mice with inactivated ENaC had nearly the
same fluid retention levels after TZDs treatment as
controls. Patch clamp studies39 on collecting duct
cells revealed that TZDs activated a non-selective
cation channel, but not ENaC and even inhibited
ENaC activity in mice. (3) In Sprague-Dawley rat
kidneys, TZD did not increase the expression of
any ENaC subunits. (4) The phenomenon of “al-
dosterone escape”: aldosterone enhances ENaC
activity in the collecting duct while inhibiting so-
dium reabsorption in other parts of the nephron.
Thus, activation of ENaC alone does not usually
cause significant sodium retention and edema38.
(5) Protein expression of the α-1 subunit of Na+-
K+-ATPase, NHE3 and NKCC2 is enhanced in
rosiglitazone treated Sprague-Dawley rat kid-
neys40. According to the distribution of these car-
riers along the nephron, another review41 in 2013
indicated that rosiglitazone is more likely to act
on the PT or loop of Henle than on the collecting
duct or distal tubule. The effect of PPAR agonists
on Na+ transport is mediated by the nongenomic
PPAR-c-Src-EGFR-extracellular signal-regulated
kinase mechanism found in PT. A similar conclu-
sion was obtained in a review38 conducted in 2015.
In the review41 conducted in 2013, a specific mech-
anism leading to increased sodium reabsorption
was mentioned. The negative potential generated
by chloride secreted into the renal tubules may
inhibit sodium reabsorption. Pioglitazone inhib-
its chloride ion secretion by the cystic fibrosis
transmembrane conductance regulator chloride
channels. Some studies33,42 considered that vascu-
lar hyperpermeability was also a prominent fac-
tor in TZD-induced fluid retention. Rosiglitazone
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 J. Zhang, M.-N. Li, G.-M. Yang, X.-T. Hou, D. Yang , M.-M. Han, Y. Zhang, Y.-F. Liu
selectively enhanced vascular permeability in
retina and adipocytes42. The vascular endothelial
growth factor activated by PPAR-γ ligands may
contribute to the increase in vascular permeabil-
ity33. TZDs may lead to congestive heart failure
in patients with diastolic dysfunction due to wa-
ter and sodium retention. However, pioglitazone
does not affect left ventricular function because
it ameliorates diastolic dysfunction and augments
myocardial insulin sensitivity43.
Effects on Electrolytes
A study44 in an animal model of T2DM and
obesity suggested that insulin resistance could in-
crease circulating visfatin levels and thus disrupt
electrolyte balance, causing hypomagnesemia, hy-
perkalemia, and hyponatremia, while rosiglitazone
improved insulin resistance, decreased circulating
visfatin levels, and reversed the changes in electro-
lyte levels. By contrast, a case report suggested that
the inappropriate ADH secretion-related hyponatre-
mia in an elderly woman with diabetes mellitus may
have been due to rosiglitazone45. Two clinical stud-
ies46,47 in patients with T2DM and in glucose-intol-
erant populations both concluded that pioglitazone
increased serum magnesium levels. Pioglitazone
also increased the concentration of free magnesium
in rat adipocytes48. Rosiglitazone prevented and
attenuated hypomagnesemia and hypokalemia in-
duced by sirolimus in Wistar rats49. Pioglitazone and
rosiglitazone slow down the development of athero-
sclerosis and reduce the incidence of cardiovascular
diseases such as myocardial infarction43. Combined
with the positive effect of magnesium ions on the
cardiovascular system, we hypothesize that the im-
provement of cardiovascular function by rosiglita-
zone and pioglitazone is partly due to the increased
concentration of magnesium ions.
SGLT2 Inhibitors
Natriuresis and Osmotic Diuresis
SGLT2i increases urinary glucose and sodium
excretion by blocking glucose and sodium reab-
sorption50. However, the increase in urinary so-
dium is temporary. No change in urinary sodium
excretion after eight weeks of treatment in type 1
diabetic patients is considered an equilibrium for-
mation51. In addition, the transient natriuretic effect
is due to increased sodium reabsorption in other
parts of the renal unit. Increased RAAS activity
facilitates this process. Some scholars52 suggest
that SGLT2i treatment briefly activates the system-
5788
ic RAAS but not the intrarenal RAAS in patients
with T2DM. In other words, plasma renin activi-
ty and serum aldosterone levels are increased, but
renal angiotensinogen expression does not change.
A sodium balance is established after 2-3 days of
SGLT2i administration based on a reduction in sys-
temic sodium levels53. SGLT2i-induced glucosuria
leads to osmotic diuresis, again transiently, and
does not cause sustained changes in osmolality54.
Patients on canagliflozin and empagliflozin had an
increase in 24-h urine output of approximately 300
mL/d after 1 day of treatment, returning to baseline
levels after several weeks51. Different findings51,54,55
have been reported on plasma volume in patients
with T2DM treated with SGLT2i. A pooled analy-
sis of several randomized controlled trials54 found
a 9.6% reduction in plasma volume after 24 weeks
of dapagliflozin use. A comparison study55 on flu-
id distribution showed that SGLT2i dapagliflozin
mainly reduced extracellular water with a slight
increase in urine volume. The effect of SGLT2i on
the distribution of body fluids is different from that
of furosemide and tolvaptan. To sum up, SGLT2i
rapidly reduces a certain amount of plasma volume
at first, but gradually stabilizes51.
SGLT2i treatment improves fasting and post-
prandial glucose, fasting lipids, blood pressure,
body weight, serum uric acid, and arterial stiff-
ness, all of which are harmful cardiovascular
factors. SGLT2i protects the heart and kidney by
affecting diuresis, fluid and sodium retention, in-
flammation, oxidative stress, myocardial function,
and vascular resistance56. Among these, osmotic
diuresis and natriuresis act as a bridge. According
to the available studies51,53,56, natriuretic sodium
should be important for SGLT2i to lower blood
pressure and also reduce atherosclerosis as a result.
Increased urinary sodium also causes a decrease in
plasma volume, thereby reducing cardiac preload,
weakening myocardial expansion, and reducing
the incidence of arrhythmias. Combination treat-
ment with ipragliflozin + pioglitazone attenuated
pioglitazone-induced fluid retention by ipragli-
flozin-induced osmotic diuresis34. Experimental
and clinical evidence generally suggests one of
the several putative mechanisms of natriuresis and
osmotic diuresis that might explain the beneficial
properties of SGLT2i on the risk of mortality57.
Effects on Electrolytes
Hyperkalemia is among the risks initially
claimed for SGLT2i in its early use. Nevertheless,
subsequently released data58 suggest that SGLT2i
is not associated with an increased risk of hyper-
 Water-sodium balance and electrolyte regulation
kalemia. A high dose of canagliflozin causes a
minor increase in serum potassium concentration.
A clinically significant increase in potassium lev-
els was documented with canagliflozin 300 mg/d,
particularly in patients having decreased glomer-
ular filtration rate and those taking agents affect-
ing potassium excretion59. A slight but nonsignif-
icant increase in potassium levels was observed
with dapagliflozin60. The mechanisms involved
in causing the small increase in serum potassium
levels due to SGLT2i are as follows. The mech-
anism that increases renal potassium excretion
and thus decreases serum potassium is currently
twofold. One is that SGLT2i-induced natriuresis
and osmotic diuresis increase tubular flow rates in
the distal convoluted and collecting tubules, while
increasing aldosterone levels due to lower plasma
volume, which increases potassium excretion. The
second is that elevated glucagon levels probably
facilitate diuresis in the distal convoluted and col-
lecting tubules. Also, glucagon is speculated to be
an intestinal factor that contributes to increased
renal potassium excretion. Conversely, elevated
serum potassium is caused by insulin-promoting
potassium entry into cells. The decrease in insulin
concentration after SGLT2i dosing could lead to
the repartition of potassium from intracellular to
extracellular23,61. Despite the negligible increase in
serum potassium concentration, careful monitor-
ing of potassium homeostasis should be prompted
in patients with renal impairment and medications
that predispose them to hyperkalemia62. Random-
ized controlled meta-analyses63 have shown that
SGLT2i dose dependency increased serum mag-
nesium levels. Similar to the small increase in se-
rum potassium, serum magnesium due to SGLT2i
is also affected by a number of factors and eventu-
ally increases slightly. Hypermagnesuria and hy-
pomagnesemia induced by downregulation of the
transient receptor potential melastatin-6 (TRPM6)
ion channel observed in T2DM rats are thought to
be related to insulin resistance. SGLT2i improves
insulin resistance and thus reduces urinary mag-
nesium excretion via TRPM6. SGLT2 may also
decrease insulin and increase glucagon levels.
Decreased insulin levels allow magnesium ions to
be transferred from intracellular to extracellular,
while glucagon increases magnesium reabsorp-
tion in the distal renal tubules50. Natriuresis and
osmotic diuresis can induce a decrease in plasma
volume, resulting in a relatively slight increase in
serum magnesium concentration. They also in-
crease aldosterone concentrations which lead to
increased magnesium excretion52.
GLP-1RAs
A study64 found that mice treated with liraglu-
tide promoted ANP release by activating atrial
cardiomyocytes. ANP induced cGMP-mediated
smooth muscle relaxation, increased urinary so-
dium excretion, and also lowered blood pressure
as a result. Moreover, liraglutide did not affect
the natriuresis of ANP knockout mice. Howev-
er, another study65 found that injection of native
GLP-1 significantly increased urine sodium ex-
cretion in humans, but no change in proANP
concentration. The natriuretic effect of GLP-1
is speculated to be unlikely caused solely by in-
creased ANP secretion. The difference between
the results of the above two studies64,65 may be
attributed to the difference between native GLP-
1 and liraglutide, or the effect of liraglutide on
rodents could not be observed in humans. With
regard to the mechanism of GLP-1’s diuretic and
natriuretic actions, previous studies66 suggested
that it is mediated by changes in renal hemody-
namics and downregulation of NHE3 activity in
the proximal renal tubules. Conversely, in heart
failure patients with reduced ejection fraction,
liraglutide treatment reduced plasma type A and
B natriuretic peptide levels and urine sodium
content after 24 weeks67.
DPP-4 Inhibitors
A study68 found an increase in sodium ex-
cretion (65%) in rats treated with DPP-4i Lys
Z(NO2)-pyrrolidide for 7 days. Accordingly, DPP-
4i increases urine output by 70% due to a decrease
in sodium and water reabsorption. Redistribution
of NHE3 is closely related to water-salt regulation
and water reabsorption by PT, and DPP4i is asso-
ciated with reduced NHE3 protein expression. As
previously mentioned, GLP-1 also promotes na-
triuresis in the kidney. Therefore, DPP-4i–medi-
ated natriuresis may be mediated by active GLP-1
levels. However, in the study by Muskiet et al69,
linagliptin enhanced GLP-1 concentrations, yet
urinary pH and fractional excretion of endoge-
nous lithium remained unaffected, in contrast to
the theory that linagliptin inhibits NHE3. They
did not find a link between linagliptin-induced
changes in the fractional excretion of sodium and
GLP-1. But they speculated that DPP-4i might
promote sodium excretion at least in part through
other pathways independent of the GLP-1R sig-
naling pathway and NHE3. Moreover, DPP-4i
5789
 J. Zhang, M.-N. Li, G.-M. Yang, X.-T. Hou, D. Yang , M.-M. Han, Y. Zhang, Y.-F. Liu
promotes distal tubular natriuresis while increas-
ing levels of a bioactive stromal cell-derived fac-
tor-1 α1-67 (SDF-1α1-67). SDF-1α1-67, a chemotactic
factor with proven natriuretic effects in studies70,
is augmented by sitagliptin.
Insulin
Sodium consumption in patients with poorly
controlled diabetes is generally speculated to be
due to glucosuria and the resulting osmotic diure-
sis or marked ketonuria. But insulin deficiency
itself can also lead to excessive sodium consump-
tion71. Therefore, studies72 showed that insulin has
a sodium-retaining effect during hyperglycemia,
which may be relevant for maintaining sodium
balance in patients with uncontrolled T2DM. Be-
cause insulin can directly increase ENaC activity,
the sodium-phosphate cotransporter, NHE3, and
Na+-K+-ATPase increase sodium reabsorption in
the PT, thick ascending limb, and distal tubule,
including the collecting duct73. The intravenous
administration of glucose can cause hyperinsu-
linemia, resulting in sudden hypokalemia that
is caused by the massive intracellular transfer of
potassium74. Further mechanisms are as follows:
after binding to specific cell-surface receptors,
insulin-releasing in vivo not only facilitates glu-
cose uptake by target tissues but also stimulates
K+ uptake by increasing Na+-K+-ATPase activity;
thus, exogenous insulin induces a decrease in se-
rum potassium levels. In addition, insulin-medi-
ated K+ uptake is differentially regulated75. The
impact of insulin on Na+-K+-ATPase is shown to
be mainly regulated in the short term. Na+-K+-AT-
Pase α1 translocates to the plasma membrane and
internalizes into the cytoplasm, and insulin reg-
ulates the efficiency of transport by changing its
molecular conformation. In addition, the activity
of Na+-K+-ATPase may also be regulated in the
long term. Insulin may promote mRNA transcrip-
tion and protein expression levels of Na+-K+-AT-
Pase or affect the abundance of Na+-K+-ATPase
α1 through two degradation pathways, the ubiq-
uitin-proteasome and the autophagy-lysosome
system76. Another mechanism by which insulin
affects plasma potassium ion concentration is
through the activation of the Na+-H+ exchanger-1.
The Na+-H+ exchanger-1 exchanges intracellu-
lar H+ with Na+ from the extracellular fluid, and
Na+ then exchanges with K+ in the extracellular
fluid through Na+-K+-ATPase23. In addition, se-
vere insulin-induced hypoglycemia induces the
5790
additional secretion of epinephrine. Epinephrine
can also stimulate cellular potassium uptake by
activating Na+-K+-ATPase77. A case report78 of a
47-year-old man with T2DM who attempted sui-
cide with 2,100 U of insulin injected subcutane-
ously was presented. The man developed hypoka-
lemia, hypophosphatemia, and hypomagnesemia
within 24 h of his suicide attempt. Hypomagne-
semia and hypophosphatemia may be due to the
rapid increase in the accumulation of magnesium
and phosphorus in cells by the addition of insulin
in vitro. Scholars79 showed that insulin induces
the transfer of magnesium from plasma to eryth-
rocytes both in vivo and in vitro. In patients with
diabetes, the urinary excretion of magnesium
increases with insulin dose independent of glu-
cosuria. Also, insulin administration in normal
men results in increased magnesium excretion79.
On the contrary, another study26 showed that in-
sulin use was positively correlated with plasma
Mg2+ levels. A trend toward higher plasma Mg2+
levels was observed in patients taking insulin
compared with those not requiring insulin thera-
py. The mechanism probably is that insulin stim-
ulates the activity of renal TRPM6, particularly
through insulin receptor substrate, via a signaling
cascade that ultimately increases cell membrane
abundance of this channel and renal Mg2+ reab-
sorption80.
Conclusions
Antidiabetic drugs change water and elec-
trolyte metabolism. Moreover, diabetes mellitus
and its complications inherently cause electrolyte
disorders; thus, the changes in water and elec-
trolytes in patients with diabetes are worthy of
attention and discussion. Several sulfonylureas
possess water-retaining properties by acting on
different sites and increasing water reabsorp-
tion; others are not antidiuretics or even diuret-
ics by increasing Na+K+Cl- reabsorption. The use
of metformin may lead to a reduction in serum
magnesium concentrations, but the mechanism is
not well understood. Although the mechanism of
TZD-induced fluid retention is vigorously debat-
ed, fluid retention is the most common and severe
adverse effect of TZD. SGLT2i can result in os-
motic diuresis caused by glycosuria and natriure-
sis. Natriuresis and osmotic diuresis are transient
but cause the effect of protecting the heart and
kidneys. The multi-faceted effects of SGLT2i on
serum magnesium and serum potassium caused
 Water-sodium balance and electrolyte regulation
a minor increase in serum magnesium and po-
tassium concentration. GLP-1RAs enhance na-
triuresis by activating atrial cardiomyocytes to
release ANP and reduce NHE3 activity. DPP-4i
also possesses natriuretic effects, the mechanism
of which is by increasing SDF-1α1-67 levels in ad-
dition to those mediated by GLP-1 levels. Insulin
has a sodium-retaining effect and promotes the
transfer of potassium, magnesium, and phos-
phate from extracellular to intracellular due to its
physiological properties. The effects of diabetes
and the use of hypoglycemic drugs on the water
and electrolyte metabolism of patients are dual
and complex. The paper provides clinicians with
a comprehensive understanding of antidiabetic
medications, an individualized and precise selec-
tion of medications, and targeted management of
patients’ water and electrolyte levels. However,
numerous factors affect water-electrolyte levels,
and the same hypoglycemic agent may have dif-
ferent effects in patients. Thus, further research
into the mechanisms by which hypoglycemic
agents affect water-electrolyte metabolism is
potentially beneficial in making more accurate
judgments about patients’ conditions to avoid
worse complications.
Acknowledgments
The authors are very grateful for the help provided by the li-
brary of Shanxi Medical University.
Funding
This work was supported by the National Natural Sci-
ence Foundation of China, No.82073909 and 81973378;
Shanxi Scholarship Council of China, No. 2020-172; Natu-
ral Science Basic Research Plan in Shanxi Province of Chi-
na, 20210302124584, 202103021223233; Postgraduate In-
novation Project in Shanxi Province of China, 2021Y408;
FSKSC and 1331KSC.
Authors’ Contributions
Jian Zhang mainly wrote and revised the manuscript,
and constructed the framework of the manuscript. Min-
Min Han and Meng-Nan Li provided constructive opin-
ions on the formation of the manuscript. Dan Yang, Gui-
Mei Yang, and Xin-Tong Hou participated in the draw-
ing of manuscript pictures and the investigation and
sorting of documents. Yi Zhang and Yun-Feng Liu par-
ticipated in the topic design, manuscript writing, man-
uscript editing, and providing instructional support. All
authors contributed to the article and approved the sub-
mitted version.
ORCID ID
Jian Zhang: 0000-0002-8543-3483
Meng-Nan Li: 0000-0003-4395-5248
Gui-Mei Yang: 0000-0002-9250-1835
Xin-Tong Hou: 0000-0002-4257-7479
Dan Yang: 0000-0001-7020-9684
Min-Min Han: 0000-0002-9864-444X
Yi Zhang: 0000-0003-0305-3127
Yun-Feng Liu: 0000-0003-2826-5804
Conflict of Interest
The authors declare that there is no conflict of interest.
Data Availability
Data sharing is not applicable to this article as no datasets were
generated or analyzed during the current study.
Informed Consent
Not applicable.
Ethics Approval
Not applicable.
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