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Endocrine
https://doi.org/10.1007/s12020-021-02729-7
REVIEW
The complex combination of COVID-19 and diabetes: pleiotropic
changes in glucose metabolism
Abdolkarim Mahrooz 1,2 ●Giovanna Muscogiuri3●Raffaella Buzzetti4●Ernesto Maddaloni4
Received: 18 January 2021 / Accepted: 9 April 2021
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021
Abstract
Purpose Angiotensin converting enzyme 2 (ACE2) is the door for SARS-CoV-2, expressed in critical metabolic tissues.
So, it is rational that the new virus causes pleiotropic alterations in glucose metabolism, resulting in the complication of pre-
existing diabetes’s pathophysiology or creating new disease mechanisms. However, it seems that less attention has been paid
to this issue. This review aimed to highlight the importance of long-term consequences and pleiotropic alterations in glucose
metabolism following COVID-19 and emphasize the need for basic and clinical research in metabolism and endocrinology.
Results SARS-CoV-2 shifts cellular metabolism from oxidative phosphorylation to glycolysis, which leads to a decrease in
ATP generation. Together with metabolic imbalance, the impaired immune system elevates the susceptibility of patients with
diabetes to this deadly virus. SARS-CoV-2-induced metabolic alterations in immune cells can result in hyper inflammation
and a cytokine storm. Metabolic dysfunction may affect therapies against SARS-CoV-2 infection. The effective control of
metabolic complications could prove useful therapeutic targets for combating COVID-19. It is also necessary to understand
the long-term consequences that will affect patients with diabetes who survived COVID-19.
Conclusions Since the pathophysiology of COVID-19 is still mostly unknown, identifying the metabolic mechanisms
contributing to its progression is essential to provide specific ways to prevent and improve this dangerous virus’s detrimental
effects. The findings show that the new virus may induce new-onset diabetes with uncertain metabolic and clinical features,
supporting a potential role of COVID-19 in the development of diabetes.
Keywords COVID-19 ●SARS-CoV-2 ●Diabetes ●Glucose metabolism ●Long-term consequences
Introduction
The 2019 novel coronavirus disease (COVID-19) pan-
demic, caused by severe acute respiratory syndrome cor-
onavirus 2 (SARS-CoV-2), is seriously threatening health
systems. As a global healthcare issue, this pandemic has
posed a tremendous threat to humans and accounts for
causing considerable morbidity and mortality worldwide.
Diabetes is one of the most frequent comorbidity associated
with COVID-19 [1], and the highest mortality rates have
been registered in people with cardiometabolic disorders
[2]. Reports from the Centers for Disease Control and
Prevention (CDC) and other national health centers
demonstrated that the risk of a fatal outcome from COVID-
19 could be up to 50% higher in diabetes patients than
people without diabetes [3]. A meta-analysis conducted on
six studies with 1527 patients showed that the incidence of
diabetes was twofold greater in severe patients compared to
their non-severe counterparts [3]. An elevated risk of severe
complications, including Adult Respiratory Distress Syn-
drome and multiorgan failure, have been observed in
patients with diabetes [4,5]. Also, COVID-19 patients with
diabetes had an increased risk of mortality based on a recent
meta-analysis (OR =2.21, 95% CI: 1.83–2.66, p< 0.001)
[6]. Furthermore, the role of systemic endothelial dysfunc-
tion in the pathophysiology of COVID-19 in patients with
cardiometabolic disorders may be essential so that it may
*Abdolkarim Mahrooz
amahrooz@mazums.ac.ir
1Molecular and Cell Biology Research Center, Mazandaran
University of Medical Sciences, Sari, Iran
2Diabetes Research Center, Imam Khomeini Hospital, Mazandaran
University of Medical Sciences, Sari, Iran
3Sezione di Endocrinologia, Dipartimento di Medicina Clinica e
Chirurgia, Università Federico II Napoli, Napoli, Italy
4Department of Experimental Medicine, Sapienza University of
Rome, Rome, Italy
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potentially be considered a new therapeutic target at mini-
mizing the severity of this infection [7].
SARS-CoV-2 infection is accompanied by the release of
many pro-inflammatory cytokines [tumor necrosis factor
(TNF), interleukin-6 (IL-6), and IL-1β] described as “cyto-
kine storm”, which correlates with vascular hyperperme-
ability, lung injury, multiorgan failure, and COVID-19
severity [8,9]. Increased inflammation and the massive
production of cytokines can generate insulin resistance and
also influence beta-cell function, involving a further reduc-
tion of insulin secretion [10]. This may induce hyperglyce-
mia, which in turn can elevate the virulence of SARS-CoV-2
and reduces the phagocytic activity and polymorphonuclear
leukocytes [4,11]. Based on the findings of Zhu et al. [12],
improved glycemic control had associated with better out-
comes in COVID-19 patients and pre-existing T2D, so that
virus people with well-controlled blood glucose (upper
limit ≤10 mmol/L) had markedly lower mortality in com-
parison to those with poorly controlled blood glucose (upper
limit > 10 mmol/L) during hospitalization.
On the other hand, it has also been suggested that
COVID-19 may trigger diabetes onset in predisposed sub-
jects. In this narrative review, we aim to describe this other
side of the coin, discussing the possible effects of COVID-19
on glucose homeostasis and related mechanisms.
Possible effects of COVID-19 on diabetes
SARS-CoV-2 infection in individuals with diabetes may
trigger stress and increase the release of hyperglycemic
hormones, such as catecholamines and glucocorticoids,
which would lead to increased blood glucose concentra-
tions and abnormal glucose variability [13], causing an
increased risk of metabolic emergencies. In particular,
COVID-19 can elevate the risk of both diabetic ketoaci-
dosis (DKA) and hyperosmolar hyperglycaemic state even
in people without previously recognized diabetes [14,15].
The risk of developing DKA is higher in people with T1D,
and additional metabolic complications can occur in these
patients [11,15]. The importance of ketoacidosis and
DKA can be prominent in children and adolescents. There
is a significant increase in DKA and severe ketoacidosis at
diabetes diagnosis in children and adolescents during the
COVID-19 pandemic. More importantly, reduced medical
services, fear of approaching the health care system, and
more complex psychosocial factors may result in the
delayed DKA diagnosis, which can be life-threatening
[16]. Furthermore, more individuals with pre-existing type
2 diabetes (T2D) are progressing to insulin therapy with
severe COVID-19 [14]. Maddaloni et al. first also hypo-
thesized that in the long term, the infection of pancreatic
beta-cells could trigger beta‐cell autoimmunity [17], which
might trigger type 1 diabetes (T1D) onset in predisposed
subjects [18]. COVID-19 was associated with new and
persistent hyperglycemia so that some individuals with
normal HbA1C levels may develop new-onset diabetes
[19]. However, the extent and phenotype of new-onset
diabetes in patients with confirmed COVID-19 with a
previous negative history of diabetes remains to be
elucidated [11].
Some medications with a proven beneficial effect in
COVID-19 and currently used for treating mild and severe
COVID-19 cases, such as corticosteroids, can exacerbate
glycemic control in patients with diabetes [11]. Although
hyperglycemia is usually considered the primary concern in
diabetes patients with COVID-19, hypoglycemic episodes
resulting from drug use, viral pathogenesis, and metabolic
perturbations of diabetes should not be ignored, particularly in
older patients and in those prone to hypoglycemia [20,21].
In addition to impaired glucose metabolism, diabetes is a
chronic inflammatory disorder characterized by several
vascular and metabolic abnormalities [22]. It is expected
that SARS-CoV-2 infection could further worsen inflam-
mation in individuals with diabetes. Together with meta-
bolic imbalance, the impaired immune system elevates the
susceptibility of patients with diabetes to pathogens such as
SARS-CoV-2 [23]. Several factors involved in the immune
dysfunction in diabetes patients, including hyperglycemia,
impaired T cell function, impaired macrophage function,
decreased neutrophil chemotaxis, and increased adherence
of microorganisms to diabetic cells [23–27].
In T2D patients, an imbalance between coagulation and
fibrinolysis carries out with increased coagulant potential,
chronic platelet activation, and relative inhibition of
fibrinolysis, predisposing the patients to the development
of a hypercoagulable prothrombotic state [28]. This con-
dition can be exacerbated in patients with COVID-19.
Diabetes people with COVID-19 show a significantly
higher D-dimer, a coagulation index, than those without
diabetes. Notably, the risk of coagulopathy and thrombosis
could be higher in diabetes and obesity, increasing sus-
ceptibility to thrombotic disorders [29]. Furthermore,
based on some evidence, endothelial injury and coagulo-
pathy may be central mediators of lung injury in SARS-
CoV-2 infection so that therapies that work on this basis
may be considered for COVID-19-related ARDS [30].
Gestational diabetes mellitus is one of the most common
medical problems found in pregnancy. Pregnant women
with diabetes may be more vulnerable to the severe effects
of SARS-CoV-2 infection [31,32]. It seems that there
are more clinical complications in pregnant women with
COVID-19, and new infection was associated with
enhanced preterm birth, preeclampsia, cesarean, and peri-
natal death [33]. Based on a case report study, pregnancy is
a high-risk period for euglycemic ketoacidosis, even in non-
diabetic women, particularly in infectious diseases such as
Endocrine
COVID-19 [34]. Drug-induced hyperglycemia or secondary
diabetes during COVID-19 treatment, particularly with
frequent use of corticosteroids, maybe one of the causes of
new-onset hyperglycemia in patients with SARS-CoV-2
infection. This can be observed especially in admitted
patients with COVID-19 without a history of dysglycemia
or diabetes and not on corticosteroids. New-onset diabetes
in COVID-19 patients has been related to significantly
higher complications and all-cause death than subjects with
normoglycemia and preexisting diabetes [35].
The long-term consequences of SARS-CoV-2
infection should be more attentioned, particularly in
individuals with diabetes
Although the long-term consequences for patients recover-
ing from COVID-19 are unknown, researchers and health-
care professionals need to be aware of the importance of
continued monitoring of long-lasting consequences in
managing this strange disease. In this context, the results
obtained for previous coronaviruses may be useful. Long-
term outcomes following severe illness caused by SARS
and MERS were analyzed in a meta-analysis of 28 studies.
Accordingly, the increased prevalence of posttraumatic
stress disorder, depression, and anxiety were reported up to
6 months after discharge [36]. The findings of a follow-up
study for 12 years on 25 recovered SARS patients also
showed that they tended to have increased hyperlipidemia,
cardiovascular abnormality, and abnormal glucose meta-
bolism, and significant differences found in serum meta-
bolomes in comparison to healthy volunteers [37]. COVID-
19 survivors may, therefore, also experience long-lasting
morbidity [38]. Based on study results, 87% of patients who
had recovered from COVID-19 experienced persistence of
at least one symptom (a mean of 60 days after onset of the
first COVID-19 symptom), particularly dyspnea and fatigue
[39]. However, it should be mentioned that adverse meta-
bolic effects of SARS-CoV-2 infection may be permanent
without specific clinical symptoms.
It is unknown at this time whether diabetes-related
changes that occur in severe COVID-19 will disappear after
the disease has resolved or will be permanent. Patients with
severe COVID-19 could develop high degrees of insulin
resistance that may be asymptomatic. This is consistent with
the SARS virus findings, causing insulin resistance in 50%
of the patients throughout infection [18]. Follow-up of the
recovered patients with underlying metabolic disorders such
as diabetes would be essential to evaluate developing
microvascular and macrovascular complications in all the
vascular beds, particularly the eye, kidney, and heart [40]. It
is unknown how recovery from the infection does or does
not differ from other forms of severe critical illness [30].
However, based on reports, sepsis recovery experiences
may be applicable to patients recovering from severe
COVID-19 [38]. Receipt of these practices has been related
to lower odds of rehospitalization or death [38]. Taken
together, it is noteworthy that post-recovery sequelae of
COVID-19 may appear months and years after recovery,
and it recommends that for many patients surviving
COVID-19, health care should not end when they are
discharged.
The key role of ACE2 in the interaction between
COVID-19 and diabetes
The interaction between SARS-CoV-2 and angiotensin-
converting enzyme 2 (ACE2) is an essential factor con-
tributing to the new virus to develop different clinical and
metabolic features. ACE2 is expressed in critical metabolic
tissues, including pancreatic beta-cells, adipose tissue, liver,
the small intestine, and the kidneys. It is rational that the
new virus causes pleiotropic alterations in glucose meta-
bolism, which would result in the complication of the
pathophysiology of pre-existing diabetes or the creation of
new mechanisms of disease [11].
ACE2 is the cellular receptor of SARS-CoV-2 and
acts as the door for SARS-CoV-2 to enter host cells.
The cellular serine protease TMPRSS2 is also needed for
ACE2-mediated coronavirus entry into the cells [41]. The
expression of ACE2 in different tissues is proportional to
various symptoms of COVID-19, such as respiratory
symptoms, which are predominant, acute cardiac and kid-
ney injuries, gastrointestinal and liver function abnormal-
ities, and beta-cell damage [4,42]. Understanding the
mechanisms of interaction between the renin-angiotensin
system (RAS) and SARS-CoV-2 can provide adequate
therapy for patients at an increased risk of COVID-19.
ACE2 is a RAS member, which cleaves a single amino acid
residue at the carboxyl terminus of Ang I (Ang 1–10) and
Ang II (Ang 1–8) to form Ang 1–9 and Ang 1–7, respec-
tively. Vasoconstrictive and inflammatory effects of Ang II
are counterbalanced with Ang 1–7, which has vasodilatory
and anti-inflammatory effects [43,44]. The endocytosis of
SARS-CoV-2 results in a reduction in ACE2 activity and a
shift from Ang 1–7 to Ang II. This alteration may lead to
lung injury, as found in the SARS-CoV infection [45].
Therefore, it should be noted that ACE2 plays different
roles related to COVID-19, so that it is the binding site for
SARS-CoV-2, and on the other hand, its reduced expression
by the virus may involve severe lung injury [44].
Moreover, a higher prevalence of hypokalemia due to
renal potassium wasting is a clinical feature in patients with
COVID-19, which can be explained by the downregulation
of ACE2. This downregulation leads to decreased degra-
dation of Ang II and, consequently, elevated aldosterone
secretion [46]. Also, a decrease in angiotensin 1–7 and an
Endocrine
increase in angiotensin II concentrations could lead to
altered glucose metabolism in the virus’s target cells.
According to a large phenome-wide Mendelian rando-
mization study, T2D was causally associated with increased
expression of ACE2 in the lung. Accordingly, elevated
ACE2 expression due to diabetes and related traits may
influence COVID-19 risk and exacerbate its complications
[47]. A recent study’sfindings proposed that patients at old
age, males, and those who have diseases associated with
high expression of ACE2, including hypertension and dia-
betes, may have elevated risk for the delayed clearance of
the virus [48]. It seems that the impacts of diabetes on ACE2
expression depend on the stage of the disease. According to
experimental studies, ACE2 expression increases in early
disease and decreases in later disease [49–51]. A study on
mice showed that the lung’s ACE2/ACE activity ratio sig-
nificantly decreased in late-stage diabetes [52].
It is noteworthy that soluble ACE2 levels have sig-
nificant associations with all metabolic syndrome compo-
nents, including insulin resistance, obesity, hyperlipidemia,
and hypertension. Intriguingly, APN01, as a recombinant
soluble human ACE2, may have a protective role against
acute lung injury and ARDS induced by SARS-CoV-2. This
drug acts as a decoy receptor and prevents the virus from
entering the cells. APN01 may be the most promising drug
among all medications currently being developed [53]. It
was suggested that the synthetic protease inhibitor camostat,
which blocks TMPRSS2, may prevent and reverse hyper-
insulinemia, hyperglycemia, and hyperlipidemia [54].
Moreover, the interaction between metformin and ACE2
can be important in COVID-19 infection. Metformin acts
through AMP-activated protein kinase (AMPK) activation
and can phosphorylate ACE2. This may result in con-
formational and functional alterations in the receptor,
leading to the decreased binding of the receptor-binding
domain of SARS-CoV-2 to ACE2 [55].
High and aberrantly glycated ACE2 in uncontrolled
hyperglycemia may affect the binding of the spike protein
to ACE2, so resulting in a higher propensity to COVID‐19
and increased disease severity [56]. It should be noted that
acute and chronic hyperglycemia could have different
impacts on ACE2 expression. While acute hyperglycemia
upregulates ACE2 expression facilitating viral cell entry,
chronic hyperglycemia contributes to downregulating
ACE2 expression, predisposing the cells to become vul-
nerable to the virus’sinflammatory effects. Therefore, both
chronic and acute hyperglycemia can have detrimental
effects [4].
SARS-CoV-2 can also exert direct effects on beta-cells
through ACE2, contributing to exacerbated outcomes in
diabetes patients. The virus’s entry into these cells may
cause an acute beta-cell dysfunction that could lead to
uncontrolled hyperglycemia [57,58]. ACE2 was found in
both islets and the exocrine glands. Strikingly, according to
the GTEx database (https://gtexportal.org), the messenger
RNA level of ACE2 was found to be higher in the pancreas
compared with the lung [58], showing that the pancreas is
an essential target of SARS-CoV-2. It was reported that
17% of severe COVID-19 patients had increased levels of
amylase and lipase. The pancreas’focal enlargement or
dilatation of the pancreatic duct was also present in 7.5%
of patients with severe COVID-19 [58]. Direct beta-cell
damage due to SARS-CoV-2 infection could theoretically
cause insulin deficiency and autoantigen spread, leading to
severe DKA, insulin dependency, and chronic pancreatic
autoimmunity [4].
ACE2 is expressed on the arterial and venous endothe-
lial cells of the adrenal glands [59]. It was also indicated
that ACE2 and TMPRSS2 are colocalized in adrenocortical
cells. The cortisol concentrations were found to be lower in
critically ill patients with COVID-19 than non-COVID-19
critically ill patients [60]. People with adrenal insufficiency
may have a higher rate of respiratory infection-related
deaths, possibly due to impaired immune function and thus
need further care during COVID-19 [59]. The adrenal
glands contribute to the physiology of the stress response
of the organism in health and disease that shows their
important roles in the course of severe COVID-19 infec-
tion. During severe COVID-19, the adrenal glands can be
seriously injured, characterized by the perivascular infil-
tration of CD3+and CD8+T-lymphocytes [61]. Further-
more, adrenal gland disorders such as hyperaldosteronism
and adrenal insufficiency can result in carbohydrate
metabolism dysregulation that can affect glucose home-
ostasis [62], and it should be given more attention in the
COVID-19 pandemic.
The importance of pleiotropic alterations in glucose
metabolism
Although SARS-CoV-2 infection is not primarily a meta-
bolic disease, it is found that COVID-19 progression could
be dependent on metabolic mechanisms. Critical conditions,
such as COVID-19, significantly increase energy demands.
SARS-CoV-2 must rewire cellular metabolism to produce
macromolecules required for replication, assembly, and
existence. Viral proteins elevate extracellular acidification,
which is evidence for direct regulation of glucose metabo-
lism by SARS-CoV-2 in addition to its transcriptional
modulation [41]. Adenosine triphosphate (ATP) is gener-
ated through two related metabolic pathways, glycolysis,
and the tricarboxylic acid (TCA) cycle (Krebs’cycle) [63].
The imbalance of glucose metabolism could be crucially
contributing to respiratory pathogenic virus infection.
Oxygen supplement at the earliest stage of COVID-19
was proposed to correct the unbalanced glucose aerobic
Endocrine
metabolism [54]. It should be noted that metabolic dys-
function may affect therapies against SARS-CoV-2 infec-
tion because some drugs significantly depend on ATP to
achieve functionality [64]. Moreover, medicines such as
fenofibrate or cloperastine (FDA-approved drugs) that tar-
get host metabolic pathways could play a role in minimizing
virus replication [41].
Like cancer cells, the metabolic milieu was rearranged
in virus-infected cells to facilitate virus production and
replication [65]. In general, viral infection in mammalian
cells shifts cellular metabolism from oxidative phos-
phorylation to glycolysis, which leads to a decrease in
ATP production [66]. Under an anaerobic condition in
COVID-19 patients, on the one hand, the pyruvate pro-
duced from glucose during glycolysis was fermented to
lactate, which leads to the generation of limited amounts of
ATP for urgent biological needs. On the other hand, high
replication of SARS-CoV-2 viruses in infected cells con-
sumes many cellular ATP. As this condition persists (ATP
depletion), lactate delivered to the liver failed to be meta-
bolized through gluconeogenesis, causing increased blood
lactate concentrations in COVID-19 patients [54].
Under the aerobic condition, glucose oxidation can also
be performed through the pentose phosphate pathway in
which nicotinamide adenine dinucleotide phosphate
(NADPH) was produced. NADPH is required to maintain
the proper ratio of oxidized glutathione to glutathione
(GSH), which is crucial for the antioxidant defense system,
contributing to tackling invasive pathogens microorganisms
along with the immune system. Under the persistent
hypoxia state, the depletion of GSH from the pentose
phosphate pathway’s blockage could induce oxidative
damage during SARS-CoV-2 infection [54,67]. Further-
more, the deficiency of glucose-6-phosphate dehy-
drogenase, the key enzyme in the pentose phosphate
pathway, could result in cell apoptosis and inflammatory
cytokine release noted in COVID-19 infection [68,69].
Cellular glucose metabolism is hijacked in cells infected
with the SARS-CoV-2 virus [70]. Pro-inflammatory cyto-
kines activate immune cells such as macrophages and
dendritic cells to change their metabolism to produce vast
amounts of cytokines. In this metabolic reprogramming,
these cells’ability to generate ATP switches from engaging
mitochondrial oxidative phosphorylation to cytosolic
glycolysis. Glycolysis allows pro-inflammatory activated
immune cells to generate increased amounts of pro-
inflammatory cytokines, including interleukins (IL-1β, IL-
2, IL-6, IL-8), interferons (IFN1αand IFN-1β), and TNF-α
as well as chemokines. These agents can induce excessive
amounts of reactive oxygen and reactive nitrogen species
resulting in extensive nitro-oxidative stress, which involves
respiratory pathophysiology [70,71]. Targeting cytokines
and effectively suppressing the cytokine storm during
SARS-CoV-2 infection could help prevent the deterioration
of COVID-19 patients and reduce mortality [9,72]. How-
ever, it should be noted that therapeutic strategies for tar-
geting the overactive cytokine response must be balanced
with maintaining an adequate inflammatory response to
clear the virus [8].
Melatonin forces activated immune cells to abandon
glycolysis in favor of mitochondrial oxidative phosphor-
ylation [70]. Furthermore, this hormone induces Bmal1, a
circadian gene, which inhibits pyruvate dehydrogenase
kinase (PDK) and leads to the disinhibition of the pyruvate
dehydrogenase complex (PDC). PDC catalyzes the mito-
chondrial conversion of pyruvate to acetyl-coenzyme A,
thereby elevating the TCA cycle, oxidative phosphorylation,
and ultimately an increase in ATP production [73]. Intri-
guingly, to counteract quarantine-related sleep disorders, it
was recommended to use food containing or promoting
serotonin and melatonin synthesis at dinner such as leaves,
roots, fruits, and seeds such as almonds, cherries, bananas,
and oats along with increased physical activity [74].
PDC links glycolysis to TCA and fatty acid synthesis
and can be a crucial modulator of energy and metabolic
homeostasis. Ang II downregulates the activity of PDC
through its phosphorylation and acetylation. The reduced
PDC can decrease the rate of glycolysis, leading to an
uncoupling between glycolysis and TCA, which would
induce intracellular acidosis and energy depletion [66].
Insulin resistance is related to elevated skeletal muscle PDK
contributing to the phosphorylation and inactivation of
PDC. It is noteworthy that dichloroacetate, as a PDK4
inhibitor, could restore PDC activity and ATP level,
improve metabolism disorders, suppress cytokine storm and
viral replication [75].
The key rate-limiting enzymes in glycolysis, including
pyruvate kinase isozyme and hexokinase 2, were upregu-
lated in SARS-CoV-2 infection [41]. The conversion of
phosphoenolpyruvate to pyruvate is a crucial step in gly-
colysis, which is catalyzed by PK. PKM1 and PKM2 are the
two major isoenzymes of PK. PKM1 is the more enzyma-
tically active form and contributes to the entry of pyruvate
into TCA. PKM2 exhibits lower enzymatic activity than
PKM1 and involves elevated glycolysis, leading to the
cytosolic accumulation of lactate and other metabolic inter-
mediates [63]. Cytosolic lactate levels and lactate to pyr-
uvate ratio were increased in COVID-19 patients requiring
ICU admission compared with healthy controls, showing
that the increase in lactate can be due to a fundamental
metabolic shift rather than merely an enhancement in overall
metabolism [63]. It was also reported that lactate dehy-
drogenase levels were moderately higher in the deceased
than in survival elderly patients with COVID-19 [76].
Inactivated immune cells, decreased TCA could lead
to the accumulation of several metabolites, including
Endocrine
succinate, which is a crucial TCA cycle intermediate. As an
endogenous danger signal, Succinate contributes to stabi-
lizing hypoxia-inducible factor-1a, which increases the
expression of IL-1ß during inflammation [76]. It was indi-
cated that the dysregulated TCA and the upregulated gly-
colysis were mediated by the inflammatory transcription
factors NF-кB and RELA [41]. In a multi-center study on
elderly patients with COVID-19, immune-related metabolic
index (an index based on the flux of corresponding meta-
bolic reactions) was found as a potential risk factor (odds
ratio: 6.42 [95% CI 2.66–15.48], p< 0.001) [76].
After entering the human cells, SARS-CoV-2 increases
the hexosamine biosynthetic pathway (HBP) to secure
excessive glucose consumption and substrates for rapid
replication. This enhanced HBP would result in an
excess of the enzyme O-GlcNAc (N- acetylglucosamine)
transferase (OGT), which would, in turn, trigger massive
amounts of interferon regulatory factor-5 (IRF5). IRF5
plays a role as a mediator in the induction of pro-
inflammatory cytokines such as IL-6, IL-12, IL-23, and
TNF-α, is contributed to the recruitment of inflammatory
genes with NF-кB and in determining the inflammatory
macrophage phenotype. IRF5 and OGT contribute to
worsening the IкBkinase-NF-кBpro-inflammatory path-
way resulting in a tremendous inflammatory cytokine gene
overexpression profile and deleterious endoplasmic reti-
culum stress that ultimately lead to hyperinflammation, a
cytokine storm, and multiorgan failure (Fig. 1)[65]. Fur-
thermore, SARS-CoV-2, through this mechanism, may
increase vascular complications in patients with diabetes,
and it may also explain the sudden cardiac deaths in
COVID-19 [77].
Glucose
Glucose-6p
Fructose-6p
NADPH
GSH
Antioxidant defense
system
Hexosamine biosynthetic
pathway
IRF5
Proinflammatory
pathways
HK2
Pentose phosphate
pathway
Pyruvate
PKM2
LDH
Lactate
PEP
PDC PDK
Pyruvate
Acetyl-CoA
TCA
cycle
Fig. 1 SARS-CoV-2-induced
alterations in glucose
metabolism. In mammalian
cells, SARS-CoV-2 shifts
cellular metabolism from
oxidative phosphorylation to
glycolysis, which results in a
decrease in ATP generation. The
key rate-limiting enzymes in
glycolysis, including PKM2 and
HK2, were upregulated in
COVID-19. The decreased PDC
can lead to an uncoupling
between glycolysis and TCA,
which would induce intracellular
acidosis and energy depletion.
Under an anaerobic condition in
COVID-19, the depletion of
GSH from the pentose
phosphate pathway’s blockage
could cause oxidative damage
by SARS-CoV-2. The new virus
elevates the hexosamine
biosynthetic pathway, which
would result in massive amounts
of IRF5. IRF5 involves
worsening pro-inflammatory
pathways that ultimately lead to
hyper inflammation, a cytokine
storm, and multiorgan failure.
GSH, glutathione; HK2,
hexokinase 2; IRF5, interferon
regulatory factor-5; LDH, lactate
dehydrogenase; NADPH,
nicotinamide adenine
dinucleotide phosphate; PDC,
pyruvate dehydrogenase
complex; PEP,
phosphoenolpyruvate; PDK,
pyruvate dehydrogenase kinase;
PKM2, pyruvate kinase isozyme
M2; TCA, tricarboxylic acid
Endocrine
Conclusion
Since the pathophysiology of COVID-19 is still mostly
unknown, identifying the metabolic mechanisms contribut-
ing to its progression is essential to provide specific ways to
prevent and improve this dangerous virus’s detrimental
effects. It is also necessary to understand the long-term
consequences that will affect the health of patients with
diabetes who survived COVID-19. SARS-CoV-2-induced
metabolic alterations in immune cells can result in hyper
inflammation and a cytokine storm. These alterations could
prove useful therapeutic targets for combating COVID-19.
The findings show that the new virus may induce new-onset
diabetes with uncertain metabolic and clinical features,
supporting a potential role of COVID-19 in the develop-
ment of diabetes.
Compliance with ethical standards
Conflict of interest The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
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