Introduction
Currently (March 2022), more than 450 million people worldwide were confirmed to be
infected with SARS-CoV-2 and more than 6 million individuals had died due to
COVID-19. After the onset of the pandemic, it was rapidly recognized that people
with comorbidities and in particular metabolic diseases have a higher risk of
developing severe COVID-19 and display an increased mortality [1]. Furthermore, it transpired that there are
sex-specific differences in relation to COVID-19; severity and mortality is higher
in men, whereas the incidence of long-COVID is higher in women (reviewed in [2]). In addition to the acute illness, people
with diabetes appeared to be more prone to long-COVID, vaccine breakthrough
infections and re-infections. Here, we will discuss this interface between diabetes,
COVID-19, and long-COVID ([Fig. 1]).
Fig. 1 Diabetes and COVID-19: When people with diabetes are infected
with SARS-CoV-2, it may lead to a number of short- and long-term
consequences.
Diabetes and acute COVID-19
Patients with diabetes frequently exhibit a chronic subclinical low-grade
inflammation due to impaired insulin signaling. This leads to a decrease in
anti-inflammatory cytokines and to a higher expression of the pro-inflammatory
cytokines TNF-α, IL-6 and IL-1β. These cytokines inhibit insulin
signaling [3], thus escalating insulin
resistance [4]. In severe COVID-19, the
inflammatory response to SARS-CoV-2 may promote insulin resistance and
endothelial dysfunction [1]. Synergy
between COVID-19 and type 2 diabetes mellitus (T2DM) may further amplify this
inflammatory response, thereby contributing to critical disease [5]. By triggering airway hyper-reactivity,
insulin resistance increases the risk of respiratory failure and cardiopulmonary
collapse in patients with diabetes and COVID-19 infection [6].
Patients with COVID-19, without any pre-existing history or diagnosis of
diabetes, are reported to have a greater prevalence of hyperglycemia [7]. However, stress hyperglycemia and
insulin resistance are also characteristics of other acute critical illnesses
[8]. Therefore, it remains unclear
whether COVID-19-associated hyperglycemia and insulin resistance is more severe
than in non-COVID patients with similar disease severity. As in non-COVID
critically ill patients, the ideal blood glucose target remains to be defined as
patients with uncontrolled or poorly controlled blood glucose levels were shown
to experience a worse disease course than those with normoglycemia [9].
Data have shown that acute COVID-19 in single cases may lead to development of
type 1 diabetes mellitus (T1DM), and in many cases an infection with SARS-CoV-2
led to a deterioration of prediabetes or pre-existing T2DM [1]. We and others have shown that
pancreatic beta-cells may be directly infected with SARS-CoV-2, which may lead
to beta-cell damage and possibly insulin resistance [10]
[11]
[12]
[13]. These findings were confirmed in a
recent study from the American Centers for Disease Control and Prevention, where
the risk for newly diagnosed diabetes in adolescents was estimated to be more
than doubled when compared to adolescents without an infection with SARS-CoV-2
or with other respiratory infections [14].
A similar study with 600 055 people showed an increased risk of new-onset T2DM
after COVID-19. This risk was higher after moderate/severe COVID-19 than
after mild symptoms [15]. Furthermore, the
risk was higher than in influenza controls excluding general morbidity after
viral illness [15].
In addition to infection-induced hyperglycemia, corticosteroid-induced
hyperglycemia is a common medical problem [16], where glucocorticoids lead to an increase in insulin resistance
with increased glucose production and inhibition of the production and secretion
of insulin in pancreatic beta-cells. This problem is also encountered during the
coronavirus pandemic due to long-term treatments with dexamethasone, which may
lead to long-lasting metabolic dysregulations [5].
Recently, it was suggested that SARS-CoV-2 might trigger T1DM via
post-translational protein modifications and the generation of neoepitopes,
which are able to induce islet autoimmunity [17]. This phenomenon is known from other autoimmune conditions, such
as rheumatoid arthritis [18] and coeliac
disease [19]. Indeed, several antibodies
to post-translationally modified islet peptides have been identified [20]. Furthermore, in newly diagnosed
patients with T1DM, these antibodies are not only more abundant than those to
native insulin [21], they are also more
sensitive when compared to standard islet autoantibodies [22]. Therefore, they can also be used as
specific biomarkers of disease progression [17].
Diabetes and long-COVID
As the COVID-19 pandemic continues to progress, awareness about its long-term
impacts has been growing, and more and more studies dealing with this question
are emerging. In long-COVID (also termed post-COVID-19 syndrome or post-acute
sequelae), one or more signs or symptoms are persisting over 12 weeks even after
the expected period of clinical recovery [23]. According to current knowledge, 10–40% of people
that were infected with SARS-CoV-2 suffer from clinically relevant symptoms of
long-COVID [24]
[25]
[26]. These symptoms are experienced 3 to 12 months after recovery
from the acute phase of COVID-19 [27]. The
main symptoms are difficulties in concentration, cognitive dysfunction, amnesia,
depression, fatigue, and anxiety [28]
[29]
[30]
[31], and especially older
age, female sex, and disease severity were identified as risk factors for
persistent neuropsychiatric symptoms [32].
Most of these COVID-19-related persistent symptoms improved over time; however,
neurological symptoms seem to last longer than other symptoms [29]. Though to a lesser extent, even people
with mild COVID-19 symptoms that were isolated at home often develop long-COVID
[24].
Mechanisms explaining the chronic symptoms after COVID-19 are not yet fully
understood, and therefore, it is still not possible to foretell the long-term
consequences for our health system. In addition to the direct effects of a
SARS-CoV-2 infection as mentioned above, it is assumed that the immune response
to the virus is partly responsible for the presence of the lasting symptoms,
possibly through facilitating an ongoing hyperinflammatory process [33]. Therefore, several hypotheses have
been suggested to explain the long-lasting effects of an infection with
SARS-CoV-2: 1) Direct infection of the organs during acute infection leading to
temporary or permanent damages, 2) virus “left-overs” in tissue
reservoirs across the body, which may not be identified by nasopharyngeal swabs,
3) cross reactivity of SARS-CoV-2-specific antibodies with host proteins
resulting in autoimmunity, 4) delayed viral clearance due to immune exhaustion
resulting in chronic inflammation and impaired tissue repair, 5) mitochondrial
dysfunction and impaired immunometabolism, and 6) alterations in the microbiome
leading to long-term health consequences [33]
[34]
[35]
[36]. In addition to viral effects, the symptoms of long-COVID can be
due to effects of hospitalization and drugs, or unrelated to these.
Presence of diabetes may further influence long-COVID via various
pathophysiological mechanisms. First investigations have shown that people with
metabolic diseases may have a higher risk of developing long-COVID symptoms.
Patients with T2DM having a COVID-19 infection had significantly more symptoms
of fatigue after the acute illness as compared to those without diabetes [37]. Furthermore, COVID-19 can add to or
exacerbate tachycardia, sarcopenia (and muscle fatigue), and microvascular
dysfunction in patients with diabetes [38].
As mentioned above, the evidence that SARS-CoV-2 could induce diabetes is
growing. However, it is not yet clear whether this might be a fulminant-type
diabetes, autoimmune diabetes, or a new-onset transient hyperglycemia [17]. In patients that were hospitalized due
to COVID-19, glycemic abnormalities were observed up to 2 months later [7]. However, other long-term studies
reported that the prevalence of dysglycemia reverted to pre-admission
frequencies in most recovered patients [9].
Antidiabetic medications and COVID-19
An additional compounding issue is the fact that the majority of T2DM patients
are taking antidiabetic drugs, which themselves may influence SARS-CoV-2
susceptibility and COVID-19 severity. SARS-CoV-2 replication is initiated by
binding of the viral spike (S) protein to the surface receptor ACE2 of the host
cell (reviewed in [39]). ACE2 catalyzes
conversion of Angiotensin II into Angiotensin 1–7 and represents the
vasoprotective, anti-inflammatory and antifibrotic component of the angiotensin
renin system [reviewed in [39]
[40]). It is still a matter of debate
whether upregulation of ACE2 is beneficial for COVID-19 prognosis or not [39]. The effects of antidiabetic
medications upon ACE2 expression have recently been summarized [41]. Agonists of “peroxisome
proliferator-activated receptor gamma”, for example, pioglitazone and
rosiglitazone, increase ACE2 gene transcription. In addition, there is
indication that pioglitazone can inhibit the secretion of pro-inflammatory
cytokines and increase anti-inflammatory ones; it can also attenuate lung injury
and reduce lung fibrotic reaction (reviewed in [42]). Metformin, the most frequently employed antidiabetic, reverses
lung fibrosis in mouse models [43], which
is desirable when treating viral pneumonia. Metformin also preserves the
permeability of alveolar capillaries and reduces the severity of
ventilator-induced lung injury in rabbits [44]. It reduces pulmonary inflammation and fibrosis in a rat model
[45], thereby prolonging survival and
attenuating pulmonary injury. Clinical studies indicate that metformin users
have a reduced probability to develop COVID-19 [46] and a lower disease mortality [47]
[48]
[49]
[50]. DPP4 inhibitors (gliptins), in addition to their antidiabetic
actions, have anti-inflammatory effects, reduce cytokine overproduction, and
have been suggested as treatment of COVID-19 [51]. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are
antidiabetic drugs with numerous pleiotropic and positive clinical effects and
have been shown to reduce the risk of cardiovascular death in patients with
heart failure regardless of diabetes mellitus status [52]. More recent studies highlight some
novel anti-inflammatory activity of SGLT-2 inhibitors which may help reduce
excessive cytokine production and inflammatory responses associated with a
COVID-19 infection [53].
Other long-term complications of COVID-19 and diabetes
Recovering COVID-19 patients, especially in India, are increasingly reported to
contract fungal infections [54].
Mucormycosis, also known as “black fungus”, is a serious and
potentially fatal fungal infection caused by a rare fungal pathogen
mucormycetes. The environmentally ubiquitous fungi, although usually innocuous,
may become life threatening in immune-compromised patients. Prior to the corona
pandemic, it was estimated that India had a 70–80-fold higher disease
burden than any other country in the world though still relatively rare [55]. The time gap between the infection
with SARS-CoV-2 and mucormycosis is around 15 days [56]
[57]
[58]. The entry of the fungi
usually begins with inhalation of sporangiospores from air/dust through
the nasopharynx. Furthermore, contaminated food, cuts/abrasion in the
skin, infection from medical devices and the ventilation system may be
responsible for an infection [54].
In the first wave of COVID-19, 44 cases and 9 deaths were reported across India
in mid-December 2020. However, in the second wave (between April and June 2021)
45 374 cases were reported with a ~50% mortality rate [59]. Two thirds of these were
COVID-19-related and the remaining third was associated with uncontrolled or
poorly controlled diabetes or immuno-compromised individuals [60]. While the exact cause of its sharp
rise suddenly and specifically during the second wave still remains debatable,
it has been observed that people with diabetes who have recovered from COVID-19
infection are more predisposed to mucormycosis. Furthermore, it has been
speculated that an indiscriminate use of steroids, antibiotics, and zinc, as a
self-medication practice in the COVID-19 pandemic, may have promoted a dysbiosis
of the gut microbiome inducing immune-suppression and making the risk groups
more susceptible to this fungus [61].
India has the second-largest number of adults with diabetes in the world [59]. Moreover, a high number of people in
India do not regularly test their blood sugar levels [62]
[63]. Therefore, it is tempting to believe that uncontrolled and
poorly controlled diabetes can be blamed for the emerging epidemic of
mucormycosis [59]. An underlying
undetected diabetes in COVID-19 patients may result in high sugar levels.
Furthermore, in combination with glucocorticoid treatment for COVID-19, this may
result in extremely high sugar levels, reaching more than
450–500 mg/dl in patients with diabetes and COVID-19
[64]
[65]. This uncontrolled glycemic level impedes the viral clearance and
reduces T-cell function by lowering the immune response [66]
[67]. In addition, the body cannot utilize this high blood sugar due
to limited insulin release, leading to alternative fat metabolism and resulting
in ketoacidosis. Thereby, both high sugar and acidic blood generate a
flourishing atmosphere for the fungus [68].
Reports suggest that 2–3 weeks of steroid therapy and prolonged ICU stays
are enough to weaken the immune system and thereby to increase the
susceptibility of patients to mucor infections. The ketoacidosis and ketonemia
in COVID-19 patients, also weakens phagocytic activity, and the risk of
mucormycosis is further increased [69].
Re-infection and vaccine breakthrough infections
Vaccination against COVID-19 is highly effective in addressing severe COVID-19
[70]. However, currently a high number
of SARS-CoV-2 vaccine breakthrough infections and reinfections occur. Obesity
and impaired metabolic health are already known to be important risk factors for
severe COVID-19. Latest findings indicate that these risk factors might also
promote vaccine breakthrough SARS-CoV-2 infections in fully vaccinated people
[71]. A recent study including fully
vaccinated patients that were admitted to the Yale New Haven Health system
hospital concluded that among all pre-existing comorbidities, overweight, T2DM,
and cardiovascular disease were frequently seen in patients with severe or
critical illness [72]. Another study
investigated the effectiveness of COVID-19 vaccination in Scotland’s
nationwide platform EAVE II. Here, T2DM, coronary heart disease and chronic
kidney disease were also associated with increased risk of severe COVID-19
outcomes [73]. These findings confirm
previous results from Israel showing that the COVID-19 vaccine effectiveness is
slightly lower among people with a higher number of coexisting conditions, such
as obesity, T2DM and hypertension, compared with people with a low number of
coexisting conditions [70]. Furthermore,
these findings are similar to data from patients with obesity and/or
T2DM suffering from immunosenescence and increased HbA1c levels, that were
demonstrated to exhibit a reduced immune response to an influenza A (H1N1)
vaccine [74].
Naturally infected populations are less likely to be re-infected by SARS-CoV-2
than infection-naïve and vaccinated individuals [75]. Although, re-infected individuals
suffer from a milder form of the disease, a remarkably high proportion of
naturally infected or vaccinated individuals were (re)-infected by new emerging
variants. A recent study from Bangladesh showed that at least one of the
comorbidities obesity, diabetes, asthma, heart disease, lung disease, and high
blood pressure was present in 50% of all reinfection cases [75].
Lockdown and its effect on diabetes
As hyperglycemia was shown to worsen the COVID-19 prognosis [9], the importance of maintaining a
well-controlled blood glucose levels has to be underlined. Around the world,
childhood obesity increased during the pandemic. This was due to changes in the
daily routines, such as a reduction in physical activity and negative changes in
the eating habits during lockdown. This also had negative effects on
psychological well-being [76]
[77]
[78]. A meta-analysis investigating the effect of lockdown on glycemic
control due to lockdown measures, however, concluded that no significant effects
could be observed in HbA1C levels in either T1DM or T2DM. Actually, a reduction
in mean glucose and glucose variability in T1DM was observed [79]. These data were confirmed in several
other studies around the world [80]
[81]. The same conclusion was reached in
different studies with children with T1DM, where the glycemic control did not
deteriorate under the lockdown [82]
[83]. There are even studies showing an
improvement in the glycemic control in T1DM children during confinement [84]. These data suggest that it was
actually easier for the children and their parents to follow a strict daily
routine when they were confined to their homes. This shows that the use of
real-time continuous glucose monitoring, parental management, and telemedicine
can display beneficial effects on T1DM care. This is further confirmed by the
fact that a deterioration was mainly observed in pubertal adolescent boys, where
reduced meal frequency mainly due to skipping breakfast, reduced physical
activity level scores, increased screen time and sleep duration could explain
the adverse impact on glycemic control [85].
The COVID-19 pandemic also affects mental health because of lockdown and
quarantine measurements [86]
[87]. Diabetes has been connected to an
increased risk of depression [88]
[89]
[90]
[91], and equally, people
with depression exhibit a more than 30% higher risk of developing
diabetes than people without depression [92]
[93]. The mechanisms behind
this relationship are not yet understood, but inflammation and insulin
resistance seem to be involved, since both diabetes and depression are
associated with a chronic state of systemic low-grade inflammation [94]. Co-occurrence of diabetes and
depression may impair the quality of life in patients with diabetes and when
self-management becomes more challenging, as during the COVID-19 pandemic, more
intensive support may be required [95].
Motivating and persuading patients with diabetes to change lifestyle and to
follow their treatment can be a demanding task. If these patients are then also
depressed, it may become even more complicated.
