Diabetes, Obesity, COVID-19, Insulin, and Other Antidiabetes Drugs
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Diabetes Care Volume 44, September 2021 1
DIABETES CARE SYMPOSIUM
Diabetes, Obesity, COVID-19, Paresh Dandona and Husam Ghanim
Insulin, and Other Antidiabetes
Drugs
Diabetes Care 2021;44:1–5 | https://doi.org/10.2337/dci21-0003
MACRONUTRIENTS INDUCE
INFLAMMATION
COVID-19, INFLAMMATION, OBESITY, AND DIABETES
The fact that obesity was associated with
oxidative stress and inflammation and
Coronavirus disease 2019 (COVID-19) viral infection, like other infections, triggers the fact that dietary restriction and
an inflammatory response that is usually confined to the respiratory system. How- weight loss led to a reduction in inflam-
ever, there is evidence that in a full-blown case, almost all systems of the body mation and oxidative stress led to the
may be involved. In addition, there is the syndrome of cytokine storm, character- concept that macronutrient intake may
ized by severe systemic inflammation and a massive release of proinflammatory be a mediator of oxidative and inflamma-
cytokines (1). It is well established that obesity and diabetes are major risk factors tory stress. Glucose and cream (saturated
for COVID-19 infections and that the morbidity and mortality in association with fat) intake has been shown to induce an
these conditions is markedly increased. Since both obesity and diabetes are associ- increase in reactive oxygen species (ROS)
ated with chronic inflammation, it is likely that the inflammatory response to generation in mononuclear cells (MNCs)
COVID-19 in such patients is affected by the background of chronic inflammation. and polymorph nuclear leucocytes as
This review aims to elucidate some of these processes and potential strategies to well as an increase in lipid peroxidation
combat them. (13,14). The intake of a fast-food high-fat,
high-calorie meal has been shown to
CHRONIC INFLAMMATORY STATES OF OBESITY AND DIABETES induce comprehensive oxidative stress
The concept that obesity is associated with inflammation was initiated with the and inflammation (15,16), as has the
intravenous infusion of a saturated fatty
cardinal work of Hotamisligil et al. (2), which demonstrated that the proinflamma-
acid, palmitic acid (17). In all these experi-
tory cytokine tumor necrosis factor-a (TNF-a) was expressed in the adipose tissue
ments, indices of oxidative stress and
and that its expression was markedly elevated in the ob/ob mouse. In addition, this
inflammation, including an increase in
increase was associated with insulin resistance. Neutralization of TNF-a with the
intranuclear nuclear factor-kB (NF-kB)
infusion of soluble TNF-a receptor resulted in the reversal of insulin resistance in and a decrease in inhibitor of kBa
the ob/ob mouse. These remarkable observations resulted in the understanding (IkBa), were induced within 60 min of
that obesity is a state of chronic inflammation and that inflammatory mediators macronutrient intake. Plasma concentra-
may contribute to the pathogenesis of insulin resistance. The same group then tion of endotoxin increased. Cytokines,
demonstrated that human adipose tissue also expresses TNF-a and that its expres- including TNF-a and IL-1β (18), and
sion is increased in obesity (3). Another research group simultaneously confirmed
this observation (4). This observation was followed by the demonstration that
Division of Endocrinology, Diabetes and Metabolism,
plasma concentration of TNF-a was significantly elevated in obese humans and Jacobs School of Medicine and Biomedical Sciences,
that TNF-a fell after weight loss (5). A more comprehensive description of inflam- State University of New York at Buffalo, Buffalo, NY
mation in obesity and its relationship to insulin resistance was demonstrated by Corresponding author: Paresh Dandona, dandona.
the work of Ghanim et al. (6,7). These features were then linked to the metabolic diabetes@gmail.com
syndrome (8). Received 21 April 2021 and accepted 10 May
These observations were further supported by the fact that human obesity was 2021
associated with chronic oxidative stress and that dietary restriction and weight loss This article is part of a special article collection
led to a marked reduction in the indices of oxidative stress even over a short available at https://care.diabetesjournals.org/
period of 4 weeks (9). These observations were confirmed by an article from Japan collection/diabetes-and-COVID19.
(10). Oxidative stress is known to trigger inflammatory processes and often occurs © 2021 by the American Diabetes Association.
Readers may use this article as long as the
concomitantly with inflammation.
work is properly cited, the use is educational
The occurrence of inflammation in association with type 2 diabetes was first and not for profit, and the work is not altered.
demonstrated by Pickup and Crook (11,12). These articles emphasize the increase More information is available at https://www.
in acute phase reactants to inflammation in patients with type 2 diabetes, including diabetesjournals.org/content/license.
sialic acid and cytokines IL-6 and TNF-a in particular. See accompanying articles, pp. XXXX and XXXX.
Diabetes Care Publish Ahead of Print, published online July 9, 20212 Diabetes and COVID-19 Diabetes Care Volume 44, September 2021
chemokines, including MCP-1 and Toll-like differences in the responses between therapeutically relevant doses of hydro-
receptor 2 (TLR-2) and TLR-4, were obese and nonobese individuals. cortisone. An intravenous injection of 100
induced (16). While TLR-2 is the receptor Obesity was associated with an inad- mg of hydrocortisone resulted in the sup-
for gram-positive bacterial products, TLR- equate immunological response to the pression of intranuclear NF-kB and an
4 is the receptor for endotoxin. Suppres- vaccine following vaccination for hepati- increase in IkBa expression in the cytosol
sor of cytokine signaling 3 (SOCS-3) and tis A virus (23). In addition, there was of MNCs (31), consistent with the previ-
p38 mitogen-activated protein kinase an early decline in antibody titers after ous observations with dexamethasone
were also induced (16,19). Both of these immunization (24). in vitro. In addition, this dose of hydrocor-
proteins interfere with insulin signaling at Obesity was also associated with tisone resulted in the suppression of ROS
the insulin receptor substrate 1 level and, diminished immunological response to generation by MNCs and polymorph
thus, may contribute to the induction of influenza vaccines and an inability to nuclear leucocytes (32). This dose of
insulin resistance. In contrast, an Ameri- sustain the magnitude of the immuno- hydrocortisone also suppressed activator
can Heart Association–based high-fruit logical response over a prolonged period protein 1 (AP-1), another proinflamma-
and high-fiber meal did not induce endo- (25). These defects were associated with tory transcription factor modulating the
toxemia, inflammation, or oxidative stress diminished expression of CD69, inter- expression of matrix metalloproteinase 2
(16). In addition, the consumption of feron-g, and granzyme B on CD81 T (MMP-2) and MMP-9 (33). When an
fresh orange juice (19) or dietary fiber cells in obese individuals. intravenous dose of 300 mg hydrocorti-
(20) with the high-fat, high-calorie meal One study demonstrated that chil- sone was administered, these actions
prevented endotoxemia, inflammation, dren (8–17 years of age) with a BMI were observed, but, in addition, an
and oxidative stress. On the basis of these above the 85th percentile (BMI 29.1 ± increase in the expression of high-mobility
data, macronutrient intake, especially rich 1.6 kg/m2) had significantly reduced group box 1 (HMG-B1), TLR-2, TLR-5, and
in fats and carbohydrates and lacking in and inadequate tetanus-specific IgG lev- TLR-9 was noted in MNCs (34). There was
els (26). A recent study of veterinary also an increase in plasma concentrations
fruit and dietary fiber, would contribute
students (27) identified that overweight of HMG-B1 and MMP-9. These are all
to chronic oxidative and inflammatory
individuals had an increased likelihood proinflammatory mediators, and, hence,
stress in obesity.
for inadequate rabies-specific antibody the higher doses of corticosteroids have
titers 2 years after vaccination. mixed anti- and proinflammatory effects.
CHRONIC INFLAMMATION, OBESITY,
In a study focused on type 2 diabetes, In addition, this dose of hydrocortisone
DIABETES, AND IMMUNE RESPONSES
it was shown that monocytes prepared results in hyperglycemia and an increase
Chronic inflammation, as described above, from such patients when challenged with in plasma free fatty acid concentrations,
in obesity and diabetes may contribute to endotoxin (lipopolysaccharide) secreted both of which are proinflammatory. These
impaired immunological responses to spe- less TNF-a than monocytes from normal actions may contribute to absence of
cific pathogens and to vaccinations. The subjects. In addition, the expression of benefits when high doses of corticoste-
immunological response to hepatitis B, TNF-a, CD11b, and CD163 were dimin- roids are administered to patients with
hepatitis A, tetanus, and influenza A vacci- ished following lipopolysaccharide chal- septicemia. However, a dose of 6 mg of
nations in obese humans is impaired (21). lenge (28). However, the secretion of the dexamethasone (equivalent to 150 mg of
In addition, the response to influenza vac- anti-inflammatory cytokine IL-10 was not hydrocortisone) has been shown to be
cine is not as durable in obese individuals diminished. Thus, it is clear that the mag- beneficial to inflammation, especially in
as it is in normal-weight subjects without nitude of specific immune responses is the context of COVID-19 (35). In fact, this
diabetes. These observations have clear diminished in both obesity and type 2 dose of dexamethasone is currently being
implications for both the magnitude and diabetes, in association with the back- used routinely in all hospital admissions
the duration of immunity induced by vac- ground of chronic inflammation. with COVID-19.
cination in this population. It is possible
that vaccination-based protection may not ANTI-INFLAMMATORY EFFECTS OF ANTI-INFLAMMATORY ACTIONS
be as effective in this population as in nor- CORTICOSTEROIDS OF INSULIN
mal subjects. A total of 55.7% of the sub- Although corticosteroids have been used The two major risk factors determining
jects tested negative for protective as anti-inflammatory agents since the morbidity and mortality that have
antibodies against hepatitis B surface anti- 1950s, their molecular mode of action emerged consistently from the patterns
gen (anti-HBs) titers (21) after nearly a was first described in 1995. Two research of clinical manifestations in COVID-19
year of vaccination. A BMI $32.88 kg/m2 groups simultaneously described that infection are obesity and diabetes with
was identified as one of the major risk fac- dexamethasone enhanced the expression and without hyperglycemia (36). Both dia-
tors for hepatitis B virus vaccine nonres- of IkBa and, thus, suppressed the intra- betes and obesity are characterized by
ponse. Only 29.5% of individuals with a nuclear transfer of the proinflammatory chronic inflammation that impairs the
BMI greater than or equal to the 75th per- transcription factor NF-kB in immune ability to generate specific immunological
centile developed protective anti-HBs cells in vitro (29,30). Since these observa- responses to infections and antigenic
titers, compared with 63.3% of individuals tions were made with high concentra- challenges. Hyperglycemia also induces
below the 75th percentile that achieved tions of dexamethasone in vitro, our inflammation and impairs the defense
protective seroconversion (22). Recombi- group took the initiative of investigating mechanisms necessary for combating
nant vaccines were associated with similar the effect of physiologically and infection. Our work over the years hascare.diabetesjournals.org Dandona and Ghanim 3 demonstrated that glucose administration response were suppressed by an intrave- MIP-1β, and vascular endothelial growth and hyperglycemia induce oxidative and nous insulin infusion (45). Genes related factor (1). In all these clinical settings, inflammatory stress (13,37), while intrave- to bronchial asthma are also suppressed the use of an anti-inflammatory therapy nously administered insulin exerts a rapid by insulin infusion: IL-4, LIGHT (homolo- that also has antithrombotic and profi- and comprehensive anti-inflammatory gous to lymphotoxin, TNF superfamily brinolytic effects would be the ideal. Since action (37,38). This insulin infusion regi- member 14), LTBR (lymphotoxin β-recep- hyperglycemia promotes these features, men (2.5 units/h with 5% dextrose 100 tor), ADAM-33 (disintegrin and metallo- reduction of glucose would have beneficial mL/h) leads to the suppression of ROS proteinase domain-containing protein 33), clinical effects. However, as described generation, NADPH oxidase subunit and TSLP (thymic stromal lymphoprotein) above, the intravenous infusion of insulin (p47phox) expression, NF-kB binding activ- are the key genes involved in the patho- at anti-inflammatory doses would have ity, and intracellular adhesion molecule 1 genesis of bronchial asthma. They are all profound additional beneficial effects since and MCP-1 expression. These changes suppressed by insulin within 2 h (46), and insulin has previously been shown sup- commence at 2 h and continue for as remain suppressed for as long as insulin press a number of these cytokines. long as the infusion is administered. It is infused. These genes may also be Recently, a marked increase in mortal- also results in the suppression of tran- involved with the pulmonary syndrome ity in COVID-19 patients with diabetes scription factors AP-1 and early growth associated with COVID-19. and hyperglycemia has been shown in response protein 1 (Egr-1) and levels of The prognostic significance of hyper- a retrospective analysis (52). Patients MMP-2, MMP-9, tissue factor, and plas- glycemia has also been demonstrated in infused with insulin to control glucose minogen activator inhibitor 1 (39,40). In the context of acute myocardial infarc- concentrations had a markedly reduced addition, this insulin regimen suppresses tion (47,48) and acute ischemic stroke rate of mortality (20% vs. 80%). While several chemokines (MCP-1, RANTES [reg- (49). Insulin infusion has been shown to diabetes and hyperglycemia were associ- ulated on activation, normal T-cell– provide benefit in acute myocardial ated with an increase in IL-6 and D- expressed and secreted (CCL5)], macro- infarction inthree separate studies, one dimer concentrations, patients infused phage inflammatory protein-1β [MIP-1β]) from our center (50), the Clinical Trial of with insulin had significantly lower lev- and chemokine receptors 2 and 5 (41). In Reviparin and Metabolic Modulation in els. Since IL-6 is marker for inflammation addition to the general effects on oxida- Acute Myocardial Infarction Treatment and D-dimer is a marker for thrombosis, tive and inflammatory stress, glucose Evaluation–Estudios Cardiologicos Latino these data are consistent with what has induces prothrombotic factors like tissue America Study Group (CREATE-ECLA) previously been shown in our work factor and platelet proaggregatory actions study (47) and the Immediate Myocardial described above. while insulin inhibits thrombotic pro- Metabolic Enhancement During Initial Dexamethasone, which has anti- cesses, inhibits platelet aggregation, and Assessment and Treatment in Emergency inflammatory effects, has been shown promotes thrombolysis (42). In addition, Care (IMMEDIATE) study (51). Hyperglycemia to improve clinical outcomes in subjects insulin is a vasodilator at the arterial, (>140 mg/dL) at admission and its change with COVID-19 infection who receive venous, and the microvascular level after admission determine the clinical out- mechanical ventilation or supplemental potentially improving blood flow and per- comes of both acute myocardial infarction oxygen (53). However, there was a fusion into various organ systems medi- and ischemic stroke. These issues are rele- potential harmful effect in patients who ated by an increase in endothelial nitric vant to COVID-19 since its infection involves did not require any respiratory support. oxide secretion and nitric oxide synthase both the heart and the brain and the vascu- We have shown that while glucocorti- (43). Hyperglycemia also induces the lature serving them. coids have a clear anti-inflammatory expression of TLR-2 and TLR-4, which are COVID-19 infection initially affects the effect at physiologically relevant doses the receptors for the products of gram- lungs and the respiratory system and (hydrocortisone 100 mg) (31,33), they positive and gram-negative (including then, through its effects on vasculature, cause hyperglycemia and an increase in endotoxin) bacteria and HMG-B1, a it can lead to thrombotic changes. plasma free fatty acid concentrations, marker of mortality in animal sepsis mod- When this process involves cerebral vas- and thus may also have a potential els (37). Thus, hyperglycemia promotes culature, it can induce the stroke syn- proinflammatory effect, at higher doses vulnerability to infection. In contrast, insu- drome. In children, it induces features (300 mg hydrocortisone is equivalent lin suppresses HMG-B1 levels and the similar to Takayasu arteritis. Respiratory to 60 mg prednisolone) through an expression of TLR-1, TLR-2, TLR-4, TLR-7, system manifestations are the most increase in expression of TLR-2, TLR-5, and TLR-9 in addition to suppressing prominent and lead to hypoxia and TLR-9, and HMG-B1 in MNCs and an PU.1, the major transcription factor respiratory failure and thus to the need increase in plasma HMG-B1 and MMP-9 responsible for the transcription of TLRs for mechanical ventilation. There are (34). Our preliminary studies have also (37,44). TLR-7 and TLR-9 are responsible profound inflammatory changes with shown an additional anti-inflammatory for mediating inflammation induced by the release of proinflammatory cyto- effect and neutralization of the potential RNA and DNA viruses, respectively. kines, chemokines, and thrombotic fac- proinflammatory effect of steroids when COVID-19 is an RNA virus. In this context, tors. A cytokine storm has also been an insulin infusion is coadministered it is also noteworthy that we have shown described, characterized by intense with high-dose glucocorticoids (54). This that the acute effects of endotoxin injec- release of proinflammatory mediators. provides an additional rationale for the tion into normal subjects inducing several The major cytokines increased in use of insulin infusion in hospitalized indices of oxidative and inflammatory COVID-19–related cytokine storm are IL- subjects with COVID-19 infection, as we indices as well as the systemic febrile 1β, IL-6, TNF-a, interferon-g, MIP-1a, expect that a majority of our patients
4 Diabetes and COVID-19 Diabetes Care Volume 44, September 2021
with severe COVID-19 infection may be potentially potent inhibition of the 15. Aljada A, Mohanty P, Ghanim H, et al.
treated with glucocorticoids. effects of COVID-19. Increase in intranuclear nuclear factor kB and
decrease in inhibitor kB in mononuclear cells after
Clearly, therefore, strategies based on a mixed meal: evidence for a proinflammatory
neutralizing hyperglycemia and provid- effect. Am J Clin Nutr 2004;79:682–690
ing insulin would be beneficial in COVID- Duality of Interest. No potential conflicts of 16. Ghanim H, Abuaysheh S, Sia CL, et al. Increase
19 infection through comprehensive interest relevant to this article were reported. in plasma endotoxin concentrations and the
expression of Toll-like receptors and suppressor of
inhibitory actions on oxidative and
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