Emerging data are linking coronavirus disease 2019 (COVID-19) with an increasedrisk of developing new-onset diabetes.The gut has been so far out of the frame ofthe discussion on the pathophysiology of COVID-19-induced diabetes, with thepancreas, liver, and adipose tissue being under the spotlight of medical research.Sodium-glucose co-transporters(SGLT) 1 represent important regulators of glucoseabsorption, expressed in the small intestine where they mediate almost all sodium-dependent glucose uptake.Similar to what happens in diabetes and otherviral infections, SGLT1 upregulation could result in increased intestinal glucoseabsorption and subsequently promote the development of hyperglycaemia inCOVID-19.Considering the above, the question whether dual SGLT (1 and 2) inhibition could contribute to improved outcomes in such cases sounds challenging,deserving further evaluation.Future studies need to clarify whether putative benefitsof dual SGLT inhibition in COVID-19 outweigh potential risks, particularly with respect to drug-induced euglycaemic diabetic ketoacidosis, gastrointestinal sideeffects, and compromised host response to pathogens.

KEYWORDS

COVID-19, diabetes, SGLT1,SGLT2

1 | BACKGROUND

Emerging data are linking coronavirus disease 2019 (COVID-19) withan increased risk of developing new-onset diabetes and severe diabeticcomplications, including diabetic ketoacidosis (DKA). Whether

this type of diabetes resembles type 1 (T1D) type 2 (T2D) or comprisesa new form of the disorder remains vague.In a recently publishedobservational study from Scotland, McGurnaghan et al.1

demonstrated substantially increased risk of fatal or critical care unittreatedCOVID-19 in people with both type of diabetes compared

with the background population.Among patients with diabetes andafter adjustment for age, sex, diabetes type, and duration, those withpoor glycaemic control, presence of complications (retinopathyand renal disease), previous history of hospitalization due tohypoglycaemia or DKA, and being on treatment with multiple

antidiabetes agents and other medication were found to be at greater

risk for severe COVID-19 than individuals who didn't have the abovementionedcharacteristics. Obesity, a major risk factor for the development

of T2D, has been also linked to poor outcomes, including

severe pneumonia, intensive care unit admission, and mortality duringCOVID-19, probably related to increased viral entry into cells and

defects in immune response.2 COVID-19-related DKA seems to manifestpeculiar——still interesting—characteristics, including the occurrencein people without a previous diagnosis of diabetes, or in those

with non-insulin-dependent diabetes and adequate metabolic controlprior to infection. In addition, hyperglycaemia without diabetes andnew-onset diabetes have been both linked to a poorer prognosis inthe context of COVID-19.3 The development of hyperglycaemia in COVID-19, either being

genuinely new or the unmasking of a previously existing occult diabetes,is the result of a pathophysiological interplay between impaired

insulin secretion and action.Up to now, putative explanations for theunderlying pathophysiological mechanisms through which the severeacute respiratory syndrome coronavirus 2 (SARS-CoV-2) can inducesevere hyperglycaemia and subsequent DKA have mainly focused ontwo directions: first, a direct viral attack against beta-cells and,

second, an exacerbation of insulin resistance (IlR), as a result of systemicinflammation.4

In this paper, we discuss a novel hypothesis according to which,intestinal sodium-glucose transport proteins might be implicated inthe pathogenesis of COVID-19-induced diabetes and could representa therapeutic target for the disorder in the future.

2 | HYPOTHESIS

The angiotensin-converting enzyme 2(ACE2), which is the entry pointfor the virus into the cells, has been shown to be expressed in the

pancreatic tissue. ln line with what is already known from studies conductedwith other coronaviruses, it has been demonstrated that

SARS-CoV-2 exerts cytotoxic effects that cause islet cell injury and

impair insulin production.5 Moreover, downregulation of ACE2 followingthe endocytosis of the virus complex results in increased

angiotensin ll concentrations, which are known to impede insulinsecretion.6,7 Similar to what happens with other viral infections,an immune-mediated beta-cell destruction triggered by the

SARS-CoV-2 infection has been also suggested.4,7 In a parallel way,COVID-19-related cytokine storm leading to overproduction ofproinflammatory molecules,predominantly interleukin (IL)-6 andtumour necrosis factor-a (TNF-a), further aggravates beta-celldysfunction and induces lR.

Over the past few years, the importance of the gut in the regulationof glucose homeostasis has been greatly recognized by identifyingits multiple roles in modulating nutrient absorption, satiety,

systemic and adipose tissue inflammation and insulin secretion andaction. Although patients with COVID-19 mainly present with respiratorysymptoms, a recent meta-analysis proved that approximately

12% of SARS-CoV-2-infected individuals will manifest gastrointestinal(GI) symptoms, with diarrhoea, nausea, or vomiting being the mostcommonly reported among them.8 While the exact mechanisms

through which the virus attacks the Gl tract are still under investigation,it is believed that following the infection of the lung tissue by

SARS-Cov-2, effector CD4+T-cells move to the small intestine

through the gut-lung axis and cause intestinal immune damage.However,the gut has been so far out of the frame of the discussion on the

pathophysiology of COVID-19-induced diabetes, with the pancreas,liver, and adipose tissue being under the spotlight of medical research.Only recently, alterations in the gut microbiome have been proposedto contribute to the pathogenesis, severity, and disease course ofCOVID-19, potentially leading to an upregulated systemic inflammatorystate, negatively affecting this way insulin production and 

sensitivity.7

Sodium-glucose co-transporters (SGLT) 1 and 2 represent importantregulators of glucose uptake across apical cell membranes.SGLT1are particularly expressed in the small intestine where they mediatealmost all sodium-dependent glucose uptake, whereas they are alsolocated in other tissues, including heart and kidneys.High expressionof ACE2 in mucosal cells of the intestine renders the organ vulnerableto SARS-Cov-2 invasion and replication.Previous research has

highlighted that ACE2-mediated downregulation of SGLT1 in theintestinal epithelium has the potential to improve glycaemic status inan experimental model of T1D.9 Inversely, ACE2-mediated SGLT1upregulation occurs in diabetes and diabetes-related diseases, whichresults in increased intestinal glucose absorption and subsequently tothe development of hyperglycemia.6 In support of the perspectivethat SGLT1 might be implicated in the metabolic disarrangement

observed in some patients with COVID-19, Dai et al.10 have demonstratedthat infection with transmissible gastroenteritis virus—another

coronavirus——results in augmented glucose uptake through enhancedSGLT1 expression in porcine intestinal columnar epithelial cells.

On the other hand, recent studies have suggested an important

role of SGLT1 activation in the host response against specific pathogens.Sharma et al.11 have showed that genetic knockout of SGLT1 in

a murine model of Listeria infection increased bacterial load in liver,spleen, kidney, and lung and significantly upregulated the hepaticexpression of lL-12 a and TNF-o, resulting in the death of

SGLT1-deficient mice, in contrast with the wild-type animals whichsurvived the infection.In a similar way, SGLT1 inhibition with

phlorizin was correlated with a decreased survival rate in a rat modelof bronchial inflammation and sepsis.12

SGLT activation has recently been a key therapeutic target inT2D, where excessive glucose reabsorption by the kidneys is

observed.1 3 Available drugs mainly inhibit SGLT2, located in the earlysegment of the proximal renal tube, thus leading to reduced renal glucosereabsorption.14 However, specific agents within the class,

namely, sotagliflozin and canagliflozin, present only 20- and 250-foldhigher inhibitory activity for SGLT2 compared with SGLT1, respectively,and are considered "dual inhibitors," manifesting their glucoseloweringactions by reducing-apart from renal—intestinal glucose absorption, as well15 (Table 1).Interestingly, dual inhibition has beenquestionably linked to a greater risk of adverse events, including lowerextremity amputations and euglycaemic DKA, compared with themore selective SGLT2 inhibitors.14,15 Although the exact mechanismsthat could explain these differences are still debatable, they may berelated to the volume depletion-mediated increased ketone bodyreabsorption in the distal tubules, which, in turn, could amplify themagnitude of ketonemia already observed with SGLT2 inhibition.16 Gladverse events, such as osmotic diarrhoea, are also more commonwith dual inhibitors, attributable to their effects on the brush borderof the small intestine.14-16

Relevant to their remarkable cardiorenal protective properties inpeople with or without diabetes, previous research has highlightedthe potential of SGLT2 inhibitors to decrease the concentrations ofproinflammatory cytokines, reduce oxidative stress, downregulate

sympathetic activity and improve cell autophagy, leading to ameliorationof both systemic and adipose-tissue inflammation.17 These seem

to be class effects and not related either to SGLT1 or SGLT2 inhibitionalone.In this context, dapagliflozin, a molecule with a 1200-foldhigher potency for SGLT2 compared with SGLT1, is currently beingtested in clinical trials as a potential treatment for acute respiratory

COVID-19 disease,17 and their results are anticipated in order to clarifywhether the class could represent an additional weapon in the

therapeutic arsenal against SARS-CoV-2.Considering the hypothesisthat ACE2-mediated intestinal SGLT1 dysregulation is implicated inthe development of cOVID-19-related hyperglycaemia, the questionwhether dual SGLT (1 and 2) inhibition could contribute to improvedoutcomes in such cases sounds challenging, deserving further

evaluation in clinical studies (Figure 1).

3 | CONCLUSION

ln conclusion, there is indirect evidence linking ACE2-mediated SGLT1upregulation to the development of hyperglycaemia and diabetesrelatedadverse outcomes in COVID-19.Thus, the excessive

activation of SGLT1 could be a potential therapeutic target forCOVID-19-induced diabetes.The testing of the hypothesis seems tobe relatively feasible, considering that dual SGLT inhibitors are alreadywidely used in daily clinical practice for the management of T2D.On the other hand, it should be noted that available data are stillvery limited.Therefore, the development of animal models for themechanistic study of the key molecular mechanisms implicated in theSARS-Cov-2 binding receptor ACE2 mediated dysregulation of intestinalnutrient transporters is needed.6 Moreover, the great heterogeneityof the clinical presentation of COVID-19 implies complex

underlying interactions between genetic and environmental componentsthat determine inter-individual variations in disease severity and

possibly in response to various treatments.Clinical studies are hence

required to investigate the potential of a tailored approach in the therapeuticmanagement of COVID-19, but also to clarify whether

putative benefits of dual SGLT inhibition outweigh potential risks,particularly with respect to drug-induced euglycaemic DKA, Gl sideeffects, and compromised host response to pathogens.

ACKNOWLEDGEMENT

The authors received no financial support for the research, authorship,and/or publication of this article.

COMPETING INTERESTS

T.K. has received honoraria as a speaker from AstraZeneca,

Boehringer lngelheim, and Novo Nordisk and has participated in sponsoredstudies by Eli-Lilly. K.K. has received honoraria for lectures/

advisory boards and research support from Astra Zeneca, BoehringerIngelheim, Pharmaserve Lilly, Sanofi-Aventis,ELPEN,MSD, and NovoNordisk.Other authors report no conflict of interest.

CONTRIBUTORS

T.K. reviewed the literature and drafted the first version of the manuscript.S.M.， P.Z.. and K.K. reviewed the literature and edited the manuscript.All authors have read and approved the final version of the

manuscript. 

ORCID

Theocharis Koufakis https://orcid.org/0000-0002-5853-1352Symeon Metallidis https://orcid.org/0000-0002-3869-5341Pantelis Zebekakis https://orcid.org/0000-0001-8821-406XKalliopi Kotsa https://orcid.org/0000-0003-2376-740xREFERENCES

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