Bidirectional Relationship between COVID-19 and Diabetes: Role of Renin-Angiotensin-Aldosterone System and Drugs Modulating It.

Numerous reports have suggested that diabetic patients are at high risk for the development of severe symptoms of coronavirus disease-2019 (COVID-19). However, a few studies have recently proposed that the relationship between diabetes and COVID-19 is bidirectional, as severe acute respiratory syndrome-coronavirus-2 also has the capability to induce diabetes. Various mechanisms have been identified and proposed to be involved in this binary association. In this review, the importance and impact of renin-angiotensin-aldosterone system (RAAS) in this two-way association of COVID-19 and diabetes has been summarized. The role and effect of drugs modulating RAAS directly or indirectly has also been discussed, as they can majorly impact the course of treatment in such patients. Further reports and data can present a clear picture of RAAS and its modulators in restoring the balance of dysregulated RAAS in COVID-19. Copyright:

INTRODUCTION

The emergence of severe acute respiratory syndrome-corona virus-2 (SARS-CoV-2) in December 2019 is an extraordinary global medical challenge. Depending on the comorbidities, the symptoms and severity of previously unknown and highly contagious coronavirus disease-2019 (COVID-19) vary from patient to patient. Severity depends on multifactor including age, diabetes, cardiovascular (CV) diseases, respiratory diseases, cancer, acute kidney injury, gender, ethnicity, obesity, pro-inflammatory, and pro-coagulative state etc.[12] Due to the worst prognosis of COVID-19 observed in diabetic patients, considerable attention has been directed to treatment and survival rates in both type 1 and type 2 diabetics.[3]

However, there are recent reports suggesting a two-way association between diabetes and COVID-19.[456] Few studies have reported that new-onset diabetes has been detected in patients of COVID-19 and also severe metabolic complications such as diabetic ketoacidosis and hyperosmolarity in patients with preexisting diabetes.[789] This association poses a further challenge to the medical professionals not only to understand the complex pathophysiology involved but also in the clinical management of such patients to obtain maximum therapeutic benefits.

WHY RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM IS IMPORTANT IN BIDIRECTIONAL ASSOCIATION OF DIABETES AND CORONAVIRUS DISEASE-2019?

Various researchers have already described the pathophysiological mechanisms involved in diabetes as a risk factor for severity and mortality in COVID-19.[12] Enhanced secretions of glucocorticoids and catecholamines,[10] occasional hypoglycemia leading to the movement of pro-inflammatory monocytes,[11] oxidative stress involvement, and release of pro-inflammatory cytokines[1213] are few of them. The connotation between virus and diabetes is not at all new as hyperglycemia disrupts the control of viremia and inflammation and hence intensify mortality and morbidity.[1214] The risk for infections including SARS-COV2 also increases in diabetic patients, for which multiple mechanisms have been proposed.[15] A plethora of literature supports affiliation between glycemic levels and risk of being hospitalized. The previous epidemics of SARS,[16] Middle East respiratory syndrome,[171819] and H1N1 influenza virus[20] have also confirmed the enhanced risk of viral infections in such patients. The better the glycemic control, the outcomes in infected patients are improved which highlight the need for management of optimal glycemic levels.[2]

However, only a few reports till now have speculated the possible pathophysiological mechanisms involved in the novel development of diabetes in COVID-19 patients.[621] The release of cytokines and chemokines in COVID-19 triggering immune responses and damaging pancreatic beta-cells, endothelial dysfunction, glycemic fluctuations, increased intestinal permeability, increased stress and depression, etc., have been overtly mentioned in the development of new-onset diabetes mellitus (DM) in COVID-19 patients.[521] Thus, in addition to the pro-inflammatory cascade induced by SARS-CoV-2, it is probable that virus may also be inducing certain pleiotropic modifications in the glycemic homeostasis, leading to the development of complications in the pathophysiology of preexisting diabetes or initiating mechanisms for the development of disease.[45] What exactly can be these pleiotropic modifications, I have proposed one possible alteration in relation to renin–angiotensin–aldosterone system (RAAS) and angiotensin-converting enzyme-2 (ACE-2)/angiotensin-(1–7)/MAS axis.

SARS-CoV-2 utilizes ACE-2 as its cell receptor which is expressed in multiple organs in the body at varying levels. In addition to the other organs such as lungs, kidneys, heart, and intestines, they are also highly expressed in pancreatic β-cells and play a significant role in maintaining the balance of the body at physiological and pathophysiological level through RAAS and ACE2/angiotensin-(1–7)/MAS axis. The angiotensin-(1–7)/MAS axis upon activation by angiotensin-(1–7) produces vasodilatory, vascular protective, antifibrotic, antiproliferative, and anti-inflammatory effects. On the contrary, when angiotensin-II (Ang-II) binds to angiotensin type 1 receptor (AT1R), vasoconstriction, hypertrophy, fibrosis, proliferation, inflammation, and oxidative stress are exerted. It is interesting to know that Ang-II effects on angiotensin type 2 receptor counteract the aforesaid effects mediated by AT1R. It has been observed that SARS-COV-2 induces downregulation of ACE-2 in multiple organs, thereby producing a localized imbalance between the RAS and ACE2/angiotensin-(1–7)/MAS axis, leading to organ injuries.[21] The defensive role of ACE2/angiotensin (1–7) in diabetes was already reported by Santos et al. before the onset of COVID-19. The ACE2/angiotensin-(1–7)/MAS axis supports in improving the survival of pancreatic β-cell, stimulates insulin release, and helps in decreasing the insulin resistance.[22]

Few studies have reported elevated serum amylase and lipase levels,[23] significant changes in pancreas on computed tomography scans,[24] and the presentation of acute pancreatitis[25] in COVID-19 patient with severe symptoms. Autopsies done in 2003 have illustrated atrophy and amyloid deterioration in the majority of pancreatic islets in the SARS patients indicating the virus causes damage to the islets.[26] Needless to mention that the corticosteroids used to manage cytokine storm in such patients can induce insulin resistance and dysglycemia, interferon β-1, and other type 1 interferon can lead to autoimmune β-cell damage, and antivirals such as lopinavir/ritonavir can also produce hyperglycemia.[27] Thus, the ACE-2 dysregulation leading to the disturbance between RAAS and ACE2/angiotensin-(1–7)/MAS axis along with the disruption of protective mechanisms on pancreas and islet degeneration could be one of the primary effects that may be involved in the onset of new diabetes in COVID-19 patients.

This hypothesis is supported by the fact that Ang-II is considered a significant promoter for the development of insulin resistance and DM. The studies on diabetic animal models have shown an early enhancement in ACE2 expression as well as in its activity.[28]

Figure 1 summarizes these observations and possible mechanisms that can lead to the onset of new diabetes mellitus in COVID-19 patients.

Figure 1

Mechanisms that can lead to the onset of new diabetes mellitus in coronavirus disease-2019 patients

Figure 2 summarizes the renin–angiotensin–aldosterone system and the target of drugs acting on it.

Figure 2

The renin–angiotensin–aldosterone system and the drug targets

ROLE AND STATUS OF ANGIOTENSIN-CONVERTING ENZYME INHIBITORS, ANGIOTENSIN RECEPTOR BLOCKERS, AND OTHER DRUGS CORONAVIRUS DISEASE-2019 AND DIABETES

Drugs acting on RAAS such as ACE inhibitors, angiotensin receptor blockers (ARBs). and aldosterone receptor blockers are the commonly prescribed drugs in CV disorders such as hypertension and congestive heart failure and in DM as well.[29] Theoretically, any drug binding/blocking ACE2 receptors will stop the entry of SARS-COV2 into the cell and henceforth the infection. Hence, clinical-grade human recombinant-soluble ACE2 have been checked endogenously and observed to block the initial stages of SARS-COV2 infection.[30] In experimental studies, the drug acting on RAAS such as ACE inhibitors, ARBs, and aldosterone receptor blockers have been shown to enhance the upregulation of ACE2 expression (which is downregulated in COVID-19). This effect leads to the strengthening of protective effects on ACE2/angiotensin-(1–7)/MAS axis.[31] Although this upregulation of ACE2 expression is till now not known in clinical studies and results are awaited, Reynolds et al. have reported the drugs acting on RAAS were not related to the significant rise in the risk for the development of severe symptoms in COVID-19 patients.[32] In an experimental study, the animal models with RAAS deactivation exhibited better symptoms in acute severe pneumonia and respiratory failure.[33]

However, few other preclinical studies have stated that usage of RAAS inhibitors might cause a compensatory induction of more ACE2, which may offer more sites of action for SARS-COV2. This effect particularly in lung infection may cause enhanced spread of COVID-19. The AT1R blockers (losartan, telmisartan, candesartan, etc.) may also can cause compensatory increase in Ang-II, leading to renoprotection.[34] The impact of RAAS inhibitors on ACE2 expression in lungs and heart is however not available.[31] Thus, both positive and negative effects can be presumed using the drugs acting/blocking RAAS.[3536]

Due to the nonavailability of any strong evidence of defensive or detrimental effects,[373839] various societies such as the American Heart Association, European Society of Cardiology Council on Hypertension, and European Society of Hypertension have recommended to continue the use of ACE inhibitors or ARBs in CV disorders and DM.[1535] Figure 2 summarizes the renin–angiotensin–aldosterone system and the target of drugs acting on it.

ROLE OF RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM AND BETA-BLOCKERS

The sympathetic/adrenergic system works in close knit association with RAAS. Recently, it has been proposed that hyperactivity of adrenergic system-ACE2-SARS-COV2 may be involved in the primary mechanisms of COVID-19.[40] Hence, by blocking the β-receptors of adrenergic system, the activation of RAAS may also be modulated in a positive way toward reaching the therapeutic benefits in COVID-19. It is proposed that beta-receptor antagonists may reduce the ACE2 level and hence the cellular entry point for SARS-COV2 at low doses in the patients with normal blood pressure.[41] The additional effects of beta-blockers that may help further in combating COVID-19 are downregulation of CD147 cells by propranolol,[42] decrease in interleukin (IL)-6 levels, and other pro-inflammatory cytokine expression such as IL-1 β, tumor necrosis factor-alpha, interferon-γ,[4043] and reduction in pulmonary edema and hypercoagulation state.[40]

The role of catecholamines in aggravating the symptoms of cytokine storm has been implemented; hence, the blockade of adrenergic receptors (beta and alpha) may be helpful in counteracting the symptoms of the potentially fatal cytokine storm.[4445] On the other hand, the ACE2 receptor overexpression has been reported by β2-receptor agonists,[40] hence the usage of such drugs in acute respiratory distress syndrome has been recommended to be avoided.[46] By enhancing the catecholamines, the β2-receptor agonists may produce a hypercoagulable state.[474849]

Taking all these proposed mechanisms and adrenergic receptors mediated effects into consideration, it would be interesting to know the levels of RAAS markers in COVID-19 patients to comprehend the role of sympathetic system in COVID-19 and hence its modulation. In this regard, the establishment of CoviDiab registry could be an important clinical tool to establish the degree of and illustrate new-onset, COVID-19-related diabetes, and to explore its pathogenesis, management, and outcomes.

More clinical data and retrospective studies on COVID-19 patients are required to provide clarity on issues and concerns such as:

Duration of hyperglycemia/new onset diabetes after recovery: is the condition permanently established or subside with time when patient's condition improved? This is particularly more important for SARS-COV-2 as hyperglycemia has been observed to continue for up to 3 years after recovering from SARS demonstrating a transient impairment to beta cells[50]

How Type 2 diabetes mellitus (T2DM) patients are managed in case when virus-induced pancreatic damage is evident: Whether T2DM patients can be still managed with antihyperglycemic/hypoglycemic agents or switched to insulin to maintain the glycemic levels?

Risk of diabetic ketoacidosis or metabolic complications mainly in Type 1 diabetes mellitus patients: this is imperative to know as the patients with diabetes hospitalized for COVID-19 have been reported to be at high risk of mechanical ventilation, ICU admission, and death, due to cardiometabolic multimorbidity (CoViDiab II)[51]

Role of ACE inhibitors/AT1R blockers: though the prophylactic/therapeutic benefits of these agents are not yet established, theoretically these drugs may improve the imbalance caused by the downregulation of ACE-2 receptors and disruption of ACE2/angiotensin-(1–7)/MAS axis. The effect of such drugs on glucose levels and insulin sensitivity in these patients can also provide useful information

In both the conditions, i.e., diabetes (chronic uncontrolled) and COVID-19, involvement of pro-inflammatory cytokines is evident.[1213] In such a case, whether the use of any nonsteroidal anti-inflammatory agent could be advantageous? Nonetheless corticosteroids being hyperglycemic and insulin resistance promoters are out of the race

Role of comorbidities: In a recently published case-controlled study (CoViDiab I), a high prevalence of chronic obstructive pulmonary disease and of chronic kidney disease in COVID-19 patients with Type 2 diabetes has been suggested, however cardiovascular disease frequency does not vary between people with diabetes with and without COVID-19 requiring hospitalization.[52] The comorbidities particularly CV complications such as hypertension, chronic heart failure, and metabolic disorders such as obesity, are also required to distinguish the role of RAAS in COVID-19-induced new diabetes.

CONCLUSION

The effects and control of ACE2/angiotensin-(1–7)/MAS axis may have a crucial role in diabetes induced by SARS-COV-2. Lucidity on these issues will require careful monitoring and follow-up studies in COVID-19 patients after their recovery to fill in the gaps. As SARS-COV-2 is able to produce multiorgan damage, the recovered patients (either previously diabetic/new onset diabetic) require frequent monitoring and critical management of pulmonary, CV, neurological, and gastrointestinal systems in addition to metabolic functions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.