Glycemic control of type 2 diabetic patients with coronavirus disease during hospitalization: a proposal for early insulin therapy

to the editor: The world is watching the progress of coronavirus disease (COVID‐19) pandemic. Older age and pre-existing medical conditions, specifically diabetes mellitus, hypertension, ischemic heart disease, and chronic lung disease, are associated with a more severe course of COVID-19 (5a). Diabetes mellitus is one of the most prevalent comorbidities among patients hospitalized due to COVID-19 (7). Data obtained from 21 hospitals in Wuhan, China, showed that 25% of the reported COVID-19 fatalities had a history of diabetes mellitus (33). Diabetes and ambient hyperglycemia were independent predictors for death and morbidity in patients with severe acute respiratory syndrome (14, 34). In this letter, we discuss the putative roles of angiotensin-converting enzyme II (ACE2) in glucose homeostasis in patients with type 2 diabetes and COVID-19 and introduce the proposed benefit of early insulin therapy in patients that warrant hospital care.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme II (ACE2) receptor for host cell entry and the serine protease TMPRSS2 for virus spike protein priming (16). The binding of SARS-CoV-1 Spike protein to ACE2 activates disintegrin and metalloprotease-17 (ADAM17) and induces ACE2 shedding via a process tightly coupled with TNF-α production (15). ADAM17-mediated ACE2 shedding facilitates SARS-CoV-1 entry and induces tissue damage by TNF-α production (15). Interestingly, Kuba et al. (22) found that SARS-CoV-1 infection downregulates ACE2 expression in the mice lungs, and this downregulation was associated with the severity of lung injury. Considering that SARS-CoV-1 and SARS-CoV-2 share >70% sequence in the Spike protein (31), SARS‐CoV‐2 infection might also downregulate the ACE2 expression in the same manner and play a role in the pathological process of the lung injury. ADAM17-mediated ACE2 ectodomain shedding might compromise the renin-angiotensin system (RAS) compensatory axis by impairing ACE2 enzymatic activity or its ability to process angiotensin II on the cell surface. Recently, Monteil et al. (23) showed that human recombinant soluble ACE2 significantly blocks SARS-CoV-2 infections, providing a rationale that soluble ACE2 might not only protect from lung injury but also block the SARS-CoV-2 from entering target cells.

ACE2 is expressed in several tissues including the kidney and recognized to be renoprotective by degrading angiotensin II to angiotensin(1–7) (9). The ACE2 receptor protects against lung injury by modulating of the RAS and decreasing angiotensin II levels (19). Accumulating evidence supports the protective roles of ACE2 in diabetes. ACE2 is expressed in the pancreas and several insulin-sensitive tissues and might play important roles in glucose homeostasis. First, ACE2 deficiency leads to altered glucose metabolism; ACE2-knockout mice showed a β-cell defect associated with a decrease in insulin secretion in a manner that is not dependent on angiotensin II but may reflect the collectrin-like action of ACE2 (2, 24). In the db/db mouse model (a classic model of type 2 diabetes), ACE2 overexpression in the pancreas significantly improved glucose tolerance, enhanced islet function, and increased β-cell proliferation and insulin content (3). Second, loss of ACE2 increases insulin resistance in high-calorie diet-fed mice, by reduction of GLUT4, and administration of angiotensin(1–7) improved insulin tolerance, suggesting a significant role of angiotensin(1–7) in glucose homeostasis (30). Angiotensin(1–7) improves the action of insulin and opposes the negative effect that angiotensin II exerts at this level (36). Third, ACE2 is thought to act as a compensatory mechanism for hyperglycemia-induced RAS activation. Hyperglycemia increases ADAM17 activity and renal ACE2 shedding into urine in mice (6, 32). This urinary ACE2 excretion correlated positively with the progression of diabetic renal injury represented by progressive albuminuria, mesangial matrix expansion, and renal fibrosis, resembling an unopposed angiotensin II effect. Loss of ACE2 in mice disrupts the balance of the RAS in a diabetic state and leads to an angiotensin II/AT1 receptor-dependent systolic dysfunction and impaired vascular function (26). In humans, urinary ACE2 levels are significantly higher in insulin-resistant patients and type 2 diabetes mellitus than in controls with normal glucose tolerance (25). In addition, urinary ACE2 appears to be positively associated with inflammatory cytokines (25).

Based on the aforementioned findings, patients with COVID-19 might be at increased risk of developing hyperglycemia. The proposed mechanism is SARS-CoV-2-mediated downregulation of ACE2 expression, which may hypothetically decrease insulin secretion and increase insulin resistance, accompanied by hyperglycemia-induced RAS activation. Moreover, the localization of ACE2 expression in the endocrine part of the pancreas suggests that SARS-CoV-2 might enter islets using ACE2 as its receptor and damage islets causing acute diabetes. In fact, Yang et al. (35) reported that ~50% of SARS patients who had no previous history of diabetes or steroid treatment, developed clinically significant hyperglycemia during hospitalization, but only 10% had diabetes after 3 yr of follow-up.

ADAM17 activation by SARS‐CoV‐2 might also increase the risk of hyperglycemia. In mice, accumulating evidence suggests that increased ADAM17 activity results in increased insulin resistance and hyperglycemia (11). ADAM17 plays a potential role in inflammation, as it can cleave and thereby activate a variety of cytokines and cytokine receptors including tumor necrosis factor α (TNFα) and the interleukin-6 receptor (IL-6R) (10). Accumulating evidence suggests that patients with severe COVID-19 and acute respiratory distress syndrome (ARDS) might have a cytokine storm syndrome, including high levels of IL-6 and TNFα (5). Meanwhile, RAS activation can propagate the acute lung injury (36). Furthermore, increased inflammation might also contribute to the development of islet β-cell failure (8).

Hyperglycemia is commonly observed during acute and critical illness (18). Controlling hyperglycemia with insulin is crucial in the management of critically ill patients. Early administration of insulin in acute illness is associated with better outcomes and lower mortality rates (18). Early insulin therapy in patients with type 2 diabetes with COVID-19 disease that warrant hospital care appears to have several advantages. First, insulin exerts immunomodulatory effects independent of glycemic control. Insulin inhibits synthesis of proinflammatory factors, including TNFα and IL-6, and might have a protective role in ARDS (17). Second, studies in mouse models suggest that management of hyperglycemia restores ACE2 and ADAM17 expression and the RAS balance. In the Akita mouse model of type 1 diabetes, insulin treatment normalized hyperglycemia, decreased urinary ACE2 excretion, restored renal ACE2 and ADAM17 expression to physiological levels, and normalized the rate of shedding (29). Furthermore, insulin significantly increased ACE2/ACE activity ratio in the nonobese diabetic (NOD) mice lung and restored ACE and ACE2 and ACE2/ACE ratio activities in serum samples (27). Thus, it can be hypothesized that insulin therapy might be protective against SARS-CoV-2-induced lung injury by restoring ACE2 expression to physiological levels on the cell surface and decreasing angiotensin II levels (19). Third, early insulin therapy reduces the risk of developing diabetic ketoacidosis (DKA) or hyperglycemic hyperosmolar states in acutely ill patients. In fact, a recent case report suggests a potential for β-cell damage caused by the SARS-CoV-2, leading to insulin deficiency and DKA (20).

Other antihyperglycemic medications might have a protective role in ARDS. Metformin, peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, glucagon-like peptide 1 (GLP-1) agonists, and dipeptidyl peptidase 4 (DPP4) inhibitors attenuated lung injury in murine models (13, 21, 38, 39). Some of these medications might modulate ACE2 expression. Pioglitazone increases ACE2 protein expression in insulin-sensitive tissues in rats with high-fat diet-induced nonalcoholic steatohepatitis (37). However, in type 2 diabetic mice, rosiglitazone normalized hyperglycemia, attenuated renal injury, and decreased urinary ACE2 excretion and renal ADAM17 protein expression but, unlike insulin, did not affect renal ACE2 expression (6). Noteworthy, liraglutide, a GLP-1 agonist, upregulated ACE2 expression in the lungs of both diabetic and control rats (28). Thus, liraglutide might theoretically exert protective effects against SARS-CoV-2 induced lung injury.

Some glucose-lowering agents lack safety data concerning their use in patients with moderate or severe COVID-19 pneumonia. Lactic acidosis associated with metformin, or diabetic ketoacidosis associated with sodium glucose cotransporter 2 (SGLT-2) inhibitors are rare events; however, recently published treatment recommendations advise these drugs should be discontinued for patients with severe symptoms of COVID-19 to reduce the risk of acute metabolic decompensation (4). No convincing evidence exists to suggest that incretin-based therapies should be discontinued; however, more prospective studies comparing these agents with insulin are required to establish their efficacy and safety in hospitalized patients.

Given the wide clinical spectrum of COVID-19 and the fact that patients needing hospital care may deteriorate rapidly, an early introduction of insulin in type 2 diabetic patients with COVID-19 is to be encouraged upon admission to the hospital. The target glucose range is 140–180 mg/dL (7.8–10.0 mmol/L) in most cases (1). Beyond controlling hyperglycemia, early administration of insulin is hypothesized to exert positive immunomodulatory effects, modulate RAS, and protect against lung injury. Future studies should be carried out to elucidate the interface between diabetes and COVID-19.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

A.N. drafted manuscript; A.N. and N.S. edited and revised manuscript; A.N. and N.S. approved final version of manuscript.