Insulin may increase disease severity and mortality of COVID-19 through Na+/H+ exchanger in patients with type 1 and type 2 diabetes mellitus

Cüre, Erkan; Cüre, Medine Cumhur

doi:10.1007/s40618-022-01951-y

Cited by 4 publications

(6 citation statements)

References 29 publications

(40 reference statements)

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“…vessels' endothelium [1], increased inflammation, and viral binding and replication [24], thus, worsening the COVID-19 course [6]. Conversely, insulin might not effectively minimize mortality by maintaining normal blood glucose rates within the expected levels' span [25], as it has variable effects (Figure 1): it increases the production of inflammatory cytokines, Tumor Necrosis Factor-a (TNF-a), interleukin IL-1B, and IL-6 through the nuclear factor kappa B pathway [25]; it increases the affinity of the SARS-CoV-2 spike protein and predisposes diabetic patients to a severe COVID-19 disease course [26]. Cumhur et al (2023) assert that, in patients with type 2 DM, the hyperactive Renin-Angiotensin System (RAS) increases Na+/H+ exchanger activity (NHE), decreasing intracellular pH and predisposes the patients to a SARS-CoV-2 infection since it infects the cell effortlessly at a low intracellular pH [26].…”

Section: • Insulinmentioning

confidence: 99%

“…Cumhur et al (2023) assert that, in patients with type 2 DM, the hyperactive Renin-Angiotensin System (RAS) increases Na+/H+ exchanger activity (NHE), decreasing intracellular pH and predisposes the patients to a SARS-CoV-2 infection since it infects the cell effortlessly at a low intracellular pH [26]. Increased NHE activity also leads to insulin resistance and further worsens hyperglycemia [26]. A meta-analysis done by Nguyen et al ( 2022) included 61 studies with 3,061,584 individuals and found insulin as a cause of increased mortality among diabetes T2 patients infected with SARS-CoV-2 (OR 1.70, 95% CI 1.33-2.19) [12].…”

Section: • Insulinmentioning

confidence: 99%

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Antidiabetic Drug Efficacy in Reduction of Mortality during the COVID-19 Pandemic

Gonikman,

Kustovs

2023

Medicina

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Background and Objectives: The COVID-19 pandemic caused by the Coronavirus SARS-CoV-2 is a complex challenge for the existing scientific and medical landscape. It is an ongoing public health crisis, with over 245,373,039 confirmed cases globally, including 4,979,421 deaths as of 29 October 2021. Exploring molecular mechanisms correlated with the disease’s severity has demonstrated significant factors of immune compromise, noted in diabetic patients with SARS-CoV-2 infections. Among diabetics, the altered function of the immune system allows for better penetration of the virus into epithelial cells, increased viral binding affinity due to hyperglycemia, reduced T cell function, decreased viral clearance, high risks of cytokine storm, and hyper-inflammatory responses, altogether increasing the susceptibility of these patients to an extreme COVID-19 disease course. Materials and Methods: This research involved a systematic literature search among various databases comprising PubMed and Google Scholar in determining credible studies about the effects of antidiabetic drugs on the high mortality rates among diabetic patients infected with COVID-19. The primary search found 103 results. Duplicated results, non-pertinent articles, and the unavailability of full text were excluded. Finally, we included 74 articles in our review. The inclusion criteria included articles published during 2020–2023, studies that reported a low risk of bias, and articles published in English. Exclusion criteria included studies published in non-peer-reviewed sources, such as conference abstracts, thesis papers, or non-academic publications. Results: Among the studied anti-diabetic drugs, Metformin, the Glucagon-like peptide 1 receptor agonist (GLP-1RA), and Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) have demonstrated decreased mortality rates among diabetic patients infected with COVID-19. Insulin and Dipeptidyl peptidase 4 inhibitors (DPP-4i) have demonstrated increased mortality rates, while Sulfonylureas, Thiazolidinedione (TZD), and Alpha-glucosidase inhibitors (AGI) have demonstrated mortality-neutral results.

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Section: • Insulinmentioning

confidence: 99%

Section: • Insulinmentioning

confidence: 99%

Antidiabetic Drug Efficacy in Reduction of Mortality during the COVID-19 Pandemic

Gonikman,

Kustovs

2023

Medicina

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“…[112a,116a] It has been proposed that insulin therapy possibly increases COVID-19 severity and mortality of COVID-19 through Na + /H + exchangers in patients with T1DM and T2DM. [117]…”

Section: Insulinmentioning

confidence: 99%

Dissecting the Interrelationship between COVID‐19 and Diabetes Mellitus

2023

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COVID‐19 disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has led to enormous morbidity and mortality worldwide. After gaining entry into the human host, the virus initially infects the upper and lower respiratory tract, subsequently invading multiple organs, including the pancreas. While on one hand, diabetes mellitus (DM) is a significant risk factor for severe COVID‐19 infection and associated death, recent reports have shown the onset of DM in COVID‐19‐recovered patients. SARS‐CoV‐2 infiltrates the pancreatic islets and activates stress response and inflammatory signaling pathways, impairs glucose metabolism, and consequently leads to their death. Indeed, the pancreatic autopsy samples of COVID‐19 patients reveal the presence of SARS‐CoV‐2 particles in β‐cells. The current review describes how the virus enters the host cells and activates an immunological response. Further, it takes a closer look into the interrelationship between COVID‐19 and DM with the aim to provide mechanistic insights into the process by which SARS‐CoV‐2 infects the pancreas and mediates dysfunction and death of endocrine islets. The effects of known anti‐diabetic interventions for COVID‐19 management are also discussed. The application of mesenchymal stem cells (MSCs) as a future therapy for pancreatic β‐cells damage to reverse COVID‐19‐induced DM is also emphasized.

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“…[ 15 ] Insulin, the most commonly used antidiabetic medication in severe cases of COVID-19 with diabetes complications, has been associated with an increased risk of poor prognosis among diabetes patients with COVID-19, as reported by studies, [ 16 ] insulin may potentially augment the severity and mortality risk among diabetes patients with COVID-19 through Na/H exchange. [ 17 ] However, there are also studies reporting an increased risk of COVID-19 among type 2 diabetes patients who use insulin without any influence on the severity of the disease. [ 15 ] There is considerable controversy surrounding the impact of sulfonylureas, DPP-4 inhibitors, SGLT-2 inhibitors, and GLP-1 receptor agonists (GLP-1RA) on diabetes patients with COVID-19.…”

Section: Introductionmentioning

confidence: 99%

The risk of common hypoglycemic and antihypertensive medications and COVID-19: A 2-sample Mendelian randomization study

Wang,

Li,

Zeng

et al. 2024

Medicine

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Background: It has been reported that diabetes and hypertension increase the adverse outcomes of coronavirus disease 2019 (COVID-19). Aside from the inherent factors of diabetes and hypertension, it remains unclear whether antidiabetic or antihypertensive medications contribute to the increased adverse outcomes of COVID-19. The effect of commonly used antidiabetic and antihypertensive medications on COVID-19 outcomes has been inconsistently concluded in existing observational studies. Conducting a systematic study on the causal relationship between these medications and COVID-19 would be beneficial in guiding their use during the COVID-19 pandemic. Methods: We employed the 2-sample Mendelian randomization approach to assess the causal relationship between 5 commonly used antidiabetic medications (SGLT-2 inhibitors, Sulfonylureas, Insulin analogues, Thiazolidinediones, GLP-1 analogues) and 3 commonly used antihypertensive medications (calcium channel blockers [CCB], ACE inhibitors, β-receptor blockers [BB]), and COVID-19 susceptibility, hospitalization, and severe outcomes. The genetic variations in the drug targets of the 5 antidiabetic medications and 3 antihypertensive medications were utilized as instrumental variables. European population-specific genome-wide association analysis (GWAS) data on COVID-19 from the Host Genetics Initiative meta-analyses were obtained, including COVID-19 susceptibility (n = 2597,856), COVID-19 hospitalization (n = 2095,324), and COVID-19 severity (n = 1086,211). The random-effects inverse variance-weighted estimation method was employed as the primary assessment technique, with various sensitivity analyses conducted to evaluate heterogeneity and pleiotropy. Results: There were no potential associations between the genetic variations in the drug targets of the 5 commonly used antidiabetic medications (SGLT-2 inhibitors, Sulfonylureas, Insulin analogues, Thiazolidinediones, GLP-1 analogues) and the 3 commonly used antihypertensive medications (CCBs, ACE inhibitors, BBs) with COVID-19 susceptibility, hospitalization, and severity (all P > .016). Conclusion: The findings from this comprehensive Mendelian randomization analysis suggest that there may be no causal relationship between the 5 commonly used antidiabetic medications (SGLT-2 inhibitors, Sulfonylureas, Insulin analogues, Thiazolidinediones, GLP-1 analogues) and the 3 commonly used antihypertensive medications (CCBs, ACE inhibitors, BBs) with COVID-19 susceptibility, hospitalization, and severity.

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Insulin may increase disease severity and mortality of COVID-19 through Na+/H+ exchanger in patients with type 1 and type 2 diabetes mellitus

Cited by 4 publications

References 29 publications

Antidiabetic Drug Efficacy in Reduction of Mortality during the COVID-19 Pandemic

Antidiabetic Drug Efficacy in Reduction of Mortality during the COVID-19 Pandemic

Dissecting the Interrelationship between COVID‐19 and Diabetes Mellitus

The risk of common hypoglycemic and antihypertensive medications and COVID-19: A 2-sample Mendelian randomization study

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