Mechanisms of COVID-19 pathogenesis in diabetes

Narasimhulu, Chandrakala Aluganti; Singla, Dinender K.

doi:10.1152/ajpheart.00204.2022

Cited by 41 publications

(36 citation statements)

References 180 publications

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“…This novel form of COVID-induced diabetes with anomalous glycemic parameters and heightened rates of DKA (diabetic ketoacidosis), occurs in severely ill patients with higher mortality rates and poorer outcomes compared to COVID-19 patients with pre-existing diabetes ( Chandrashekhar Joshi and Pozzilli, 2022 ). The underlying pathobiological mechanism for this induced diabetes in COVID-19 patients has not been clearly delineated although it is suspected that SARS-CoV-2 could damage the beta cells of the pancreas and precipitate insulin resistance ( Aluganti Narasimhulu and Singla, 2022 ). There are some plausible mechanisms that underlie this new diabetes onset.…”

Section: Mechanisms Of Emerging Pasc Pathogenesesmentioning

confidence: 99%

Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)

Sherif

Gómez

Connors

et al. 2023

eLife

127

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COVID-19, with persistent and new onset of symptoms such as fatigue, post-exertional malaise, and cognitive dysfunction that last for months and impact everyday functioning, is referred to as Long COVID under the general category of post-acute sequelae of SARS-CoV-2 infection (PASC). PASC is highly heterogenous and may be associated with multisystem tissue damage/dysfunction including acute encephalitis, cardiopulmonary syndromes, fibrosis, hepatobiliary damages, gastrointestinal dysregulation, myocardial infarction, neuromuscular syndromes, neuropsychiatric disorders, pulmonary damage, renal failure, stroke, and vascular endothelial dysregulation. A better understanding of the pathophysiologic mechanisms underlying PASC is essential to guide prevention and treatment. This review addresses potential mechanisms and hypotheses that connect SARS-CoV-2 infection to long-term health consequences. Comparisons between PASC and other virus-initiated chronic syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome will be addressed. Aligning symptoms with other chronic syndromes and identifying potentially regulated common underlining pathways may be necessary for understanding the true nature of PASC. The discussed contributors to PASC symptoms include sequelae from acute SARS-CoV-2 injury to one or more organs, persistent reservoirs of the replicating virus or its remnants in several tissues, re-activation of latent pathogens such as Epstein–Barr and herpes viruses in COVID-19 immune-dysregulated tissue environment, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation dysregulation, dysfunctional brainstem/vagus nerve signaling, dysautonomia or autonomic dysfunction, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage specific patients.

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Section: Mechanisms Of Emerging Pasc Pathogenesesmentioning

confidence: 99%

Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)

Sherif

Gómez

Connors

et al. 2023

eLife

127

View full text Add to dashboard Cite

show abstract

“…The composition of the MPs as to the cell origin was not different between normal and diabetic plasma, but the MP count was significantly increased in each subpopulation in patients with diabetes. The increased MPs observed in these patients with diabetes could be attributed to their hyperglycemia and obesity states, the two recognized risk factors associated with increased production of inflammatory cytokines and reactive oxygen species ( 2 , 6 , 24 ). The median age of control group is a little bit older than diabetic group, but we do not consider this small difference in age has a significant effect on the large difference in MP quantity identified between groups in this study.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous study provided visual evidence of MP release from activated ECs and adherent neutrophils in intact microvessels of diabetic rats ( 32 ). Clinical studies indicated that the circulating levels of MPs in patients with diabetes are correlated with the hyperglycemic state ( 2 , 53 , 58 , 59 ). To investigate the role of diabetes-associated MP increase in the development of severe forms of COVID-19, this study selected blood samples from normal subjects and patients with type 2 diabetes with poor glycemic control (HbA1c between 6% and 9%).…”

Section: Discussionmentioning

confidence: 99%

Increased circulating microparticles contribute to severe infection and adverse outcomes of COVID-19 in patients with diabetes

Sun

Kumar

et al. 2022

American Journal of Physiology-Heart and Circulatory Physiology

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COVID-19 patients with diabetes have greater mortality than those without comorbidities, but the underlying mechanisms remain unknown. This study aims to identify the mechanistic interactions between diabetes and severe COVID-19. Microparticles (MPs), the cell membrane-derived vesicles released upon cell activation, are largely increased in diabetic patients. To date, many mechanisms have been postulated for increased severity of COVID-19 in patients with underlying conditions, but the contributions of excessive MPs in diabetic patients have been overlooked. This study characterizes plasma MPs from normal and type 2 diabetic human subjects in terms of amount, cell origins, surface adhesive properties, ACE2 expression, spike protein binding capacity, and their roles in SARS-CoV-2 infection. Results showed that over 90% of plasma MPs express ACE2 that binds the spike protein of SARS-CoV-2. MPs in diabetic patients increase 13-fold in quantity and 11-fold adhesiveness when compared with normal subjects. Perfusion of human plasma with pseudotyped SARS-CoV-2 virus or spike protein-bound MPs into human endothelial cells-formed microvessels-on-a chip demonstrated that MPs from diabetic patients, not normal subjects, interact with endothelium and carry SARS-CoV-2 into cells through endocytosis, providing additional virus entry pathways and enhanced infection. Results also showed a large percentage of platelet-derived tissue factor-bearing MPs in diabetic plasma, which could contribute to thrombotic complications with SARS-CoV-2 infection. This study reveals a dual role of diabetic MPs in promoting SARS-CoV-2 entry and propagating vascular inflammation. These findings provide novel mechanistic insight into the high prevalence of COVID-19 in diabetic patients and their propensity to develop severe vascular complications.

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“…Although ACE2 seems to be the principal receptor for SARS-CoV-2 entry, studies suggest that DPP-4 also interacts with the novel coronavirus [ 10 , 27 , 28 ]. Recent reviews and in silico analyses propose that several receptors such as DPP-4, DPP-6, DPP-10, TLR4, C-lectin type receptors (CLRs), neuropilin-1 (NRP1) may interact with the SARS-CoV-2 receptor-binding domain [ 11 , 29 , 30 ].…”

Section: Virus-dpp-4 Interactionmentioning

confidence: 99%

DPP-4 Inhibitors as a Savior for COVID-19 Patients with Diabetes

et al. 2023

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Diabetic patients are at particular risk of severe COVID-19. Human dipeptidyl peptidase-4 (DPP-4) is a membrane-bound aminopeptidase that regulates insulin release by inactivating incretin. DPP-4 inhibitors (DPP-4is) are therefore used as oral anti-diabetic drugs to restore normal insulin levels. These molecules also have anti-inflammatory and anti-hypertension effects. Recent studies on the interactions of SARS-CoV-2 spike glycoprotein and DPP-4 predict a possible entry route for SARS-CoV-2. Therefore, DPP-4is could be effective at reducing the virus-induced ‘cytokine storm’, thereby ceasing inflammatory injury to vital organs. Moreover, DPP-4is may interfere with viral entry into host cells. Herein, we have reviewed the efficacy of DPP-4is as potential repurposed drugs to reduce the severity of SARS-CoV-2 infection in patients with diabetes.

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Mechanisms of COVID-19 pathogenesis in diabetes

Cited by 41 publications

References 180 publications

Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)

Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)

Increased circulating microparticles contribute to severe infection and adverse outcomes of COVID-19 in patients with diabetes

DPP-4 Inhibitors as a Savior for COVID-19 Patients with Diabetes

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