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Review
. 2021 Mar 1;13(1):23.
doi: 10.1186/s13098-021-00639-2.

Diabetes, obesity, and insulin resistance in COVID-19: molecular interrelationship and therapeutic implications

Andrey Santos  1 , Daniéla Oliveira Magro  2 , Rosana Evangelista-Poderoso  3 , Mario José Abdalla Saad  4
Affiliations
Review

Diabetes, obesity, and insulin resistance in COVID-19: molecular interrelationship and therapeutic implications

Andrey Santos et al. Diabetol Metab Syndr. .

Abstract

Background: Our understanding of the pathophysiology of the COVID-19 manifestations and evolution has improved over the past 10 months, but the reasons why evolution is more severe in obese and diabetic patients are not yet completely understood.

Main text: In the present review we discuss the different mechanisms that may contribute to explain the pathophysiology of COVID-19 including viral entrance, direct viral toxicity, endothelial dysfunction, thromboinflammation, dysregulation of the immune response, and the renin-angiotensin-aldosterone system.

Conclusions: We show that the viral infection activates an integrated stress response, including activations of serine kinases such as PKR and PERK, which induce IRS-1 serine phosphorylation and insulin resistance. In parallel, we correlate and show the synergy of the insulin resistance of COVID-19 with this hormonal resistance of obesity and diabetes, which increase the severity of the disease. Finally, we discuss the potential beneficial effects of drugs used to treat insulin resistance and diabetes in patients with COVID-19.

Keywords: COVID-19; Diabetes; ISR; Insulin resistance; Metformin; Obesity; iDPP4.

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Conflict of interest statement

The authors declare that they have no competing interests

Figures

Fig. 1
Fig. 1
Pathophysiology. a Viral entrance: ACE2 and DPP4. The coronavirus entrance in cells is facilitated by its spike protein using ACE2. b Endothelial cell damage and thromboinflammation. ACE2-mediated entry of SARS-CoV-2 in endothelial cells induce inflammation and the generation of a prothrombotic milieu, and results in increased thrombin production associated with inhibition of fibrinolysis and activation of complement pathways, a cascade which will lead to microthrombi deposition. The cross-talk between platelets and neutrophils and the activation of macrophages has an important role in the proinflammatory effects, characterized by cytokine release, the formation of neutrophil extracellular traps (NETs), and microthrombus deposition. c Dysregulation of the immune response. Dysregulation of the immune response of COVID-19, in which there is an increase in cytokine release associated with an attenuation of interferon response
Fig. 2
Fig. 2
Clinical manifestations and complications of this insulin resistance syndrome and the parallel with obesity/diabetes. T2D and obesity, without infections, have an increase in the basal inflammatory response and a potential decrease in an interferon response. Thus, the synergy between COVID-19 and T2D/obesity may amplify the inflammatory response and downregulate even more the interferon response, contributing to more severe disease in these patients
Fig. 3
Fig. 3
Dysregulation of the RAAS. ACE2 cleaves AI and AII into inactive angiotensin 1–9 and angiotensin 1–7, respectively, and the later has vasodilator and antifibrotic effects, but SARS-CoV binds and downregulates the expression of ACE2, which is associated with the unopposed AII action
Fig. 4
Fig. 4
Integrated stress response (ISR). The ISR signaling pathway initiates when distinct stressors activate at least one member of a family of four serine/threonine kinases—PERK, PKR, HRI, GCN2, and these activations will converge to induce phosphorylation of eIF2a on serine. At least two of the four serine/threonine kinases activated by distinct stressors—PKR and PERK—can downregulate the insulin signaling pathway through serine phosphorylation of insulin receptor substrates, attenuating insulin action. Specifically for COVID-19, fragments of viral RNA can activate PKR, which will induce IRS-1 serine phosphorylation and consequently insulin resistance
Fig. 5
Fig. 5
Insulin resistance induced inflammation. Insulin resistance in adipose tissue induces macrophage infiltration, developing an inflammatory state. In the insulin signaling pathway (IRS-1/2:PI3K:AKT:mTORC2) the MCP1 gene is suppressed by mTORC2 in adipose. In situations of insulin resistance, the downregulation of insulin signaling with reduced activity of mTORC2 will derepress MCP1 and will attract monocytes to adipose tissue, which will be converted into M1 macrophage
Fig. 6
Fig. 6
Airway hyperreactivity. The central insulin action is able to control airway reactivity, and in obesity central hyperinsulinemia induces an increased airway hyper-reactivity by stimulating airway-related pre-ganglionic parasympathetic fibers at the dorsal motor nucleus of the vagus (DMV) and nucleus ambiguous (NA), by the ERK signaling pathway
Fig. 7
Fig. 7
Similarities and synergy between insulin resistance/obesity/diabetes and COVID-19. COVID-19. In symptomatic patients with COVID-19 the course of the disease can be didactically divided into four phases. Phase 1: Viral entrance in cells is facilitated by ACE2. Phase 1 starts when an individual becomes symptomatic. The most frequent manifestations in this phase are fever and dry cough, and many individuals may lose their senses of taste and smell and feel a general malaise, and for most individuals, the disease is limited to this phase. Phase 1/Phase 2: Immune cell migration to the lungs. Phase 2: Is the pulmonary stage of the disease when individuals develop pulmonary inflammation and pneumonia. In this phase there is an impaired early antiviral interferon response and cytokine storm. Based on the presence or not of hypoxia this phase can be subdivided in 2b or 2a. Most individuals need hospitalization, and some with prolonged hypoxia need mechanical ventilation. Phase 3: the patients develop ARDS and extrapulmonary systemic hyper inflammation syndrome, shock, vasoplegia, respiratory failure, cardiopulmonary collapse, myocarditis, and acute kidney injury, with poor prognosis and increased mortality. Phase 4: Is the recovery and survival stage
Fig. 8
Fig. 8
Diabetes treatment in patients with COVID-19. There is no reason to stop metformin therapy during COVID-19 infection unless there are severe gastrointestinal symptoms, or risk of lactic acidosis. Metformin can be a beneficial adjuvant therapy for patients in acute, chronic, and even recovery phases of COVID-19. The continued use of sulfonylurea in stable patients with COVID-19 who are eating regular meals may be justified. However, we need to be alert to any potential risks of hypoglycemia, especially in patients with COVID-19 in intensive care units. A theoretical anti-viral effect of SGLT2-inhibitors was suggested, however caution should be taken when using these drugs because they require hydration and appropriateness of insulin doses to prevent euglycemic ketoacidosis. GLP-1 receptor agonists should be carefully evaluated in severely ill patients with COVID-19 considering their anorexic effects. However, their potential beneficial effects should also be balanced, because these drugs have anti-inflammatory and lung protection actions and can be valuable weapons to combat COVID-19. DPP-4 inhibitors are a group of drugs associated with many advantages, even in severe cases of COVID-19, because they are well tolerated, can be used independent of renal function, and have a low risk of hypoglycemia. In this regard, we should consider recommending a more widespread use of DPP4 inhibitors in diabetic inpatients with severe COVID-19. In most studies, DM2 patients with COVID-19 on insulin have shown a worse prognostic, usually attributed to the severity of diabetes in these patients. However, by lowering the doses of insulin, by association with oral anti-hyperglycemic agents, it is possible to attenuate this potential worse effect of high doses of insulin
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References

    1. Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, Bikdeli B, Ahluwalia N, Ausiello JC, Wan EY, et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020;26(7):1017–32. doi: 10.1038/s41591-020-0968-3. - DOI - PubMed
    1. Cariou B, Hadjadj S, Wargny M, Pichelin M, Al-Salameh A, Allix I, Amadou C, Arnault G, Baudoux F, Bauduceau B, et al. Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study. Diabetologia. 2020;63(8):1500–15. doi: 10.1007/s00125-020-05180-x. - DOI - PMC - PubMed
    1. Li H, Liu L, Zhang D, Xu J, Dai H, Tang N, Su X, Cao B. SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet. 2020;395(10235):1517–20. doi: 10.1016/S0140-6736(20)30920-X. - DOI - PMC - PubMed
    1. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and Is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271–80.e278. doi: 10.1016/j.cell.2020.02.052. - DOI - PMC - PubMed
    1. Puelles VG, Lütgehetmann M, Lindenmeyer MT, Sperhake JP, Wong MN, Allweiss L, Chilla S, Heinemann A, Wanner N, Liu S, et al. Multiorgan and renal tropism of SARS-CoV-2. N Engl J Med. 2020;383(6):590–2. doi: 10.1056/NEJMc2011400. - DOI - PMC - PubMed

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