Diabetes mellitus is a chronic inflammatory condition characterized by several macrovascular and microvascular abnormalities. As with hypertension and CVD, many of the above cited studies have also revealed that diabetic patients were overrepresented among the most severely ill patients with COVID-19 and those succumbing to the disease. Among the 23,698 in-hospital COVID-19-related deaths during the first months in the UK, a third occurred in people with diabetes: 7,434 (31.4%) in people with type 2 diabetes, 364 (1.5%) in those with type 1 diabetes (Barron 2020).
Current data suggest that diabetes in patients with COVID-19 is associated with a two-fold increase in mortality as well as severity of COVID-19, as compared to non-diabetics. In a meta-analysis of 33 studies and 16.003 patients (Kumar 2020), diabetes was found to be significantly associated with mortality from COVID-19 with a pooled odds ratio of 1.90 (95% CI: 1,37-2,64). Diabetes was also associated with severe COVID-19 and a pooled odds ratio of 2.75 (95% CI: 2,09-3,62). The pooled prevalence of diabetes in patients with COVID-19 was 9,8% (95% CI: 8,7%-10,9%). However, it is too early to say whether diabetes is acting as an independent factor responsible for COVID severity and mortality or if it is just a confounding factor.
A large retrospective study on the impact of type 2 diabetes (T2D) carefully analyzed 7337 cases of COVID-19 in Hubei Province, China, among them 952 with pre-existing T2D (Zhu 2020). The authors found that subjects with T2D required more medical interventions and had a significantly higher mortality (7,8% versus 2,7%; adjusted hazard ratio, 1,49) and multiple organ injury than non-diabetic individuals. Of note, well-controlled blood glucose was associated with markedly lower mortality (in-hospital death rate 1,1% versus 11,0%) compared to individuals with poorly controlled blood glucose. Similar results were found in a large UK cohort (Holman 2020).
A recent review has made some suggestions on the possible pathophysiological mechanisms of the relationship between diabetes and COVID-19, and its management (Hussain 2020). Rigorous glucose monitoring and careful consideration of drug interactions might attenuate worsening of symptoms and adverse outcomes. In a retrospective cohort study of 1213 hospitalized individuals with COVID-19 and pre-existing T2D, metformin use was significantly associated with a higher incidence of acidosis, particularly in cases with severe COVID-19, but not with 28-day COVID-19-related mortality (Cheng 2020).
Some treatment strategies for COVID-19 such as steroids and lopinavir/r bear a risk for hyperglycemia. On the other hand, hydroxychloroquine may improve glycemic control in decompensated, treatment-refractory patients with diabetes (Gerstein 2002, Rekedal 2010). However, it remains unclear which COVID-19 treatment strategy works best and if treatment of diabetic patients has to be different from those without diabetes. It is also unclear whether specific diabetes drugs such as DPP4 inhibitors increase or decrease the susceptibility or severity of SARS-CoV-2 infection.
Isolated reports of new-onset diabetes in COVID-19 cases have also led to the hypothesis that SARS-CoV-2 is directly cytotoxic to pancreatic islet β cells. However, a careful investigation (Coate 2020) suggested that the interaction of diabetes and SARS-CoV-2 is mediated by systemic inflammation and/or metabolic changes in other organs such as liver, muscle or adipose tissue (and not by a direct infection of β cells in the pancreas).
References
Barron E, Bakhai C, Kar P, et al. Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study. Lancet Diabetes Endocrinol. 2020 Oct;8(10):813-822. PubMed: https://pubmed.gov/32798472. Full-text: https://doi.org/10.1016/S2213-8587(20)30272-2
Cheng X, Liu YM, Li H, et al. Metformin Is Associated with Higher Incidence of Acidosis, but Not Mortality, in Individuals with COVID-19 and Pre-existing Type 2 Diabetes. Cell Metab. 2020 Oct 6;32(4):537-547.e3. PubMed: https://pubmed.gov/32861268. Full-text: https://doi.org/10.1016/j.cmet.2020.08.013
Coate KC, Cha , Shrestha S. SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 are Expressed in the Microvasculature and Ducts of Human Pancreas but are Not Enriched in β Cells. Cell Metabolism November 13, 2020. Full-text: https://doi.org/10.1016/j.cmet.2020.11.006
Gerstein HC, Thorpe KE, Taylor DW, Haynes RB. The effectiveness of hydroxychloroquine in patients with type 2 diabetes mellitus who are refractory to sulfonylureas–a randomized trial. Diabetes Res Clin Pract. 2002 Mar;55(3):209-19. PubMed: https://pubmed.gov/11850097. Full-text: https://doi.org/10.1016/s0168-8227(01)00325-4
Holman N, Knighton P, Kar P, et al. Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: a population-based cohort study. Lancet Diabetes Endocrinol. 2020 Oct;8(10):823-833. PubMed: https://pubmed.gov/32798471. Full-text: https://doi.org/10.1016/S2213-8587(20)30271-0
Hussain A, Bhowmik B, do Vale Moreira NC. COVID-19 and diabetes: Knowledge in progress. Diabetes Res Clin Pract. 2020 Apr;162:108142. PubMed: https://pubmed.gov/32278764. Full-text: https://doi.org/10.1016/j.diabres.2020.10814
Kumar A, Arora A, Sharma P, et al. Is diabetes mellitus associated with mortality and severity of COVID-19? A meta-analysis. Diabetes Metab Syndr. 2020 May 6;14(4):535-545. PubMed: https://pubmed.gov/32408118. Full-text: https://doi.org/10.1016/j.dsx.2020.04.044
Rekedal LR, Massarotti E, Garg R, et al. Changes in glycosylated hemoglobin after initiation of hydroxychloroquine or methotrexate treatment in diabetes patients with rheumatic diseases. Arthritis Rheum. 2010 Dec;62(12):3569-73. PubMed: https://pubmed.gov/20722019. Full-text: https://doi.org/10.1002/art.27703
Zhu L, She ZG, Cheng X, et al. Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes. Cell Metab. 2020 Jun 2;31(6):1068-1077.e3. PubMed: https://pubmed.gov/32369736. Full-text: https://doi.org/10.1016/j.cmet.2020.04.021