Diabetes, obesity, metabolism, and SARS-CoV-2 infection: the end of the beginning

Abstract

The increased prevalence of obesity, diabetes, and cardiovascular risk factors in people hospitalized with severe COVID-19 illness has engendered considerable interest in the metabolic aspects of SARS-CoV-2-induced pathophysiology. Here, I update concepts informing how metabolic disorders and their co-morbidities modify the susceptibility to, natural history, and potential treatment of SARS-CoV-2 infection, with a focus on human biology. New data informing genetic predisposition, epidemiology, immune responses, disease severity, and therapy of COVID-19 in people with obesity and diabetes are highlighted. The emerging relationships of metabolic disorders to viral-induced immune responses and viral persistence, and the putative importance of adipose and islet ACE2 expression, glycemic control, cholesterol metabolism, and glucose- and lipid-lowering drugs is reviewed, with attention to controversies and unresolved questions. Rapid progress in these areas informs our growing understanding of SARS-CoV-2 infection in people with diabetes and obesity, while refining the therapeutic strategies and research priorities in this vulnerable population.

Keywords: adipose tissue; glucose; immunity; islet; vaccination; virus.

Figure 1

Factors modifying viral entry, replication, and clinical secerity Depiction of cell surface receptors and co-factors facilitating SARS-CoV-2 entry, the importance of cholesterol metabolism (top panel), and cellular, immune, and pathophysiological abnormalities predisposing people with obesity and diabetes to more severe COVID-19 outcomes (bottom panel). ACE2, angiotensin-converting enzyme 2; HMGB1, high-mobility group box 1 protein; NPR1, neuropilin 1; SR-B1, scavenger receptor class B type 1; TMPRSS2, transmembrane serine protease 2; TMEM41B, transmembrane protein 41B.

Figure 2

The relationship between medication use, type 2 diabetes, and severity of COVID-19 infection The progressive use of glucose-lowering medicines during the evolution of type 2 diabetes and severity of acute illness in people with COVID-19. More advanced stages of T2D necessitate use of multiple agents to achieve glucose control, and choice of agents is skewed toward insulin, SGLT-2 inhibitors, and GLP-1R agonists in people at risk of or with established cardiovascular and renal complications. CKD, chronic kidney disease; CVD, cardiovascular disease; DPP-4i, dipeptidyl peptidase-4 inhibitors; GLP-1-RA, glucagon-like peptide-1 receptor agonists; SGLT-2i, sodium glucose cotransporter-2 inhibitors; SU, sulfonylureas; T2D, type 2 diabetes.

Figure 3

ACE2 is expressed in the non-endocrine compartment within human islets Expression of ACE2 in 9,940 human pancreatic cells, including mRNA transcripts for different cell lineages in islet endocrine cells (insulin [INS], glucagon [GCG], somatostatin [SST], and pancreatic polypeptide [PPY] for β, α, δ, and PP cells, respectively), acinar cells (PRSS2), ductal cells (KRT19), and endothelial cells (PECAM1). Data were retrieved and aggregated from Segerstolpe et al. (2016), Enge et al. (2017), and Camunas-Soler et al. (2020).

Figure 4

ACE2 expression in human adipose tissue ACE2 mRNA transcripts are expressed at low levels in human subcutaneous adipose tissue and at higher levels in visceral adipose tissue. The majority of adipose tissue ACE2 expression is in non-adipocyte cell types. ACE2 and TMPRSS2 expression in 5,041 cells from human neck subcutaneous WAT is shown in the left panel. VWF (endothelial cells), DCLK1 (preadipocytes), ADIPOQ (adipocytes), and PTPRC (CD45+ immune cell). Expression of ACE2 in 26,961 cells in human adipose stromal vascular fraction is depicted in the right panel. PECAM1 marks the endothelial cell population. Data were retrieved from Sun et al. (2020) and Vijay et al. (2020).

Figure 5

Key considerations for SARS-CoV-2 infection in people with obesity and diabetes Major morbidities arising in people with severe SARS-CoV-2 infection (left panel) and emerging therapeutic interventions with potential benefit in people with diabetes and COVID-19 (right panel).