Diabetes Mellitus, Energy Metabolism, and COVID-19

Abstract

Obesity, diabetes mellitus (mostly type 2), and COVID-19 show mutual interactions because they are not only risk factors for both acute and chronic COVID-19 manifestations, but also because COVID-19 alters energy metabolism. Such metabolic alterations can lead to dysglycemia and long-lasting effects. Thus, the COVID-19 pandemic has the potential for a further rise of the diabetes pandemic. This review outlines how preexisting metabolic alterations spanning from excess visceral adipose tissue to hyperglycemia and overt diabetes may exacerbate COVID-19 severity. We also summarize the different effects of SARS-CoV-2 infection on the key organs and tissues orchestrating energy metabolism, including adipose tissue, liver, skeletal muscle, and pancreas. Last, we provide an integrative view of the metabolic derangements that occur during COVID-19. Altogether, this review allows for better understanding of the metabolic derangements occurring when a fire starts from a small flame, and thereby help reducing the impact of the COVID-19 pandemic.

Keywords: SARS-CoV-2; adipose tissue; diabetes; liver; pancreas; skeletal muscle.

Graphical Abstract

Figure 1.

COVID-19 and the adipose tissue (see also Table 2). Abbreviations: ADN, adiponectin; FFA, free fatty acids; IP-10, interferon-γ–induced protein-10; IRF-1, interferon regulatory factor 1; LEP, leptin; MCSF1, macrophage colony-stimulating factor 1; MIF, macrophage migration inhibitory factor; MPO, myeloperoxidase; PDGFAA, platelet-derived growth factor AA; PDGFAB/BB, platelet-derived growth factor AB/BB; SAT, subcutaneous adipose tissue; VAT, visceral adipose tissue; VEGFA, vascular endothelial growth factor A.

Figure 2.

COVID-19 and the liver. (A) Mechanisms by which COVID-19 might cause or worsen hepatic steatosis. (B) Mechanisms by which COVID-19 might increase hepatic endogenous glucose production. Abbreviations: CA, catecholamines; ER, endoplasmic reticulum; FFA, free fatty acids; GLU, glucose; GP73, Golgi protein 73; IHTG, intrahepatic triglyceride; INS/IGF, insulin/insulin-like growth factor; IRF-1, interferon regulatory factor 1; OAA, oxaloacetate; PEP, phosphoenolpyruvate; PEPCK, phosphoenolpyruvate carboxykinase; PYR, pyruvate; ROS, reactive oxygen species.

Figure 3.

COVID-19 and the skeletal muscle. (A) Effects of acute COVID-19 on skeletal muscle. (B) Potential consequences of COVID-19 on skeletal muscle. Dashed arrows indicate hypothesized mechanisms. Abbreviations: ACE, angiotensin-converting enzyme 2; ADN, adiponectin; LEP, leptin.

Figure 4.

COVID-19 and the pancreas. (A) SARS-CoV-2 entry factors in pancreatic cells; (B) in vitro effects of SARS-CoV-2 on β cells. (C) Histopathological and imaging findings in people with COVID-19. Abbreviations: ACE2, angiotensin-converting enzyme 2; DPP4, dipeptidyl-peptidase 4; HMBG1, high-mobility group box 1 protein; NRP1, neuropilin 1; TFRC, transferrin receptor; TMPRSS2, transmembrane protease serine 2.

Figure 5.

Schematic representation of the effects of SARS-CoV-2 on organs involved in energy metabolism. SARS-CoV-2 infects the adipose tissue, enhancing preexisting inflammation in people with obesity/diabetes, which may result in an uncontrolled inflammatory response. COVID-19 and inflammation lead to adipocyte dysfunction, causing multiorgan insulin resistance, which in skeletal muscle is also promoted by elevations in interferon gamma that impair the insulin/IGF pathway, and downregulation of the angiotensin-converting enzyme 2 (ACE2) receptor. In adipose tissue, insulin resistance and possibly endothelial dysfunction result in increased lipolysis. Free fatty acids (FFA) that are released into the circulation may further worsen insulin resistance and, in the liver, may lead to lipid accumulation and promote hepatic gluconeogenesis, which is also enhanced by hyperinsulinemia secondary to insulin resistance and SARS-CoV-2-induced Golgi protein 73 (GP73) production. Altered mitochondrial function in the liver may impair fatty acid β oxidation and ketogenesis, which increases with increased COVID-19 severity, but is blunted in comparison to acute respiratory distress syndrome resulting from influenza virus. Muscle disuse and disease-related malnutrition result in muscle mass loss and further impairment of glucose disposal. Hyperglycemia in patients with COVID-19 may result from these mechanisms, and it is likely that only individuals who are predisposed to impaired glucose metabolism, possibly because of preexisting metabolic dysfunction, will develop long-term hyperglycemia and metabolic dysfunction, with COVID-19 acting as a second hit. In these persons, especially those who had severe COVID-19, weight regain with preferential fat catch-up during recovery may further worsen metabolic health, leading to persistent metabolic dysfunction and post-acute sequelae of COVID-19 (PASC). Abbreviations: ACE2, angiotensin-converting enzyme 2; BHB, beta-hydroxybutyrate; FFA, free fatty acids.