Diabetes and respiratory infectious diseases are devastating on their own, but they become significantly more problematic when they intersect. Diabetes is characterized by the dysfunction of glucose utilization due to the lack of insulin production (type 1) or insulin action (type 2), leading to greater amounts of glucose remaining in circulation i.e. hyperglycemia. This resulting metabolic state is more detrimental to the host during respiratory infections such as: severe acute respiratory syndrome causing coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV). Therefore, tight control of blood glucose is essential for diabetics, especially during times of peak respiratory infections. We demonstrated alterations in whole-body glucose metabolism of healthy domestic cats infected with SARS-CoV-2. Both the USA-WA1/2020 (WT) and B.1.617.2 (delta) isolates elevated blood glucose to a pre-diabetic level. Cortisol and angiotensin 2 were elevated while ketones remained unchanged. There was only decreased insulin 12 days following infection. GLUT expression varied depending on strain; the delta variant increased GLUT expression in the heart and lungs, yet GLUT expression was not altered in peripheral insulin sensitive tissues, i.e. skeletal muscle. Increased GLUT expression was accompanied by activation of AMPK. Concurrently, we cultured primary human bronchial epithelial cells (HBECs) in various metabolic modulators and assessed the effect on IAV H1N1 replication. Expectedly, increased glucose availability lead to greater IAV replication. However, we observed a divergent path when it comes to intracellular glucose utilization. Essentially, glucose allowed to metabolize in the cytosol, ultimately leading to lactate, allowed for greater IAV replication. On the other hand, shuttling glycolytic substrate to the mitochondria impaired IAV replication. In order to control glucose availability during infection, better long-term metabolic treatments are required. We have identified protein disulfide isomerase (PDI) as a potential therapeutic target for long-term glucose regulation. Exogenous PDI treatment was observed to increase glucose tolerance for up to 5 days post-delivery in mice. Overall, we have demonstrated that respiratory infections can co-opt metabolic mechanisms for its own benefit, which can be exacerbated during diabetes. Therefore, a better understanding of virus-host interactions and glucose control could lead to better outcomes for diabetes following respiratory infections.
Matthew T. Rochowski (Fri,) studied this question.