Interaction of Adipocytes with Ani-diabetic Medication May Play a Role in COVID-19 Severity

Background: SARS-CoV-2 infection is worse in people with obesity or diabetes. Expression of Angiotensin I Converting Enzyme 2 (ACE2), a receptor for viral entry in cells, is linked with worse health outcomes in COVID-19. We determined if common anti-diabetic drugs modify ACE2 expression in various human cell types. Methods: Human Embryonic Kidney cell line (HEK293), human lung cancer cell line (A549) and differentiated Human Adipose derived Stromal Cells (hASC) were treated with 1, 4 or 10mM of Metformin (MET) or 10, 25, 50 or 100uM pioglitazone (PIO) for 12, 24 or 48h. Cells without drugs served as control. ACE2 expression was determined by RT-PCR. Results: Overall, ACE2 expression was low. Including various treatment conditions, the assays were repeated several times and yielded different results of ACE2 expression. Following data show the % of the times ACE2 expression significantly increased/decreased/not changed, vs. control. In HEK293 cells, MET showed ACE2 expression 11/0/89%, and PIO showed 21/14/65% of the times. In A549 cells, MET showed ACE2 expression 0/25/75% and PIO showed 0/50/50%. In hASC, the ACE2 expression was 60/20/20% for MET and 40/20/40% for PIO. Importantly, in hASC, ACE2 expression in presence of MET or PIO depended on the degree of adipocyte differentiation. ACE2 expression was significantly greater in presence of MET or PIO in less differentiated hASC (as confirmed by adipogenic marker gene SCD1). Whereas, fully differentiated hASC had significantly lower ACE2 expression in presence of either drug. Conclusions: Probably, low level of ACE2 expression led to variability of response to MET or PIO. Both drugs significantly lowered ACE2 expression in fully differentiated adipocytes. This may be important considering the reports of lower ACE2 expression in adipose tissue of individuals with greater health risk. Additional confirmation of ACE2 expression in adipose tissue of individuals on various anti-diabetic drugs is needed.

The triumvirate: why hypertension, obesity, and diabetes are risk factors for adverse effects in patients with COVID-19.

The outbreak of coronavirus disease 2019 (COVID-19) caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a pandemic. The cellular receptor for SARS-CoV-2 entry is the angiotensin-converting enzyme 2, a membrane-bound homolog of angiotensin-converting enzyme. Henceforth, this has brought the attention of the scientific community to study the interaction between COVID-19 and the renin-angiotensin system (RAS), as well as RAS inhibitors. However, these inhibitors are commonly used to treat hypertension, chronic kidney disorder, and diabetes. Obesity is a known risk factor for heart disease, diabetes, and hypertension, whereas diabetes and hypertension may be indirectly related to each other through the effects of obesity. Furthermore, people with hypertension, obesity, diabetes, and other related complications like cardiovascular and kidney diseases have a higher risk of severe COVID-19 infection than the general population and usually exhibit poor prognosis. This severity could be due to systemic inflammation and compromised immune response and RAS associated with these comorbid conditions. Therefore, there is an urgent need to develop evidence-based treatment methods that do not affect the severity of COVID-19 infection and effectively manage these chronic diseases in people with COVID-19.