Renin-Angiotensin System Overactivation in Type 2 Diabetes: A Risk for SARS-CoV-2 Infection?
The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), binds to target cells via the angiotensin-converting enzyme 2 (ACE2) receptor found in cells in blood vessels, lungs, heart, intestines, and kidneys. Type 2 diabetes (T2D) is a risk factor for acquiring SARS-CoV-2 infection and is associated with severe disease, acute respiratory distress syndrome, and increased mortality (1). Patients with diabetes have ACE2 overexpressed in kidneys and the circulation;
... circulation; further, ACE2 expression may be increased in other tissues (for example, in lungs) as a consequence of angiotensin-receptor blocker (ARB) therapy (a treatment widely used for patients with diabetes), potentially increasing susceptibility to SARS-CoV-2 infection. Previously, circulatory renin-angiotensin system (RAS) activity was described in the setting of sustained hyperglycemia in diabetes (2). Here, we hypothesized that acute normalization of glycemia would modulate RAS overactivation in T2D. Therefore, plasma RAS-related protein levels were determined for T2D subjects versus control subjects at baseline and for T2D subjects after 1-h hyperinsulinemiceuglycemic clamp. A case-control study of T2D and control subjects was approved by the Yorkshire and the Humber Research Ethics Committee, and all study participants signed an informed consent form prior to participation. The clamp was performed as detailed previously (3) ; all patients underwent a 10-h fast prior to the clamp, but ad libitum water ingestion was encouraged. Patients were admitted 1 h prior to the clamp procedure and remained in a supine position throughout the study. For the T2D subjects, baseline glucose was mean 6 SE 7.6 6 0.4 mmol/L (136.8 6 7.2 mg/dL) and was reduced to 4.5 6 0.07 mmol/L (81 6 1.2 mg/dL) with 1-h clamp. For control subjects, glucose was maintained at 4.9 6 0.1 mmol/L (88.2 6 1.8 mg/dL). Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement (4) was used to determine RAS-related proteins: renin (REN), angiotensinogen (AGT), and ACE2. Statistical analysis was performed using GraphPad Prism 8.0. T2D (n 5 23) and control (n 5 23) subjects were matched for age (P 5 not significant [ns]); T2D subjects had higher BMI (P 5 0.0012) and duration of disease 4.5 6 2.9 years. Nine T2D subjects were treated with ACE inhibitor (ACEi) therapy. In T2D subjects, total basal renin levels were elevated (1,730 6 566 vs. 675 6 72 relative fluorescent units [RFU], T2D vs. control, P , 0.05) (Fig. 1A) , whereas angiotensinogen levels were decreased (3,786 6 174 vs. 5,005 6 574 RFU, T2D vs. control, P , 0.05) (Fig. 1B) . ACE2 levels did not differ between T2D and control subjects (291 6 31 vs. 281 6 18 RFU, T2D vs. control, P 5 ns) (Fig. 1C) . Acute normalization of hyperglycemia to euglycemia had no effect on levels of these RASrelated proteins (Fig. 1A-C) . RAS is overactivated in obesity (5), and the T2D subjects had higher BMI. To elucidate a potential relationship, T2D subjects (and control subjects) were stratified into tertiles according to BMI; however, no trends in the protein levels were seen with increasing BMI in either group. Stratification of T2D subjects into those treated or not with ACEi revealed no differences in basal RAS-related protein levels or in response to acute normalization of glycemia (ACEi vs. non-ACEi: basal AGT 4,106 6 228 vs. 3,580 6 235 RFU, normalized AGT 4,324 6 275 vs. 4,125 6 365 RFU, P 5 ns; basal REN 1,358 6 258 vs. 1,969 6 923 RFU, normalized REN 1,250 6 207 vs. 1,903 6 843 RFU, P 5 ns; basal ACE2 253 6 10 vs. 317 6 50 RFU,