Angiotensin converting enzyme 2: A new important player in the regulation of glycemia

Abstract

In spite of the novel anti-diabetic drugs available on the market, type 2 diabetes mellitus (T2DM) affects nearly 25 million people in the USA and causes about 5% of all deaths globally each year. Given the rate and proportion by which T2DM is affecting human beings, it is indispensable to identify new therapeutic targets that can control the disease. Recent pre-clinical and clinical studies suggest that attenuating the activity of the renin-angiotensin system (RAS) could improve glycemia in diabetic patients. Angiotensin converting enzyme 2 (ACE2) counteracts RAS over-activity by degrading Ang-II, a vasoconstrictor, to Ang-(1-7) which is a vasodilator. A decrease in ACE2 and an increase in ADAM17-mediated shedding activity have been observed with the progression of T2DM suggesting the importance of this mechanism in the disease. Indeed, restoration of ACE2 improves glycemia in db/db and Ang-II-infused mice. The beneficial effects of ACE2 can be attributed to reduced oxidative stress and ADAM17 expression in the islets of Langerhans in addition to the improvement of blood flow to the β-cells. The advantage of ACE2 over other RAS blockers is that ACE2 not only counteracts the negative effects of Ang-II but also increases Ang-(1-7)/MasR [a receptor through which Ang-(1-7) produces its actions] signaling in the cells. Increased Ang-(1-7)/MasR signaling has been reported to improve insulin sensitivity and glycemia in diabetic animals. Altogether, ACE2/Ang-(1-7)/MasR axis of the RAS appears to be protective in T2DM and strategies to restore ACE2 levels in the disease seem to be a promising therapy for Ang-II-mediated T2DM.

Modulation of the action of insulin by angiotensin-(1–7)

“…This is in good correlation with the observation that pregnancy tends to elevate the plasma level of Ang-(1-7), but women with gestational diabetes have lower levels of Ang-(1-7) compared with healthy pregnant women [45]. In general it appears that local levels of Ang-(1-7) correlate with ACE2 levels [46,47]. Administration of a high-fat diet to mice is associated with insulin resistance and results in reduced kidney ACE2 activity, increased levels of plasma AngII and decreased levels of plasma Ang-(1-7) [48].…”

“…ACE2, on the other hand, acts directly on AngII, irrespective of the pathways involved in the production of this octapeptide. Thus, by ensuring depletion of AngII in the body, ACE2 therapy also increases the possibility of Ang-(1-7) emerging as a more efficient treatment than ACE inhibition in combating AngII-mediated hyperglycaemia [47,168,169]. The safety and tolerability, as well as the pharmacokinetics and pharmacodynamics of intravenous administration of recombinant soluble human ACE2 (known as APN01), is under evaluation currently [Safety and Tolerability Study of APN01 (Recombinant Human Angiotensin Converting Enzyme 2); ClinicalTrials.gov Identifier: NCT00886353].…”

COVID-19 Spiraling of Frailty in Older Italian Patients

“…At the moment, older patients with diabetes seem to have a significantly higher risk of mortality with COVID-19. Over the years, there has been substantial data underling an important role of the renin-angiotensin system (RAS) on glycemic control (17). In particular, ACE-2 seems to play a role on blocking Angiotensin II-mediated hyperglycemia.…”

The double burden of disease of COVID-19 in cardiovascular patients: overlapping conditions could lead to overlapping treatments

“…The ACE2 receptor is an integral membrane protein highly expressed in the lungs and heart that physiologically counteracts the activity of RAS by converting the vasoconstrictor angiotensin-II (Ang-II) to the vasodilator angiotensin-(1-7). Evidence from experimental studies indicates that a decrease in ACE2 is associated with the progression of type 2 diabetes mellitus [8] and myocardial hypertrophy [9]. Conversely, upregulated ACE2 improves glycaemic control in diabetes [8], prevents myocardial fibrosis, and improves cardiac function after myocardial infarction [10].…”

“…Evidence from experimental studies indicates that a decrease in ACE2 is associated with the progression of type 2 diabetes mellitus [8] and myocardial hypertrophy [9]. Conversely, upregulated ACE2 improves glycaemic control in diabetes [8], prevents myocardial fibrosis, and improves cardiac function after myocardial infarction [10]. Known protective effects of ACE2 through angiotensin-(1-7) might be attributable to antagonism of Ang-II signalling.…”