Molecular Dissection of the Role of ACE2 in Glucose Homeostasis

Angiotensin Converting Enzyme 2 (ACE2) was discovered 25 years ago as a negative regulator of renin-angiotensin system, opposing the effects of angiotensin-II. Beyond its well-demonstrated roles in cardiovascular regulation and Covid-19 pathology, ACE2 is involved in a plethora of physio-pathological processes. In this review, we summarize the latest discoveries on the role of ACE2 in glucose homeostasis and regulation of metabolism. In the endocrine pancreas, ACE2 is expressed at low levels in β cells, but loss of its expression inhibits glucose-stimulated insulin secretion and impairs glucose tolerance. Conversely, overexpression of ACE2 improved glycemia and suggests that recombinant ACE2 might be a future therapy for diabetes. In the skeletal muscle of ACE2-deficient mice, a progressive triglyceride accumulation was observed, whereas in diabetic kidney the initial increase in ACE2 is followed by a chronic reduction of expression in kidney tubules and impairment of glucose metabolism. At the intestinal level, dysregulation of the enzyme alters the amino acid absorption and intestinal microbiome, while at the hepatic level, ACE2 protects against diabetic fatty liver disease. Not least, ACE2 is upregulated in adipocytes in response to nutritional stimuli and administration of recombinant ACE2 decreased body weight and increased thermogenesis. In addition to tissue-specific regulation of ACE2 function, the enzyme undergoes complex cellular posttranslational modifications which are changed during diabetes evolution, with at least proteolytic cleavage and ubiquitination leading to modifications in ACE2 activity. Detailed characterization of ACE2 in specific cellular- and tissue-manner holds promise for improving therapeutic outcomes in diabetes and metabolic disorders.