ACE2 and Diabetes: ACE of ACEs?

The mechanisms involved in the development of diabetes and its complications are complex, with a long list of potential derangements on different pathways (1,2). In this commentary, we discuss angiotensin converting enzyme 2 (ACE2) as a potential participant in the development of both islet β-cell insufficiency early on and in the development of nephropathy later. ACE has long been recognized as the key enzyme within the renin-angiotensin system (RAS) mainly by cleaving angiotensin (Ang) I to form Ang II, which is the main active peptide within the system. ACE2, a homologue of ACE, is a monocarboxypeptidase that preferentially removes carboxy-terminal amino acids from various substrates, including Ang II, Ang I, and apelin (3–6). ACE2 cleaves Ang II to form Ang-(1-7) with a high catalytic efficiency, suggesting an important role in preventing Ang II accumulation, while enhancing Ang-(1-7) formation (7) (Fig. 1). Other mammalian homologues of ACE, such as collectrin and, more recently, ACE3, have also been described (8). ACE2, however, is the only known homologue of ACE with enzymatic activity (3–5). FIG. 1. Potential therapeutic role of ACE2 amplification in diabetes, both at the level of the pancreatic islets and at that of the kidney. ACE2 amplification leads to reduced Ang II overactivity and increased Ang-(1–7) activity. Please note that the actions of ACE2 on angiotensin peptides are just the opposite of those of ACE, which promotes Ang II formation while increasing Ang-(1–7) degradation. In general, the effects of Ang-(1–7) (blue) are less well documented (as reflected by the question marks) than those of Ang II (red). It is possible that the benefits of ACE2 amplification result largely from reduced ACE2 overactivity and not so much from increased Ang-(1–7) activity, but that needs to be further studied. There are also potential effects of Ang-(1–7) on …