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 insulin sensitivity (not shown).
In the kidney, ACE2 colocalizes with ACE on the apical surface area of the proximal
tubules and is also localized in the glomerulus (9). In the pancreas, ACE2 was found
to be localized to acini and islets following a similar distribution to that of ACE
(10). In rodent models of diabetes, pharmacological inhibition of ACE2 (9,11) and
genetic ablation (12) have both been shown to worsen albuminuria and the associated
glomerular lesions. Moreover, decreased glomerular expression of ACE2 has been described
in rodent models of diabetes (9) and in human kidney biopsies from patients with diabetic
nephropathy (13). Accordingly, ACE2 has been proposed as a target for therapies aimed
at increasing the activity of this enzyme as a way to treat diabetic kidney disease
(9,14) (Fig. 1).
In ACE2 deficient mice, alterations in glucose tolerance and reduced first-phase insulin
secretion have been described, suggesting a potential role of ACE2 in the development
of diabetes (15). Collectrin, another homologue of ACE, has also been shown to be
expressed in β-cells of the pancreas, and although its function is unknown, it could
also be implicated in insulin secretion and β-cell proliferation (16). Much like in
the kidney, the pancreas expresses key components of a local angiotensin peptide generating
system as described by Chappell et al. (17) almost 2 decades ago. These authors found
Ang II to be the predominant angiotensin peptide in the pancreas, with lower levels
of Ang-(1-7) and low to nondetectable levels of Ang I. The effects of Ang II in the
pancreas could be counterbalanced by Ang-(1-7), as it has been proposed to do in the
kidneys and other tissues (18). The levels of both peptides in the pancreas were several-fold
higher than those observed in the plasma (17). Carlsson et al. (19) later found that
Ang II can delay insulin secretion and reduces blood flow in the islets of Langerhans
in a dose-dependent manner. Consistent with this effect of Ang II, blockade of RAS
with either ACE inhibitors or Ang II receptor antagonists increases islet blood flow
(19). Moreover, these agents have been shown to attenuate pancreatic inflammation
and fibrosis (20). Also of note is the finding of Tikellis et al. (10) that RAS blockade
in the Zucker diabetic fatty (ZDF) rat not only reduced islet fibrosis, but also improved
structural parameters in association with improvement in first-phase insulin secretion.
These findings are particularly relevant given clinical evidence that RAS blockade
may be associated with reduced incidence of new-onset type 2 diabetes (21). Although
recent trials have called these results into question (22), there are ongoing studies
specifically designed to demonstrate that blockade of the RAS helps prevent the development
of type 2 diabetes.
In the October issue of Diabetes, Bindom et al. (23) report studies examining ACE2
gene therapy in the db/db model of type 2 diabetes. ACE2 gene therapy targeting the
islet cells through the use of adenoviral vectors increased pancreatic ACE2 expression
and activity in both db/db and db/m mice, with a peak occurring 7 days after infection.
Prior to gene therapy at 8 weeks of age, pancreatic ACE2 was increased in the db/db
mice. This finding is consistent with a previous report by Tikellis et al. (10) in
the ZDF rat model of type 2 diabetes in which ACE as well as AT1 receptor expression
was increased. It is likely that the increase in ACE2 was an adaptive effort to counter
ACE overactivity. ACE2 gene therapy in the db/db mice resulted in improved fasting
blood glucose levels and glucose tolerance (23). An increase in first-phase insulin
secretion and β-cell proliferation, as well as a reduction in β-cell apoptosis when
compared with db/db mice receiving control adenoviral infection were also observed
(23).
Unlike at 8 weeks of age, at 16 weeks of age db/db mice showed a decrease in pancreatic
ACE2 mRNA expression. Also of note, 16-week-old db/db mice had much more severe diabetes
than the younger group, as indicated by higher levels of fasting glucose, and they
benefited much less from ACE2 gene therapy, showing no improvement in glucose tolerance,
first-phase insulin secretion, β-cell proliferation, or apoptosis (23). Possibly,
by 16 weeks of age it is too late to intervene with ACE2 therapies because significant
β-cell failure may not be readily reversible. It will be of interest to study whether
increasing ACE2 activity early on can improve insulin secretion in models of type
1 diabetes such as the NOD mice and therefore help prevent or delay the onset of the
disease.
How could ACE and its homologues be involved in the development of diabetes? The most
obvious possibility is that ACE and ACE2, by regulating the levels of Ang II and/or
Ang-(1-7) in pancreatic islets, are involved in the control of insulin secretion to
the extent that blood flow is influenced by local levels of angiotensin peptides as
noted above. Other effects of these peptides relevant to insulin secretion in islet
cells are listed in the figure. Similar actions of these peptides at the kidney level
may determine the fate of the decline in glomerular filtration rate at later phases
of diabetes. It should be noted that, unlike insulin secretion, insulin sensitivity
did not improve after ACE2 gene therapy in the db/db model at either 8 or 16 weeks
of age (23). This lack of effect is somewhat unexpected because ACE2 overexpression
should increase Ang-(1-7) levels, as recently shown after recombinant ACE2 protein
administration (7). Ang-(1-7) has been shown to increase insulin sensitivity (24),
and moreover, mice with genetic ablation of the Mas receptor, on which Ang-(1-7) acts,
develop features of metabolic syndrome, including hyperinsulinemia and impaired glucose
tolerance (25). The finding that β-cell function improvement by ACE2 overexpression
was attenuated when a Mas-receptor blocker was given, suggests, at least in part,
mediation by Ang-(1-7) (23).
In summary, ACE2 may play a pivotal role in diabetes: in the pancreas, a relative
deficiency of ACE2 as the disease progresses may contribute to decreased insulin secretion,
whereas in the kidney glomerulus it may foster proteinuria, as a result of both impaired
degradation of Ang II and the attendant Ang II accumulation locally. The findings
of Bindom et al. (23) that ACE2 overexpression by means of adenoviral gene delivery
can improve pancreatic islet β-cell function in db/db mice are exciting and are in
keeping with an important role of ACE2 as a therapeutic target for diabetic kidney
disease and several other conditions in which overactivity of Ang II is undesirable.
ACE2, by fostering the degradation of Ang II and the formation of Ang-(1-7), may have
beneficial effects on both the kidney and pancreas (Fig. 1). ACE2 truly seems to be
the “good” ACE, and therapies aimed at amplifying its activity should be explored
in the prevention and treatment of diabetes and its complications.