The direct effects of the angiotensin-converting enzyme inhibitors, zofenoprilat and enalaprilat, on isolated human pancreatic islets.
OBJECTIVE
Data from prospective studies suggest a significant reduction in the risk of new diabetes from drug therapies containing angiotensin-converting enzyme (ACE) inhibitors. Since the renin-angiotensin system (RAS) has been found locally in several tissues and cells, including pancreatic islets, we hypothesized that the positive metabolic effects of ACE inhibitors may be due to a beneficial action of these compounds on insulin-secreting beta-cells.


METHODS
Isolated human pancreatic islets were studied after 24 h of incubation with 22.2 mmol/l glucose, with or without the presence in the incubation medium of 0.5-6.0 mmol/l zofenoprilat or enalaprilat, ACE inhibitor drugs which differ by the presence of a sulphydryl or a carboxyl group in their structural formula. Functional and molecular studies were then performed to assess insulin secretion, redox balance, mRNA and protein expression.


RESULTS
Angiotensinogen, ACE and angiotensin type 1 receptor mRNA expression increased in islets cultured in high glucose; this was similarly prevented by the presence of either ACE inhibitor. As expected, preculture of human islets in high glucose determined a marked reduction in insulin secretion which was associated with enhanced oxidative stress, as shown by increased nitrotyrosine concentrations, and enhanced expression of protein kinase C beta and NADPH oxidase. The presence of either of the ACE inhibitors counteracted several of the deleterious effects of high glucose exposure, including reduction of insulin secretion and increased oxidative stress; zofenoprilat showed significantly more marked effects.


CONCLUSIONS
These results showed that: (a) RAS molecules are present in human islets and their expression is sensitive to glucose concentration, (b) ACE inhibitors, and in particular zofenoprilat, protect human islets from glucotoxicity and (c) the effects of ACE inhibition are associated with decreased oxidative stress. Together, these findings provide evidence that the possible beneficial effects of ACE inhibitors in human diabetes are due, at least in part, to a protective action on pancreatic beta-cells.
Lupi
Roberto
R
Metabolic Unit, Department of Endocrinology and Metabolism, University of Pisa, Ospedale Cisanello, via Paradisa 2, 56100 Pisa, Italy.
Del Guerra
Silvia
S
Bugliani
Marco
M
Boggi
Ugo
U
Mosca
Franco
F
Torri
Scilla
S
Del Prato
Stefano
S
Marchetti
Piero
P
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D002216:Captopril / Q000031:analogs & derivatives* / Q000494:pharmacology; D015773:Enalaprilat / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012313:RNA / Q000737:chemistry / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D000806:Angiotensin-Converting Enzyme Inhibitors; D007328:Insulin; D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen; C002744:3-nitrotyrosine; D014443:Tyrosine; C065520:zofenoprilate; D012313:RNA; D002216:Captopril; D051057:Proto-Oncogene Proteins c-akt; D007703:Peptidyl-Dipeptidase A; D015773:Enalaprilat; D005947:Glucose