Abstract: Objective To investigate the effects of angiotensin II type 1 receptor (AT1R) knockdown on the first-phase insulin
secretion in isolated islets of db/db mice and explore the possible mechanisms. Methods Islets were isolated from db/db and
db/m mice and the expression level of AT1R in the islets was assayed. A recombinant adenovirus containing siRNA targeting
AT1R (Ad-siAT1R) and a recombinant adenovirus with nonspecific siRNA (Ad-siControl) were constructed to infect the
isolated islets for 72 h. AT1R, GLUT-2, and GCK expressions in the islets were investigated and islet perifusion was performed
to evaluate the kinetics of insulin release. Results The expression level of AT1R in the isolated islets from db/db mice was twice
that of islets from db/m mice. The islets treated with Ad-siAT1R showed significantly decreased AT1R mRNA and protein
levels and significantly increased expression of GLUT-2 (by 190% ) and GCK (by 121% ) compared to those treated with
Ad-siControl (P<0.05). In response to stimulation with 16.7 mmol/L glucose, the first-phase insulin secretion was impaired in
both Ad-siControl group and mock infected group with the peak insulin levels only 1.8 times of the basal level; the first-phase
insulin secretion was markedly improved in islets treated with Ad-siAT1R, with a peak insulin level reaching 2.8 times of the
basal level. Conclusions In isolated islets of db/db mice, selective AT1R inhibition can restore the first phase insulin secretion
by up-regulating GLUT-2 and GCK, which may be one of the potential mechanisms by which AT1R blockers improve insulin
secretion function.