Acetyl-CoA carboxylase 1 (ACC1) currently is being investigated as a target for treatment of
obesity-associated
dyslipidemia and
insulin resistance. To investigate the effects of ACC1 inhibition on insulin secretion, three
small interfering RNA (
siRNA) duplexes targeting ACC1 (siACC1) were transfected into the INS-1-derived cell line, 832/13; the most efficacious duplex was also cloned into an adenovirus and used to transduce isolated rat islets. Delivery of the siACC1 duplexes decreased ACC1
mRNA by 60-80% in 832/13 cells and islets and
enzyme activity by 46% compared with cells treated with a non-targeted
siRNA. Delivery of siACC1 decreased
glucose-stimulated insulin secretion (GSIS) by 70% in 832/13 cells and by 33% in islets. Surprisingly, siACC1 treatment decreased
glucose oxidation by 49%, and the
ATP:
ADP ratio by 52%, accompanied by clear decreases in
pyruvate cycling activity and tricarboxylic acid cycle intermediates. Exposure of siACC1-treated cells to the
pyruvate cycling substrate dimethylmalate restored GSIS to normal without recovery of the depressed
ATP:
ADP ratio. In siACC1-treated cells,
glucokinase protein levels were decreased by 25%, which correlated with a 36% decrease in
glycogen synthesis and a 33% decrease in glycolytic flux. Furthermore, acute addition of the ACC1 inhibitor
5-(tetradecyloxy)-2-furoic acid (
TOFA) to beta-cells suppressed [(14)C]
glucose incorporation into
lipids but had no effect on GSIS, whereas chronic
TOFA administration suppressed GSIS and
glucose metabolism. In sum, chronic, but not acute, suppression of ACC1 activity impairs GSIS via inhibition of
glucose rather than lipid metabolism. These findings raise concerns about the use of ACC inhibitors for diabetes
therapy.