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- Title
Suppression of Acetyl CoA Carboxylase 1 Expression in Beta Cells Impairs Mitochondrial Glucose Oxidation and Glucose-Stimulated Insulin Secretion.
- Authors
Ronnebaum, Sarah M.; Joseph, Jamie W.; Ilkayeva, Olga; Lu, Danhong; Jensen, Mette V.; Becker, Thomas C.; Newgard, Christopher B.
- Abstract
We have recently shown that suppression of the mitochondrial citrate/isocitrate carrier impairs citrate and isocitrate export from beta cell mitochondria and attenuates glucose-stimulated insulin secretion (GSIS). Cytosolic citrate is cleaved to oxaloacetate and acetyl CoA, which can be directed for de novo lipogenesis, a pathway implicated in GSIS. We transfected INS-1-derived 832/13 cells with a small interfering RNA (siRNA) duplex targeting acetyl CoA carboxylase 1 (siACC1), the enzyme catalyzing the first committed step of fatty acid synthesis; this duplex was also cloned into an adenovirus used to transduce isolated rat islets. ACC1 suppression decreased ACC1 mRNA by approximately 60% in both 832/13 cells and islets, and decreased GSIS at stimulatory glucose concentrations by 36±6% in 832/13 cells and by 33±9% in isolated islets. Similar results were observed in 832/13 cells transfected with two independent siACCI duplexes. In siACCl-treated 832/13 cells, ACCI protein decreased 67±3%, and glucose incorporation into lipids decreased 57±12%. Unexpectedly, glucose oxidation decreased 49±10%, which accompanied a 52±11% decrease in ATP:ADP ratio. In addition, organic acid profiling by GC/MS revealed dramatic decreases in pyruvate, α-ketoglutarate, and malate, which are all necessary for pyruvate cycling. We have previously demonstrated that dimethylmalate (DMM) increases GSIS by increasing pyruvate cycling. Exposure of siACC1-treated cells to 10 mM DMM rescued GSIS without restoring the ATP:ADP ratio, suggesting that DMM restored GSIS by increasing pyruvate cycling. While palmitate and oleate oxidation were unaffected by siACC 1 treatment, acetylcamitine decreased 47±15%, suggesting decreased mitochondrial acetyl CoA. In separate studies, we have found that siRNA-mediated suppression of citrate lyase does not affect GSIS. Taken together, our data suggest that ACC1 suppression impairs GSIS by suppressing mitochondrial glucose metabolism and pyruvate cycling activity, rather than via its effects on lipogenesis.
- Subjects
ACETYLCOENZYME A; PANCREATIC beta cells; OXIDATION; BLOOD sugar; GLUCOSE; INSULIN; PYRUVATES; ORGANIC acids
- Publication
Diabetes, 2007, Vol 56, pA441
- ISSN
0012-1797
- Publication type
Article