Abstract 452: Signal Transducer and Activator of Transcription 4 Deficiency Improves the Metabolic Phenotype and Skeletal Muscle Insulin Signaling in LDLr-/- Mice on Diabetogenic High-Cholesterol Diet
Insulin resistance and type2 diabetes are associated with increased incidence of cardiovascular disease. About 80% of the subjects with type2 diabetes die due to cardiovascular complications. We previously showed that STAT4 deficiency improves insulin resistance in C57Bl6 mice on high fat diet and STAT4-/-ApoE-/- mice develop significantly lower atherosclerosis compared to ApoE-/- controls. The goal of this project was to determine the effect of STAT4 deficiency in a combined model of atherosclerosis and insulin resistance. To this purpose we generated STAT4-/-LDLr-/- mice and fed them either a chow diet or a high carbohydrate (36.6%), high cholesterol (0.15%) (DDC) diet for 16 weeks (n=7-10). The LDLr-/- on DDC diet developed glucose intolerance and insulin resistance as well as atherosclerosis and hypercholesterolemia compared to chow fed controls. STAT4-/-LDLr-/- mice on DDC diet, although hypercholesterolemic had significantly reduced atherosclerotic plaques by en face staining (p<0.05). Also STAT4 deficient mice on DDC diet had significantly lower area under curve for both the insulin and glucose tolerance tests (p<0.01), as well as reduced fasted glucose (p<0.05) compared to LDLr-/- mice despite similar body weights. Glucose stimulated insulin secretion in isolated pancreatic islets was blunted in LDLr-/- mice on DDC compared to chow controls and STAT4 deficiency restored the insulin secretion in islets from DDC fed mice at levels comparable to chow controls. In vivo insulin challenge showed reduced activation of IR, IRS-1 and Akt in LDLr-/- mice on DDC compared to chow controls in adipose tissue and skeletal muscle. STAT4-/-LDLr-/- on DDC diet had significantly improved activation of IRS-1 and Akt in skeletal muscle but not in adipose tissue. IR activation was constitutively higher in in STAT4-/-LDLr-/- mice on DDC compared to chow and did not change after insulin stimulation suggesting that STAT4 deficiency restores insulin signaling via a post-receptor mechanism. In conclusion, STAT4 deficiency reduces insulin resistance and improves glucose intolerance primarily by improving insulin signaling in skeletal muscle and by increasing islet insulin secretion. This may explain in part the athero-protective phenotype in STAT4-/-LDLr mice.
Author Disclosures: K. Ma: None. M. Hatcher: None. L. Glenn: None. P. Tagavie-Moghadan: None. J. Nadler: None. A.D. Dobrian: None.
- © 2014 by American Heart Association, Inc.