title: Hyperglycemia and hyperlipidemia blunts the Insulin-Inpp5f negative feedback loop in the diabetic heart.
abstract: The leading cause of death in diabetic patients is diabetic cardiomyopathy, in which alteration of Akt signal plays an important role. Inpp5f is recently found to be a negative regulator of Akt signaling, while its expression and function in diabetic heart is largely unknown. In this study, we found that in both the streptozotocin (STZ) and high fat diet (HFD) induced diabetic mouse models, Inpp5f expression was coordinately regulated by insulin, blood glucose and lipid levels. Increased Inpp5f was inversely correlated with the cardiac function. Further studies revealed that Insulin transcriptionally activated Inpp5f in an Sp1 dependent manner, and increased Inpp5f in turn reduced the phosphorylation of Akt, forming a negative feedback loop. The negative feedback plays a protective role under diabetic condition. However, high blood glucose and lipid, which are characteristics of uncontrolled diabetes and type 2 diabetes, increased Inpp5f expression through activation of NF-κB, blunts the protective feedback. Thus, our study has revealed that Inpp5f provides as a negative feedback regulator of insulin signaling and downregulation of Inpp5f in diabetes is cardioprotective. Increased Inpp5f by hyperglycemia and hyperlipidemia is an important mediator of diabetic cardiomyopathy and is a promising therapeutic target for the disease.
authors.affiliation: Department of Cardiology, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, China.|323 Hospital of PLA, Xi'an 710054, China.
authors.forename: Danna
authors.initials: D
authors.lastname: Bai
authors.affiliation: Department of Ultrasound Diagnostics, Tangdu Hospital, the Fourth Military Medical University, Xi'an 710038, China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, China.|Department of Cardiology, Hainan Branch of PLA General Hospital, Sanya 572013, China.
authors.forename: Mingzhi
authors.initials: M
authors.lastname: Shen
authors.affiliation: 323 Hospital of PLA, Xi'an 710054, China.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Sun
authors.affiliation: 323 Hospital of PLA, Xi'an 710054, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xia
authors.affiliation: Department of Cardiology, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xuedong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Haichang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Ultrasound Diagnostics, Tangdu Hospital, the Fourth Military Medical University, Xi'an 710038, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Yuan
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000097:blood / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000235:genetics* / Q000473:pathology; D006949:Hyperlipidemias / Q000097:blood / Q000235:genetics* / Q000473:pathology; D000072181:Inositol Polyphosphate 5-Phosphatases / Q000097:blood / Q000235:genetics*; D007328:Insulin / Q000097:blood / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000097:blood / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000097:blood / Q000235:genetics; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000097:blood / Q000235:genetics; D013311:Streptozocin; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D007328:Insulin; D016328:NF-kappa B; D016329:Sp1 Transcription Factor; D014280:Triglycerides; D013311:Streptozocin; D002784:Cholesterol; D051057:Proto-Oncogene Proteins c-akt; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606434:Inpp5f protein, mouse