Hyperglycemia and hyperlipidemia blunts the Insulin-Inpp5f negative feedback loop in the diabetic heart

Danna Bai; Yajun Zhang; Mingzhi Shen; Yongfeng Sun; Qing Xia; Yingmei Zhang; Xuedong Liu; Haichang Wang; Lijun Yuan

doi:10.1038/srep22068

Hyperglycemia and hyperlipidemia blunts the Insulin-Inpp5f negative feedback loop in the diabetic heart

Sci Rep. 2016 Feb 24:6:22068. doi: 10.1038/srep22068.

Authors

Danna Bai^{1

2}, Yajun Zhang³, Mingzhi Shen^{1

4}, Yongfeng Sun², Qing Xia², Yingmei Zhang¹, Xuedong Liu⁵, Haichang Wang¹, Lijun Yuan³

Affiliations

¹ Department of Cardiology, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, China.
² 323 Hospital of PLA, Xi'an 710054, China.
³ Department of Ultrasound Diagnostics, Tangdu Hospital, the Fourth Military Medical University, Xi'an 710038, China.
⁴ Department of Cardiology, Hainan Branch of PLA General Hospital, Sanya 572013, China.
⁵ Department of Neurology, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood Glucose / metabolism
Cholesterol / blood
Diabetes Mellitus, Experimental / blood
Diabetes Mellitus, Experimental / etiology
Diabetes Mellitus, Experimental / genetics*
Diabetes Mellitus, Experimental / pathology
Diabetes Mellitus, Type 2 / blood
Diabetes Mellitus, Type 2 / genetics
Diabetes Mellitus, Type 2 / pathology
Diabetic Cardiomyopathies / blood
Diabetic Cardiomyopathies / etiology
Diabetic Cardiomyopathies / genetics*
Diabetic Cardiomyopathies / pathology
Diet, High-Fat / adverse effects
Feedback, Physiological
Gene Expression Regulation
Humans
Hyperglycemia / blood
Hyperglycemia / genetics*
Hyperglycemia / pathology
Hyperlipidemias / blood
Hyperlipidemias / genetics*
Hyperlipidemias / pathology
Inositol Polyphosphate 5-Phosphatases / blood
Inositol Polyphosphate 5-Phosphatases / genetics*
Insulin / blood
Insulin / genetics*
Male
Mice
Mice, Inbred C57BL
Myocardium / metabolism*
Myocardium / pathology
NF-kappa B / blood
NF-kappa B / genetics
Proto-Oncogene Proteins c-akt / blood
Proto-Oncogene Proteins c-akt / genetics
Signal Transduction
Sp1 Transcription Factor / blood
Sp1 Transcription Factor / genetics
Streptozocin
Triglycerides / blood

Substances

Blood Glucose
Insulin
NF-kappa B
Sp1 Transcription Factor
Triglycerides
Streptozocin
Cholesterol
Proto-Oncogene Proteins c-akt
Inositol Polyphosphate 5-Phosphatases
Inpp5f protein, mouse