title: Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes.
abstract: Obese and diabetic individuals are at increased risk for impairments in diastolic relaxation and heart failure with preserved ejection fraction. The impairments in diastolic relaxation are especially pronounced in obese and diabetic women and predict future cardiovascular disease (CVD) events in this population. Recent clinical data suggest sodium glucose transporter-2 (SGLT2) inhibition reduces CVD events in diabetic individuals, but the mechanisms of this CVD protection are unknown. To determine whether targeting SGLT2 improves diastolic relaxation, we utilized empagliflozin (EMPA) in female db/db mice. Eleven week old female db/db mice were fed normal mouse chow, with or without EMPA, for 5 weeks. Blood pressure (BP), HbA1c and fasting glucose were significantly increased in untreated db/db mice (DbC) (P < 0.01). EMPA treatment (DbE) improved glycemic indices (P < 0.05), but not BP (P > 0.05). At baseline, DbC and DbE had already established impaired diastolic relaxation as indicated by impaired septal wall motion (>tissue Doppler derived E'/A' ratio) and increased left ventricular (LV) filling pressure (<E/E' ratio). Although these abnormalities persisted throughout the study period in DbC, diastolic function improved with EMPA treatment. In DbC, myocardial fibrosis was accompanied by increased expression of profibrotic/prohypertrophic proteins, serum/glucocorticoid regulated kinase 1 (SGK1) and the epithelial sodium channel (ENaC), and the development of these abnormalities were reduced with EMPA. DbC exhibited eccentric LV hypertrophy that was slightly improved by EMPA, indicated by a reduction in cardiomyocyte cross sectional area. In summary, EMPA improved glycemic indices along with diastolic relaxation, as well as SGK1/ENaC profibrosis signaling and associated interstitial fibrosis, all of which occurred in the absence of any changes in BP.
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes and Cardiovascular Center, University of Missouri, School of Medicine, Columbia, USA.|Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA.
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes and Cardiovascular Center, University of Missouri, School of Medicine, Columbia, USA.|Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA.
authors.forename: Annayya R
authors.initials: AR
authors.lastname: Aroor
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes and Cardiovascular Center, University of Missouri, School of Medicine, Columbia, USA.|Department of Medical Pharmacology and Physiology, University of Missouri, School of Medicine, Columbia, USA.|Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA.|The Dalton Cardiovascular Research Center, Columbia, MO, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes and Cardiovascular Center, University of Missouri, School of Medicine, Columbia, USA.|Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA.
authors.forename: Guanghong
authors.initials: G
authors.lastname: Jia
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes and Cardiovascular Center, University of Missouri, School of Medicine, Columbia, USA.
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes and Cardiovascular Center, University of Missouri, School of Medicine, Columbia, USA.|Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA.
authors.forename: Mona
authors.initials: M
authors.lastname: Garro
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes and Cardiovascular Center, University of Missouri, School of Medicine, Columbia, USA.|Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA.
authors.forename: Brady
authors.initials: B
authors.lastname: Barron
authors.affiliation: Department of Cardiometabolic Diseases Research, Boehringer-Ingelheim, Biberach, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Mayoux
authors.affiliation: Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA.|Departments of Medicine-Gastroenterology and Hepatology and Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Rector
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes and Cardiovascular Center, University of Missouri, School of Medicine, Columbia, USA.|Division of Nephrology, University of Missouri, School of Medicine, Columbia, USA.|Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Whaley-Connell
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes and Cardiovascular Center, University of Missouri, School of Medicine, Columbia, USA. demarcov@missouri.edu.|Department of Medical Pharmacology and Physiology, University of Missouri, School of Medicine, Columbia, USA. demarcov@missouri.edu.|Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA. demarcov@missouri.edu.
authors.forename: Vincent G
authors.identifier: 0000-0003-2092-9995
authors.initials: VG
authors.lastname: DeMarco
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D003971:Diastole / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005960:Glucosides / Q000494:pharmacology / Q000627:therapeutic use*; D038321:Glycemic Index / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051297:Sodium-Glucose Transporter 2 / Q000502:physiology; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D016277:Ventricular Function, Left / Q000187:drug effects* / Q000502:physiology
chemical_list: D001559:Benzhydryl Compounds; D005960:Glucosides; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C570240:empagliflozin
keywords: Diastolic function; Empagliflozin; SGLT2 inhibitor