SGLT2 inhibition with empagliflozin improves coronary microvascular function and cardiac contractility in prediabetic ob/ob−/− mice

Abstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) is the first class of anti-diabetes treatment that reduces mortality and risk for hospitalization due to heart failure. In clinical studies it has been shown that SGLT2i’s promote a general shift to fasting state metabolism chara...

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Main Authors: Damilola D. Adingupu, Sven O. Göpel, Julia Grönros, Margareta Behrendt, Matus Sotak, Tasso Miliotis, Ulrika Dahlqvist, Li-Ming Gan, Ann-Cathrine Jönsson-Rylander
Format: Article
Language:English
Published: BMC 2019-02-01
Series:Cardiovascular Diabetology
Subjects:
Online Access:http://link.springer.com/article/10.1186/s12933-019-0820-6
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language English
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author Damilola D. Adingupu
Sven O. Göpel
Julia Grönros
Margareta Behrendt
Matus Sotak
Tasso Miliotis
Ulrika Dahlqvist
Li-Ming Gan
Ann-Cathrine Jönsson-Rylander
spellingShingle Damilola D. Adingupu
Sven O. Göpel
Julia Grönros
Margareta Behrendt
Matus Sotak
Tasso Miliotis
Ulrika Dahlqvist
Li-Ming Gan
Ann-Cathrine Jönsson-Rylander
SGLT2 inhibition with empagliflozin improves coronary microvascular function and cardiac contractility in prediabetic ob/ob−/− mice
Cardiovascular Diabetology
Coronary
Endothelial
Microvascular
Prediabetes
SGLT2
author_facet Damilola D. Adingupu
Sven O. Göpel
Julia Grönros
Margareta Behrendt
Matus Sotak
Tasso Miliotis
Ulrika Dahlqvist
Li-Ming Gan
Ann-Cathrine Jönsson-Rylander
author_sort Damilola D. Adingupu
title SGLT2 inhibition with empagliflozin improves coronary microvascular function and cardiac contractility in prediabetic ob/ob−/− mice
title_short SGLT2 inhibition with empagliflozin improves coronary microvascular function and cardiac contractility in prediabetic ob/ob−/− mice
title_full SGLT2 inhibition with empagliflozin improves coronary microvascular function and cardiac contractility in prediabetic ob/ob−/− mice
title_fullStr SGLT2 inhibition with empagliflozin improves coronary microvascular function and cardiac contractility in prediabetic ob/ob−/− mice
title_full_unstemmed SGLT2 inhibition with empagliflozin improves coronary microvascular function and cardiac contractility in prediabetic ob/ob−/− mice
title_sort sglt2 inhibition with empagliflozin improves coronary microvascular function and cardiac contractility in prediabetic ob/ob−/− mice
publisher BMC
series Cardiovascular Diabetology
issn 1475-2840
publishDate 2019-02-01
description Abstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) is the first class of anti-diabetes treatment that reduces mortality and risk for hospitalization due to heart failure. In clinical studies it has been shown that SGLT2i’s promote a general shift to fasting state metabolism characterized by reduced body weight and blood glucose, increase in glucagon/insulin ratio and modest increase in blood ketone levels. Therefore, we investigated the connection between metabolic changes and cardiovascular function in the ob/ob−/− mice; a rodent model of early diabetes with specific focus on coronary microvascular function. Due to leptin deficiency these mice develop metabolic syndrome/diabetes and hepatic steatosis. They also develop cardiac contractile and microvascular dysfunction and are thus a promising model for translational studies of cardiometabolic diseases. We investigated whether this mouse model responded in a human-like manner to empagliflozin treatment in terms of metabolic parameters and tested the hypothesis that it could exert direct effects on coronary microvascular function and contractile performance. Methods Lean, ob/ob−/− untreated and ob/ob−/− treated with SGLT2i were followed for 10 weeks. Coronary flow velocity reserve (CFVR) and fractional area change (FAC) were monitored with non-invasive Doppler ultrasound imaging. Food intake, urinary glucose excursion and glucose control via HbA1c measurements were followed throughout the study. Liver steatosis was assessed by histology and metabolic parameters determined at the end of the study. Results Sodium-glucose cotransporter 2 inhibitors treatment of ob/ob−/− animals resulted in a switch to a more catabolic state as observed in clinical studies: blood cholesterol and HbA1c were decreased whereas glucagon/insulin ratio and ketone levels were increased. SGLT2i treatment reduced liver triglyceride, steatosis and alanine aminotransferase, an indicator for liver dysfunction. l-Arginine/ADMA ratio, a marker for endothelial function was increased. SGLT2i treatment improved both cardiac contractile function and coronary microvascular function as indicated by improvement of FAC and CFVR, respectively. Conclusions Sodium-glucose cotransporter 2 inhibitors treatment of ob/ob−/− mice mimics major clinical findings regarding metabolism and cardiovascular improvements and is thus a useful translational model. We demonstrate that SGLT2 inhibition improves coronary microvascular function and contractile performance, two measures with strong predictive values in humans for CV outcome, alongside with the known metabolic changes in a preclinical model for prediabetes and heart failure.
topic Coronary
Endothelial
Microvascular
Prediabetes
SGLT2
url http://link.springer.com/article/10.1186/s12933-019-0820-6
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spelling doaj-d8d21f00761e46e7a13409051bf1ea062020-11-25T01:19:52ZengBMCCardiovascular Diabetology1475-28402019-02-0118111510.1186/s12933-019-0820-6SGLT2 inhibition with empagliflozin improves coronary microvascular function and cardiac contractility in prediabetic ob/ob−/− miceDamilola D. Adingupu0Sven O. Göpel1Julia Grönros2Margareta Behrendt3Matus Sotak4Tasso Miliotis5Ulrika Dahlqvist6Li-Ming Gan7Ann-Cathrine Jönsson-Rylander8Bioscience, Cardiovascular, Renal and Metabolic Diseases, IMED Biotech Unit, AstraZeneca GothenburgBioscience, Cardiovascular, Renal and Metabolic Diseases, IMED Biotech Unit, AstraZeneca GothenburgBioscience, Cardiovascular, Renal and Metabolic Diseases, IMED Biotech Unit, AstraZeneca GothenburgBioscience, Cardiovascular, Renal and Metabolic Diseases, IMED Biotech Unit, AstraZeneca GothenburgBioscience, Cardiovascular, Renal and Metabolic Diseases, IMED Biotech Unit, AstraZeneca GothenburgTranslational Science, Cardiovascular, Renal and Metabolic Diseases, IMED Biotech Unit, AstraZeneca GothenburgBioscience, Cardiovascular, Renal and Metabolic Diseases, IMED Biotech Unit, AstraZeneca GothenburgEarly Clinical Development, Cardiovascular, Renal and Metabolic Diseases, IMED Biotech Unit, AstraZeneca GothenburgBioscience, Cardiovascular, Renal and Metabolic Diseases, IMED Biotech Unit, AstraZeneca GothenburgAbstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) is the first class of anti-diabetes treatment that reduces mortality and risk for hospitalization due to heart failure. In clinical studies it has been shown that SGLT2i’s promote a general shift to fasting state metabolism characterized by reduced body weight and blood glucose, increase in glucagon/insulin ratio and modest increase in blood ketone levels. Therefore, we investigated the connection between metabolic changes and cardiovascular function in the ob/ob−/− mice; a rodent model of early diabetes with specific focus on coronary microvascular function. Due to leptin deficiency these mice develop metabolic syndrome/diabetes and hepatic steatosis. They also develop cardiac contractile and microvascular dysfunction and are thus a promising model for translational studies of cardiometabolic diseases. We investigated whether this mouse model responded in a human-like manner to empagliflozin treatment in terms of metabolic parameters and tested the hypothesis that it could exert direct effects on coronary microvascular function and contractile performance. Methods Lean, ob/ob−/− untreated and ob/ob−/− treated with SGLT2i were followed for 10 weeks. Coronary flow velocity reserve (CFVR) and fractional area change (FAC) were monitored with non-invasive Doppler ultrasound imaging. Food intake, urinary glucose excursion and glucose control via HbA1c measurements were followed throughout the study. Liver steatosis was assessed by histology and metabolic parameters determined at the end of the study. Results Sodium-glucose cotransporter 2 inhibitors treatment of ob/ob−/− animals resulted in a switch to a more catabolic state as observed in clinical studies: blood cholesterol and HbA1c were decreased whereas glucagon/insulin ratio and ketone levels were increased. SGLT2i treatment reduced liver triglyceride, steatosis and alanine aminotransferase, an indicator for liver dysfunction. l-Arginine/ADMA ratio, a marker for endothelial function was increased. SGLT2i treatment improved both cardiac contractile function and coronary microvascular function as indicated by improvement of FAC and CFVR, respectively. Conclusions Sodium-glucose cotransporter 2 inhibitors treatment of ob/ob−/− mice mimics major clinical findings regarding metabolism and cardiovascular improvements and is thus a useful translational model. We demonstrate that SGLT2 inhibition improves coronary microvascular function and contractile performance, two measures with strong predictive values in humans for CV outcome, alongside with the known metabolic changes in a preclinical model for prediabetes and heart failure.http://link.springer.com/article/10.1186/s12933-019-0820-6CoronaryEndothelialMicrovascularPrediabetesSGLT2