Empagliflozin lessened cardiac injury and reduced visceral adipocyte hypertrophy in prediabetic rats with metabolic syndrome.
BACKGROUND
The potential benefit of SGLT2 inhibitors in metabolic syndrome is with prediabetic stage unclear. This work was undertaken to investigate the non-glycemic effect of empagliflozin on metabolic syndrome rats with prediabetes.


METHODS
SHR/NDmcr-cp(+/+) rats (SHRcp), a model of metabolic syndrome with prediabetes, were given empagliflozin for 10 weeks to examine the effects on urinary sodium and water balance, visceral and subcutaneous adipocyte, and cardiac injury. Further, the effect of empagliflozin on blood pressure and autonomic nervous system was continuously investigated by using radiotelemetry system.


RESULTS
Empagliflozin significantly reduced urinary sodium and water balance of SHRcp only within 1 week of the treatment, but later than 1 week did not alter them throughout the treatment. Empagliflozin significantly reduced body weight of SHRcp, which was mainly attributed to the significant reduction of subcutaneous fat mass. Empagliflozin significantly reduced the size of visceral adipocytes and increased the number of smaller size of adipocytes, which was associated with the attenuation of oxidative stress. Empagliflozin ameliorated cardiac hypertrophy and fibrosis of SHRcp, in association with the attenuation of cardiac oxidative stress and inflammation. However, empagliflozin did not significantly change blood pressure, heart rate, sympathetic activity, or baroreceptor function, as evidenced by radiotelemetry analysis.


CONCLUSIONS
Our present work provided the evidence that SGLT2 inhibition reduced visceral adipocytes hypertrophy and ameliorated cardiac injury in prediabetic metabolic syndrome rat, independently of diuretic effect or blood pressure lowering effect. Thus, SGLT2 inhibition seems to be a promising therapeutic strategy for prediabetic metabolic syndrome.
Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
Hiroaki
H
Kusaka
Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
Nobutaka
N
Koibuchi
Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
Yu
Y
Hasegawa
Department of Cardiovascular Medicine, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Hisao
H
Ogawa
Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan. mitsuyam@gpo.kumamoto-u.ac.jp.
Shokei
S
Kim-Mitsuyama
D052438:Adipocytes, White / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050154:Adiposity / Q000187:drug effects*; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood / Q000652:urine; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004231:Diuresis / Q000187:drug effects; D005960:Glucosides / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006984:Hypertrophy; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D050152:Intra-Abdominal Fat / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects; D011236:Prediabetic State / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011918:Rats, Inbred SHR; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013997:Time Factors; D014882:Water-Electrolyte Balance / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects
D001559:Benzhydryl Compounds; D015415:Biomarkers; D005960:Glucosides; D007004:Hypoglycemic Agents; C490300:Slc5a2 protein, rat; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C570240:empagliflozin
Adipose tissue; Cardiac protection; Inflammation; Metabolic syndrome; Natriuresis; Oxidative stress; Prediabetes