Diabetic cardiomyopathy (DCM) characterized by diastolic and systolic dysfunction independently of hypertension and coronary heart disease, eventually develops into heart failure, which is strongly linked to a high prevalence of mortality in people with diabetes mellitus (DM). Sodium-glucose cotransporter type2 inhibitors (SGLT2Is) are a novel type of hypoglycemic agent in increasing urinary glucose and sodium excretion. Excitingly, the EMPA-REG clinical trial proved that empagliflozin significantly reduced the relative risk of cardiovascular (CV) death and hospitalization for heart failure (HHF) in patients with type 2 DM (T2DM) plus CV disease (CVD). The EMPRISE trial showed that empagliflozin decreased the risk of HHF in T2DM patients with and without a CVD history in routine care. These beneficial effects of SGLT2Is could not be entirely attributed to glucose-lowering or natriuretic action. There could be potential direct mechanisms of SGLT2Is in cardioprotection. Recent studies have shown the effects of SGLT2Is on cardiac iron homeostasis, mitochondrial function, anti-inflammation, anti-fibrosis, antioxidative stress, and renin-angiotensin-aldosterone system activity, as well as GlcNAcylation in the heart. This article reviews the current literature on the effects of SGLT2Is on DCM in preclinical studies. Possible molecular mechanisms regarding potential benefits of SGLT2Is for DCM are highlighted, with the purpose of providing a novel strategy for preventing DCM.

/pdf/sglt2-inhibitors-a-novel-player-in-the-treatment-and-21ap4awuc9.pdf

SGLT2 Inhibitors: A Novel Player in the Treatment and Prevention of Diabetic Cardiomyopathy

The extensive innervations of the heart include a complex network of sympathetic, parasympathetic, and sensory nerves connected in loops that serve to regulate cardiac output. Metabolic dysfunction in diabetes affects many different organ systems, including the cardiovascular system; it causes cardiac arrhythmias, silent myocardial ischemia, and sudden cardiac death, among others. These conditions are associated with damage to the nerves that innervate the heart, cardiac autonomic neuropathy (CAN), which is caused by various pathophysiological mechanisms. In this review, the main facts about the anatomy of cardiac innervations and the current knowledge of CAN, its pathophysiological mechanisms, and its diagnostic approach are discussed. In addition, anatomical evidence for CAN from human and animal studies has been summarized.

Cardiac innervations in diabetes mellitus-Anatomical evidence of neuropathy.

/pdf/significance-of-the-renin-angiotensin-system-in-clinical-2m8z6zw2k5.pdf

Significance of the Renin-Angiotensin System in Clinical Conditions

The present study investigated the possible cardioprotective effects of GLP1 and SGLT2i against diabetic cardiomyopathy (DCM) in type 2 diabetic rats and the possible underlying mechanisms. Methods: Thirty-two male Sprague Dawley rats were randomly subdivided into 4 equal groups: (a) control group, (b) DM group, type 2 diabetic rats with saline daily for 4 weeks, (c) DM + GLP1, as DM group with GLP1 analogue (liraglutide) at a dose of 75 µg/kg for 4 weeks, and (d) DM + SGLT2i as DM group with SGLT2 inhibitor (dapagliflozin) at a dose of 1 mg/kg for 4 weeks. By the end of treatment (4 weeks), serum blood glucose, homeostasis model assessment insulin resistance (HOMA-IR), insulin, and cardiac enzymes (LDH, CK-MB) were measured. Also, the cardiac histopathology, myocardial oxidative stress markers (malondialdehyde (MDA), glutathione (GSH) and CAT) and norepinephrine (NE), myocardial fibrosis, the expression of caspase-3, TGF-β, TNF-α, and tyrosine hydroxylase (TH) in myocardial tissues were measured. Results: T2DM caused significant increase in serum glucose, HOMA-IR, serum CK-MB, and LDH (p < 0.05). Also, DM caused significant myocardial damage and fibrosis; elevation of myocardial MDA; NE with upregulation of myocardial caspase-3, TNF-α, TGF-β, and TH; and significant decrease in serum insulin and myocardial GSH and CAT (p < 0.05). Administration of either GLP1 analog or SGLT2i caused a significant improvement in all studied parameters (p < 0.05). Conclusion: We concluded that both GLP1 and SGLT2i exhibited cardioprotective effects against DCM in T2DM, with the upper hand for SGLT2i. This might be due to attenuation of fibrosis, oxidative stress, apoptosis (caspase-3), sympathetic nerve activity, and inflammatory cytokines (TNF-α and TGF-β).

https://www.mdpi.com/2227-9059/8/3/43/pdf

Comparative Study of the Effects of GLP1 Analog and SGLT2 Inhibitor against Diabetic Cardiomyopathy in Type 2 Diabetic Rats: Possible Underlying Mechanisms.

Introduction: The mitochondria are important sources of reactive oxygen species (ROS) in the heart. Mitochondrial ROS production and subsequent oxidative damage have been implicated in the pathogenesis of diabetic cardiomyopathy. We hypothesized that therapeutic strategies specifically targeting mitochondrial ROS may have benefit in diabetic cardiomyopathy. Hypothesis: We hypothesized that therapeutic inhibition of mitochondrial ROS with mito-TEMPO reduces diabetic cardiomyopathy. Methods: The mitochondria-targeted antioxidant mito-TEMPO was administrated after diabetes onset in a mouse model of streptozotocin (STZ)-induced type-1 diabetes and type-2 diabetic db/db mice. Cardiac adverse changes were analyzed and myocardial function assessed. Cultured adult cardiomyocytes were stimulated with high glucose, and single mitochondrial superoxide generation and cell death were measured. Results: Incubation with high glucose increased mitochondria superoxide generation in cultured adult cardiomyocytes, which was prevented by mito-TEMPO. Co-incubation with mito-TEMPO also abrogated high glucose-induced cell death. Mitochondrial ROS generation, and intracellular ROS formation and oxidative damage were induced in both type-1 and type-2 diabetic mouse hearts. Daily injection of mito-TEMPO for 30 days inhibited mitochondrial ROS generation, prevented intracellular ROS formation and oxidative damage, decreased apoptosis and reduced myocardial hypertrophy in diabetic hearts without change of blood glucose, leading to improvement of myocardial function in both type-1 and type-2 diabetic mice. Mechanistic study revealed that the protective effects of mito-TMEPO were associated with down-regulation of ERK1/2 phosphorylation in diabetic hearts and high glucose-stimulated cardiomyocytes. Conclusions: Therapeutic inhibition of mitochondrial ROS by mitochondria-targeted antioxidant mito-TEMPO reduced adverse cardiac changes and mitigated myocardial dysfunction in both type-1 and type-2 diabetic mice. Thus, mitochondria-targeted antioxidants may be an effective therapy for diabetic cardiac complications.

Abstract 13631: Therapeutic Inhibition of Mitochondrial Reactive Oxygen Species With Mito-tempo Reduces Diabetic Cardiomyopathy

Objective The present study was designed to investigate the effects of renin angiotensin system (RAS) blockade on cardiac arrhythmias and sympathetic nerve remodelling in heart tissues of type 2 diabetic rats. Methods Thirty-two male Sprague Dawley rats were randomly allocated into 4 equal groups; a) normal control group: normal rats, b) DM group; after type 2 diabetes induction, rats received 2ml oral saline daily for 4 weeks, c) DM+ ACEi: after type 2 diabetes induction, rats were treated with enalapril (10 mg/kg, orally for 4 weeks) and d) DM+ ARBs: after type 2 diabetes induction, rats were treated with losartan (30 mg/kg, orally for 4 weeks). Results In type 2 diabetic rats, the results demonstrated significant prolongation in Q-T interval and elevation of blood sugar, HOMA-IR index, TC, TGs, LDL, serum CK-MB, myocardial damage, myocardial MDA, myocardial norepinephrine and tyrosine hydroxylase (TH) density with significant reduction in serum HDL, serum insulin and myocardial GSH and CAT. On the other hand, blockade of RAS at the level of either ACE by enalapril or angiotensin (Ag) receptors by losartan resulted in significant improvement in ECG parameters (Q-T), cardiac enzymes (CK-MB), cardiac morphology, myocardial oxidative stress (low MDA, high CAT and GSH) and myocardial TH density. Conclusion RAS plays a role in the cardiac sympathetic nerve sprouting and cardiac arrhythmias induced by type 2 DM and its blockade might have a cardioprotective effect via attenuation of sympathetic nerve fibres remodelling, myocardial norepinephrine contents and oxidative stress.

Blockade of Renin Angiotensin System Ameliorates the Cardiac Arrhythmias and Sympathetic Neural Remodeling in Hearts of Type 2 DM Rat Model.

Probiotics (PR) and intermittent fasting (IF) are believed to alleviate dysbiosis, which contributes to Non-alcoholic fatty liver disease (NAFLD) pathogenesis. Our study investigated the effect of PR, IF, and their combination (IP) on fatty liver in a rat model induced by a high-fat diet (HFD) We used 40 male rats, which were randomly assigned to one of five groups: control (fed standard chow), HFD (fed HFD for 12 weeks), PR (HFD for 12 weeks + probiotics (a daily dose of 10 × 109 CFU orally in the last 4 weeks), IF (HFD for 12 weeks + alternate day fasting (ADF) in the last 4 weeks), and IP (HFD for 12 weeks + probiotics (a daily dose of 10 × 109 CFU orally) + ADF in the last 4 weeks). Serum liver enzymes, lipids, and the HOMA-IR score were considerably lower in the IF and IP groups than in the HFD group. These changes were reflected in the pathological view. PR, IF, and IP noticeably upregulated serum FGF19, serum and hepatic FGF21, and reduced Lipopolysaccharides (LPS) and flavin containing dimethylaniline monoxygenase 3 (FMO3), indicating improvement in gut dysbiosis suggestive a hepatoprotective impact of IF and PR on NAFLD via modulating. 

https://www.tandfonline.com/doi/pdf/10.1080/2314808X.2023.2229107?needAccess=true&role=button

Intermittent fasting and probiotics in non-alcoholic fatty liver in rats: interplay between FGF19 and FGF21

Perioperative complications of the right multiport thoracoscopic thymectomy in patients with myasthenia gravis, safeguards, and pitfalls

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Blockade of Renin Angiotensin System Ameliorates the Cardiac Arrhythmias and Sympathetic Neural Remodeling in Hearts of Type 2 DM Rat Model.

Intermittent fasting and probiotics in non-alcoholic fatty liver in rats: interplay between FGF19 and FGF21

Perioperative complications of the right multiport thoracoscopic thymectomy in patients with myasthenia gravis, safeguards, and pitfalls