Cardiac Function In Type Research Articles

Genetic deletion or pharmacologic inhibition of histone deacetylase 6 protects the heart against ischaemia/reperfusion injury by limiting tumour necrosis factor alpha-induced mitochondrial injury in experimental diabetes.

The histone deacetylase 6 (HDAC6) inhibitor, tubastatin A (TubA), reduces myocardial ischaemia/reperfusion injury (MIRI) in type 1 diabetic rats. It remains unclear whether HDAC6 regulates MIRI in type 2 diabetic animals. Diabetes augments the activity of HDAC6 and the generation of tumour necrosis factor alpha (TNF-α) and impairs mitochondrial complex I (mCI). Here, we examined how HDAC6 regulates TNF-α production, mCI activity, mitochondria, and cardiac function in type 1 and type 2 diabetic mice undergoing MIRI. HDAC6 knockout, streptozotocin-induced type 1 diabetic, and obese type 2 diabetic db/db mice underwent MIRI in vivo or ex vivo in a Langendorff-perfused system. We found that MIRI and diabetes additively augmented myocardial HDAC6 activity and generation of TNF-α, along with cardiac mitochondrial fission, low bioactivity of mCI, and low production of adenosine triphosphate. Importantly, genetic disruption of HDAC6 or TubA decreased TNF-α levels, mitochondrial fission, and myocardial mitochondrial nicotinamide adenine dinucleotide levels in ischaemic/reperfused diabetic mice, concomitant with augmented mCI activity, decreased infarct size, and improved cardiac function. Moreover, HDAC6 knockout or TubA treatment decreased left ventricular dilation and improved cardiac systolic function 28 days after MIRI. H9c2 cardiomyocytes with and without HDAC6 knockdown were subjected to hypoxia/reoxygenation injury in the presence of high glucose. Hypoxia/reoxygenation augmented HDAC6 activity and TNF-α levels and decreased mCI activity. These negative effects were blocked by HDAC6 knockdown. HDAC6 is an essential negative regulator of MIRI in diabetes. Genetic deletion or pharmacologic inhibition of HDAC6 protects the heart from MIRI by limiting TNF-α-induced mitochondrial injury in experimental diabetes.

MCT4-dependent lactate transport: a novel mechanism for cardiac energy metabolism injury and inflammation in type 2 diabetes mellitus

Diabetic cardiomyopathy (DCM) is a major contributor to mortality in diabetic patients, characterized by a multifaceted pathogenesis and limited therapeutic options. While lactate, a byproduct of glycolysis, is known to be significantly elevated in type 2 diabetes, its specific role in DCM remains uncertain. This study reveals an abnormal upregulation of monocarboxylate transporter 4 (MCT4) on the plasma membrane of cardiomyocytes in type 2 diabetes, leading to excessive lactate efflux from these cells. The disruption in lactate transport homeostasis perturbs the intracellular lactate-pyruvate balance in cardiomyocytes, resulting in oxidative stress and inflammatory responses that exacerbate myocardial damage. Additionally, our findings suggest increased lactate efflux augments histone H4K12 lactylation in macrophages, facilitating inflammatory infiltration within the microenvironment. In vivo experiments have demonstrated that inhibiting MCT4 effectively alleviates myocardial oxidative stress and pathological damage, reduces inflammatory macrophage infiltration, and enhances cardiac function in type 2 diabetic mice. Furthermore, a clinical prediction model has been established, demonstrating a notable association between peripheral blood lactate levels and diastolic dysfunction in individuals with type 2 diabetes. This underscores the potential of lactate as a prognostic biomarker for DCM. Ultimately, our findings highlight the pivotal involvement of MCT4 in the dysregulation of cardiac energy metabolism and macrophage-mediated inflammation in type 2 diabetes. These insights offer novel perspectives on the pathogenesis of DCM and pave the way for the development of targeted therapeutic strategies against this debilitating condition.

Irisin deficiency exacerbates diet-induced insulin resistance and cardiac dysfunction in type II diabetes in mice.

Irisin is involved in the regulation of a variety of physiological conditions, metabolism, and survival. We and others have demonstrated that irisin contributes critically to modulation of insulin resistance and the improvement of cardiac function. However, whether the deletion of irisin will regulate cardiac function and insulin sensitivity in type II diabetes remains unclear. We utilized the CRISPR/Cas-9 genome-editing system to delete irisin globally in mice and high-fat diet (HFD)-induced type II diabetes model. We found that irisin deficiency did not result in developmental abnormality during the adult stage, which illustrates normal cardiac function and insulin sensitivity assessed by glucose tolerance test in the absence of stress. The ultrastructural analysis of the transmission electronic microscope (TEM) indicated that deletion of irisin did not change the morphology of mitochondria in myocardium. Gene expression profiling showed that several key signaling pathways related to integrin signaling, extracellular matrix, and insulin-like growth factors signaling were coordinately downregulated by deletion of irisin. However, when mice were fed a high-fat diet and chow food for 16 wk, ablation of irisin in mice exposed to HFD resulted in much more severe insulin resistance, metabolic derangements, profound cardiac dysfunction, and hypertrophic response and remodeling as compared with wild-type control mice. Taken together, our results indicate that the loss of irisin exacerbates insulin resistance, metabolic disorders, and cardiac dysfunction in response to HFD and promotes myocardial remodeling and hypertrophic response. This evidence reveals the molecular evidence and the critical role of irisin in modulating insulin resistance and cardiac function in type II diabetes.NEW & NOTEWORTHY By utilizing the CRISPR/Cas-9 genome-editing system and high-fat diet (HFD)-induced type II diabetes model, our results provide direct evidence showing that the loss of irisin exacerbates cardiac dysfunction and insulin resistance while promoting myocardial remodeling and a hypertrophic response in HFD-induced diabetes. This study provides new insight into understanding the molecular evidence and the critical role of irisin in modulating insulin resistance and cardiac function in type II diabetes.

Shexiang Tongxin Dropping Pills improve cardiac function in type 2 diabetic rats by promoting angiogenesis

This study aims to investigate the effect of Shexiang Tongxin Dropping Pills(STDP) on angiogenesis in type 2 diabetic rats. Thirty-two healthy male SD rats were randomized into a control group(n=6) and a type 2 diabetes mellitus(T2 D) group(n=26). The T2 DM rat model was established with a high-fat diet combined with intraperitoneal injection of streptozotocin(STZ). The model rats were randomized into a model group, a metformin group(200 mg·kg~(-1)·d~(-1)), a high-dose STDP group(40 mg·kg~(-1)·d~(-1)), and a low-dose STDP group(20 mg·kg~(-1)·d~(-1)). The corresponding agents were administered continuously for 8 weeks. The cardiac function indexes were detected by ultrasound at the experiment endpoint, and the myocardial pathological changes were observed via hematoxylin-eosin(HE) staining. The myocardial collagen fiber deposition was detected by sirius red staining, the myocardial microvascular density by immunohistochemistry, and the myocardial hypertrophy by immunofluorescence assay. Western blot was employed to measure the protein levels of vascular endothelial growth factor(VEGF), phosphorylated vascular endothelial growth factor receptor 2(p-VEGFR2), angiogenin-1(Ang1), and TEK tyrosine kinase endothelial(Tie2) in the myocardial tissue. Compared with the model group, STDP improved the left ventricular ejection fraction(EF) and fractional shortening(FS)(P<0.05), alleivated the arrangement disorder of myocardial cells and local myocardial fiber rupture. Sirius red staining showed that STDP, especially the high-dose group(P<0.01), repaired the deposition of myocardial collagen fibers in the model group. The results of immunohistochemistry showed that the cluster of differentiation 31(CD31) expression in myocardial tissue of the STDP groups was higher than that of the model group(P<0.01). The immunofluorescence results showed that STDP mitigated the hypertrophy of myocardial cells(P<0.01). Furthermore, STDP up-regulated the protein levels of VEGF, p-VEGFR2, Angl, and Tie2 compared with the model group(P<0.01). In conclusion, STDP can effectively promote angiogenesis and improve cardiac function in type 2 diabetic rats by up-regulating the expression of VEGF, p-VEGFR2, Ang1, and Tie2.

876-P: Empagliflozin-Induced Metabolic Changes and Cardiac Function in Patients with Type 2 Diabetes: A Randomized Crossover MRI Study with Insulin as Comparator

Introduction: Empagliflozin reduces cardiovascular risk in type 2 diabetes, possibly through improved cardiac function associated with metabolic changes including lowered glucose and insulin concentrations and elevated free fatty acids (FFA) . We aimed to evaluate the influence of these metabolic changes on cardiac function in type 2 diabetes (T2D) . Materials and Method: 17 subjects (13 males) with T2D, aged 58±3 years (mean±sem) , BMI 32.9±0.9 kg/m2, HbA1c 52.4±2.4 mmol/L, TD2 duration of 8.9±1.3 years were treated with empagliflozin (E) and NPH-insulin (I) for 5 weeks in a cross-over design with 3 weeks of washout between treatments. Insulin was titrated to produce similar glycemic control as during empagliflozin. Patients were studied before and at the end of each treatment period. Metabolic changes were evaluated with fasting glucose, FFAs and insulin concentrations, cardiac function with cardiac MRI during rest and chronotropic stress on two separate days without and with acute lowering of FFAs with acipimox. Cardiac endpoints were changes in left ventricular peak filling rate (∆LVPFR) and left ventricular ejection fraction (∆LVEF) . Results: Fasting glucose was reduced from 8.7±0.5 mM during washouts to 7.6±0.3 mM on both treatments, while serum insulin was lower (E: 103±14 pM; I: 141±16 pM, p<0.01) and FFAs higher (E: 0.60±0.03 mM; I: 0.50±0.mM, p=0.02) on empagliflozin compared with insulin treatment. Cardiac function did not differ between treatments in rest or during stress (rest: ∆LVPFR E: -2±19;I: -11±20 ml/s, p=1.0; ∆LVEF -1 ±1, -1±1%, p=0.8; stress: ∆LVPFR E:-32±20, I: -14±24 ml/s; ∆LVEF E: 1±2, I: 0±2%) . Acipimox reduced FFAs by ∼35% at all visits but did not reveal any cardiac effects of treatments. Conclusion: Neither empagliflozin nor insulin treatment change cardiac function in patients with T2D. Treatment specific metabolic effects play no role for cardiac function under the studied conditions. Disclosure R.Thirumathyam: None. J.Goetze: Consultant; Novo Nordisk A/S. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. N.Vejlstrup: None. S.Madsbad: None. P.L.Madsen: None. N.B.Jørgensen: Advisory Panel; Novo Nordisk A/S, Research Support; Boehringer Ingelheim International GmbH, Speaker's Bureau; Novo Nordisk A/S, Stock/Shareholder; Eli Lilly and Company, Novo Nordisk A/S. Funding Boehringer Ingelheim Gmbh. Investigator initiated study grant.

Ketone Ester D-β-Hydroxybutyrate-(R)-1,3 Butanediol Prevents Decline in Cardiac Function in Type 2 Diabetic Mice.

BackgroundHeart failure is responsible for approximately 65% of deaths in patients with type 2 diabetes mellitus. However, existing therapeutics for type 2 diabetes mellitus have limited success on the prevention of diabetic cardiomyopathy. The aim of this study was to determine whether moderate elevation in D‐β‐hydroxybutyrate improves cardiac function in animals with type 2 diabetes mellitus.Methods and ResultsType 2 diabetic (db/db) and their corresponding wild‐type mice were fed a control diet or a diet where carbohydrates were equicalorically replaced by D‐β‐hydroxybutyrate‐(R)‐1,3 butanediol monoester (ketone ester [KE]). After 4 weeks, echocardiography demonstrated that a KE diet improved systolic and diastolic function in db/db mice. A KE diet increased expression of mitochondrial succinyl‐CoA:3‐oxoacid‐CoA transferase and restored decreased expression of mitochondrial β‐hydroxybutyrate dehydrogenase, key enzymes in cardiac ketone metabolism. A KE diet significantly enhanced both basal and ADP‐mediated oxygen consumption in cardiac mitochondria from both wild‐type and db/db animals; however, it did not result in the increased mitochondrial respiratory control ratio. Additionally, db/db mice on a KE diet had increased resistance to oxidative and redox stress, with evidence of restoration of decreased expression of thioredoxin and glutathione peroxidase 4 and less permeability transition pore activity in mitochondria. Mitochondrial biogenesis, quality control, and elimination of dysfunctional mitochondria via mitophagy were significantly increased in cardiomyocytes from db/db mice on a KE diet. The increase in mitophagy was correlated with restoration of mitofusin 2 expression, which contributed to improved coupling between cytosolic E3 ubiquitin ligase translocation into mitochondria and microtubule‐associated protein 1 light chain 3–mediated autophagosome formation.ConclusionsModerate elevation in circulating D‐β‐hydroxybutyrate levels via KE supplementation enhances mitochondrial biogenesis, quality control, and oxygen consumption and increases resistance to oxidative/redox stress and mPTP opening, thus resulting in improvement of cardiac function in animals with type 2 diabetes mellitus.

Differential Regulation of mTOR Complexes with miR-302a Attenuates Myocardial Reperfusion Injury in Diabetes.

SummaryPersistent activation of mTOR (mammalian target of rapamycin) in diabetes increases the vulnerability of the heart to ischemia/reperfusion (I/R) injury. We show here that infusion of rapamycin (mTOR inhibitor) at reperfusion following ischemia reduced myocardial infarct size and apoptosis with restoration of cardiac function in type 1 diabetic rabbits. Likewise, treatment with rapamycin protected hyperglycemic human-pluripotent-stem-cells-derived cardiomyocytes (HG-hiPSC-CMs) following simulated ischemia (SI) and reoxygenation (RO). Phosphorylation of S6 (mTORC1 marker) was increased, whereas AKT phosphorylation (mTORC2 marker) and microRNA-302a were reduced with concomitant increase of its target, PTEN, following I/R injury in diabetic heart and HG-hiPSC-CMs. Rapamycin inhibited mTORC1 and PTEN, but augmented mTORC2 with restoration of miRNA-302a under diabetic conditions. Inhibition of miRNA-302a blocked mTORC2 and abolished rapamycin-induced protection against SI/RO injury in HG-hiPSC-CMs. We conclude that rapamycin attenuates reperfusion injury in diabetic heart through inhibition of PTEN and mTORC1 with restoration of miR-302a-mTORC2 signaling.

Impact of glucagon like peptide-1 receptor agonist and sodium glucose cotransporter 2 inhibitors on type 2 diabetes patients with renal impairment.

Introduction:Diabetes mellitus is a progressive disease with cardiovascular complications. We evaluated the impact of a glucagon like peptide-1 (GLP-1) receptor agonist and sodium glucose cotransporter 2 (SGLT-2) inhibitors dapagliflozin and empagliflozin on renal and cardiac function in type 2 diabetes patients with renal impairment.Materials and methods:A total of 156 patients referred with suboptimal glycemic control were assigned to Group G (GLP-1): n = 72 or Group S (SGLT-2 inhibitor)—dapagliflozin (n = 52) or empagliflozin (n = 32). Renal function was assessed every 3 months for 36 months. Cardiovascular parameters were evaluated every 12 months for 36 months.Results:Compared with baseline, HbA1c and systolic blood pressure significantly decreased in both groups (p < 0.05). The estimated glomerular filtration rate decreased, but without significance. Albuminuria decreased significantly in both groups and then subsequently increased after 30 months in Group S. Diastolic cardiac function, assessed by E/e′ or left atrial volume index, decreased only in Group G at 36 months.Conclusions:The GLP-1 receptor agonist and SGLT-2 inhibitors were effective for glycemic and blood pressure control and for maintaining renal function. The GLP-1 receptor agonist improved diastolic function at 36 months.

Diastolic and systolic function of diabetic cardiomyopathy are affected by diffuse myocardial fibrosis: a cardiac MRI study

Abstract Background Increased myocardial extracellular volume (ECV) likely is suggested to be of importance for cardiac function in type 2 diabetes (T2DM). Purpose We analysed the effect of increasing ECV on cardiac myocardial structure and function and association to typical complications related to diabetes Methods 296 patients (pt.) with T2DM and 25 controls were recruited. Cardiac magnetic resonance scan with adenosine stress and gadolinium was performed. Left ventricle (LV) diastolic function was evaluated by echo Doppler. Results 246 pt. scan and all control scans were available for analysis. ECV was significantly different between pts. and controls (29.5±3.3 vs 26.1±1.5, P&amp;lt;0.001). Pts. were grouped in ECV percentiles: ≤25, 25–75, and ≥75. Pts. with ECV in the highest percentile had lowered LV ejection fraction (LVEF) and increased LV end-diastolic (EDV) and end-systolic (ESV) volumes, and left atrial (LA) maximal volume. No difference was found on LV mass. With increasing ECV a lowered LV myocardial perfusion index (MPRI) and an increased prevalence of albuminuria, retinopathy, and autonomic neuropathy was found. Of interest, with increasing ECV lateral as well as septal e' were lowered and the E/e' increased. Conclusions In combination with lowered myocardial perfusion but independently of myocardial hypertrophy, myocardial interstitial diffuse fibrosis is related to the diastolic dysfunction of diabetic cardiomyopathy. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): NSR hospital, Denmark and the Danish Heart Foundation

CD133+Exosome Treatment Improves Cardiac Function after Stroke in Type 2 Diabetic Mice.

Cardiac complications post-stroke are common, and diabetes exacerbates post-stroke cardiac injury. In this study, we tested whether treatment with exosomes harvested from human umbilical cord blood derived CD133+ cells (CD133+Exo) improves cardiac function in type 2 diabetes mellitus (T2DM) stroke mice. Adult (3-4m), male, BKS.Cg-m+/+Leprdb/J (db/db, T2DM) and non-DM (db+) mice were randomized to sham or photothrombotic stroke groups. T2DM-stroke mice were treated with phosphate-buffered saline (PBS) or CD133+Exo (20μg, i.v.) at 3days after stroke. T2DM sham and T2DM+CD133+Exo treatment groups were included as controls. Echocardiography was performed, and mice were sacrificed at 28days after stroke. Cardiomyocyte hypertrophy, myocardial capillary density, interstitial fibrosis, and inflammatory factor expression were measured in the heart. MicroRNA-126 expression and its target gene expression were measured in the heart. T2DM mice exhibit significant cardiac deficits such as decreased left ventricular ejection fraction (LVEF) and shortening fraction (LVSF), increased left ventricular diastolic dimension (LVDD), and reduced heart rate compared to non-DM mice. Stroke in non-DM and T2DM mice significantly decreases LVEF compared to non-DM and T2DM-sham, respectively. Cardiac dysfunction is worse in T2DM-stroke mice compared to non-DM-stroke mice. CD133+Exo treatment of T2DM-stroke mice significantly improves cardiac function identified by increased LVEF and decreased LVDD compared to PBS treated T2DM-stroke mice. In addition, CD133+Exo treatment significantly decreases body weight and blood glucose but does not decrease lesion volume in T2DM-stroke mice. CD133+Exo treatment of T2DM mice significantly decreases body weight and blood glucose but does not improve cardiac function. CD133+Exo treatment in T2DM-stroke mice significantly decreases myocardial cross-sectional area, interstitial fibrosis, transforming growth factor beta (TGF-β), numbers of M1 macrophages, and oxidative stress markers 4-HNE (4-hydroxynonenal) and NADPH oxidase 2 (NOX2) in heart tissue. CD133+Exo treatment increases myocardial capillary density in T2DM-stroke mice as well as upregulates endothelial cell capillary tube formation in vitro. MiR-126 is highly expressed in CD133+Exo compared to exosomes derived from endothelial cells. Compared to PBS treatment, CD133+Exo treatment significantly increases miR-126 expression in the heart and decreases its target gene expression such as Sprouty-related, EVH1 domain-containing protein 1 (Spred-1), vascular cell adhesion protein (VCAM), and monocyte chemoattractant protein 1 (MCP1) in the heart of T2DM-stroke mice. CD133+Exo treatment significantly improves cardiac function in T2DM-stroke mice. The cardio-protective effects of CD133+Exo in T2DM-stroke mice may be attributed at least in part to increasing miR-126 expression and decreasing its target protein expression in the heart, increased myocardial capillary density and decreased cardiac inflammatory factor expression.

Carvedilol and metoprolol are both able to preserve myocardial function in type 2 diabetes.

PurposeIncreasing cohorts of patients present with diabetic cardiomyopathy, and with no targeted options, treatment often rely on generic pharmaceuticals such as β‐blockers. β‐blocker efficacy is heterogenous, with second generation β‐blocker metoprolol selectively inhibiting β1‐AR, while third generation β‐blocker carvedilol has α1‐AR inhibition, antioxidant, and anti‐apoptotic actions alongside nonselective β‐AR inhibition. These additional properties have led to the hypothesis that carvedilol may improve cardiac contractility in the diabetic heart to a greater extent than metoprolol. The present study aimed to compare the efficacy of metoprolol and carvedilol on myocardial function in animal models and cardiac tissue from patients with type 2 diabetes and preserved ejection fraction.MethodsEchocardiographic examination of cardiac function and assessment of myocardial function in isolated trabeculae was carried out in patients with and without diabetes undergoing coronary artery bypass grafting (CABG) who were prescribed metoprolol or carvedilol. Equivalent measures were undertaken in Zucker Diabetic Fatty (ZDF) rats following 4 weeks treatment with metoprolol or carvedilol.ResultsPatients receiving carvedilol compared to metoprolol had no difference in cardiac function, and no difference was apparent in myocardial function between β‐blockers. Both β‐blockers similarly improved myocardial function in diabetic ZDF rats treated for 4 weeks, without significantly affecting in vivo cardiac function.ConclusionsMetoprolol and carvedilol were found to have no effect on cardiac function in type 2 diabetes with preserved ejection fraction, and were similarly effective in preventing myocardial dysfunction in ZDF rats.

P196 Effect of tofogliflozin on systolic and diastolic cardiac function in type 2 diabetic patients

Abstract Funding Acknowledgements None Background Recent studies have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors have a favorable effect on cardiovascular events in diabetic patients. However, the underlying mechanism associated with favorable outcome has not been clearly identified. Purpose The purpose of this study was to investigate the effect of tofogliflozin, SGLT2 inhibitor, on systolic and diastolic cardiac function in patients with type 2 diabetes mellitus (T2DM). Methods We enrolled 26 consecutive T2DM out-patients on glucose-lowering drugs who initiated tofogliflozin and underwent echocardiogram before and ≥ 6 months after tofogliflozin administration. During this period, we also enrolled 162 T2DM out-patients taking other glucose-lowering drugs as a control group. Propensity score analysis was performed to match the patient characteristics. As a result, 40 patients (tofogliflozin group: 20 patients and control group: 20 patients) were finally used for analysis. Left ventricular systolic function was assessed by measuring 2D-echocardiographic left ventricular ejection fraction (LVEF) and diastolic cardiac function by pulsed wave Doppler derived early diastolic velocity (E/e’). Results There were no significant differences in patient characteristics and echocardiographic parameters at baseline. Follow-up E/e’ was significantly improved in tofogliflozin compared to control (11.7 ± 3.5 vs. 14.4 ± 4.5, p = 0.037). Moreover, the change in LVEF from baseline to follow up was 5.8± 7.2% in tofogliflozin group and 1.2 ± 6.9% in control group; difference significant: p = 0.047. Conclusions In addition to conventional oral glucose-lowering drugs, additional tofogliflozin administration had a favorable effect on left ventricular systolic and diastolic function in patients with T2DM.

Inhibition of Hypothalamic Inhibitor κB Kinase β/Nuclear Transcription Factor κB Pathway Attenuates Metabolism and Cardiac Dysfunction in Type 2 Diabetic Rats

Background: Inflammation and oxidative stress play important roles in energy imbalance and its complications. Recent research indicates that hypothalamic inflammation may contribute to the pathogenesis of metabolic syndrome and cardiac dysfunction, but the mechanisms remain unclear. We hypothesized that suppression of the proinflammatory IKKβ/NF-κB pathway in the hypothalamus can improve energy balance and cardiac function in type 2 diabetic (T2D) rats. Methods: Normal and T2D rats received bilateral hypothalamic arcuate nucleus (ARC) infusions of the IKKβ inhibitor SC-514 or vehicle via osmotic minipump. Metabolic phenotyping, immunohistochemical analyses, and biochemical analyses were used to investigate the outcomes of inhibition of the hypothalamic IKKβ. Echocardiography and glucometer were used for measuring cardiac function and blood glucose, respectively. Blood samples were collected for the evaluation of circulating proinflammatory cytokines. Heart was harvested for cardiac morphology evaluations. The ARC was harvested and analyzed for IKKβ, NF-κB, proinflammatory cytokines, reactive oxygen species (ROS), and NAD(P)H (gp91^phox, p47^phox) oxidase activity levels and neuropeptides. Results: Compared with normal rats, T2D rats were characterized by hyperglycemia, hyperinsulinemia, glucose intolerance, cardiac dysfunction, as well as higher ARC levels of IKKβ, NF-κB, proinflammatory cytokines, ROS, gp91^phox, and p47^phox. ARC infusion of the IKKβ inhibitor SC-514 attenuated all these changes in T2D rats, but not in normal rats. Conclusions: Our results indicate that the hypothalamic IKKβ/NF-κB pathway plays a key role in modulating energy imbalance and cardiac dysfunction, suggesting its potential therapeutic role during type 2 diabetes mellitus.

Changes of myocardial function in diabetic rats and its mechanism

To investigate the role of calcium-sensing receptor (CaSR) in the decrease of cardiac function in type 2 diabetic rats. Wistar rats were randomly divided into 3 groups including control, diabetic-4 week and diabetic-8 week groups. Rats in the diabetes group were fed with high-glucose and high-fat diet, and intraperitoneal injection of streptozocin (STZ,30 mg/kg) was conducted 4 weeks later to establish a type 2 diabetes model. Cardiac morphological changes were observed by HE staining, cardiac function was detected by echocardiography, and CaSR and PKC-αprotein expressions in cardiac tissue were detected by Western blot. Compared with the control group, the myocardium of diabetic rats showed irregular contraction zone, decreased expression of CaSR protein, increased expression of PKC-α protein, decreased systolic and diastolic functions, and gradually worsened with the prolongation of the course of the disease. Hyperglycemia inhibits the expression of CaSR protein in myocardium of diabetic rats by activating PKC-α, which can cause intracellular calcium disorder and lead to decreased cardiac function.

Effect of Tofogliflozin on Systolic and Diastolic Cardiac Function in Type 2 Diabetic Patients.

Recent studies have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors have a favorable effect on cardiovascular events in diabetic patients. However, the underlying mechanism associated with a favorable outcome has not been clearly identified. The purpose of this study was to investigate the effect of tofogliflozin, SGLT2 inhibitor, on systolic and diastolic cardiac function in patients with type 2 diabetes mellitus (T2DM). We enrolled 26 consecutive T2DM out-patients on glucose-lowering drugs who initiated tofogliflozin and underwent echocardiography before and ≥ 6months after tofogliflozin administration. During this period, we also enrolled 162 T2DM out-patients taking other glucose-lowering drugs as a control group. Propensity score analysis was performed to match the patient characteristics. As a result, 42 patients (tofogliflozin group 21 patients and control group 21 patients) were finally used for analysis. Left ventricular systolic function was assessed by measuring 2D-echocardiographic left ventricular ejection fraction (LVEF) and diastolic cardiac function by pulsed wave Doppler-derived early diastolic velocity (E/e'). There were no significant differences in patient characteristics and echocardiographic parameters at baseline. The change in LVEF from baseline to follow-up was 5.0 ± 6.9% in the tofogliflozin group and - 0.6 ± 5.5% in the control group; difference significant, p = 0.006. The change in E/e' was - 1.7 ± 3.4 in the tofogliflozin group and 0.7 ± 4.1 in the control group; difference significant, p = 0.024. In addition to conventional oral glucose-lowering drugs, additional tofogliflozin administration had a favorable effect on left ventricular systolic and diastolic function in patients with T2DM.

Phosphodiesterase 5 Associates With β2 Adrenergic Receptor to Modulate Cardiac Function in Type 2 Diabetic Hearts.

BackgroundIn murine heart failure models and in humans with diabetic‐related heart hypertrophy, inhibition of phosphodiesterase 5 (PDE5) by sildenafil improves cardiac outcomes. However, the mechanism by which sildenafil improves cardiac function is unclear. We have observed a relationship between PDE5 and β2 adrenergic receptor (β2AR), which is characterized here as a novel mechanistic axis by which sildenafil improves symptoms of diabetic cardiomyopathy.Methods and ResultsWild‐type and β2AR knockout mice fed a high fat diet (HFD) were treated with sildenafil, and echocardiogram analysis was performed. Cardiomyocytes were isolated for excitation‐contraction (E‐C) coupling, fluorescence resonant energy transfer, and proximity ligation assays; while heart tissues were implemented for biochemical and histological analyses. PDE5 selectively associates with β2AR, but not β1 adrenergic receptor, and inhibition of PDE5 with sildenafil restores the impaired response to adrenergic stimulation in HFD mice and isolated ventriculomyocytes. Sildenafil enhances β adrenergic receptor (βAR)‐stimulated cGMP and cAMP signals in HFD myocytes. Consequently, inhibition of PDE5 leads to protein kinase G–, and to a lesser extent, calcium/calmodulin‐dependent kinase II–dependent improvements in adrenergically stimulated E‐C coupling. Deletion of β2AR abolishes sildenafil's effect. Although the PDE5‐β2AR association is not altered in HFD, phosphodiesterase 3 displays an increased association with the β2AR‐PDE5 complex in HFD myocytes.ConclusionsThis study elucidates mechanisms by which the β2AR‐PDE5 axis can be targeted for treating diabetic cardiomyopathy. Inhibition of PDE5 enhances β2AR stimulation of cGMP and cAMP signals, as well as protein kinase G–dependent E‐C coupling in HFD myocytes.

Abstract 16593: Deficiency of Myocardial miR-17-92 Cluster Exacerbates Ischemic Injury and Abrogates Rapamycin-Induced Protection in Diabetic Mice

Background: Chronic treatment with rapamycin (RAPA, an mTOR inhibitor) improves cardiac function in type 2 diabetic (T2D) mice through attenuation of oxidative stress and alteration of antioxidants and contractile protein expression. The miR-17-92 cluster is indispensable for the cardiac development; its deletion leads to neonatal lethality due to severe anomalies of the cardiovascular system. Following microRNA array analysis, we identified that miR-17 and miR-20a were significantly up-regulated in diabetic hearts with RAPA treatment. We therefore investigated their role in RAPA-induced protection in diabetic mice following ischemia/reperfusion (I/R) injury. Methods and Results: Adult male db/db T2D mice were treated daily with RAPA (0.25 mg/kg, i.p.) for 28 days. RAPA significantly reduced myocardial infarct size following global I (30 min) and R (60 min) in Langendorff mode ( Fig. A ). Real-time PCR showed that miR-17 and -20a, part of miR-17-92 cluster, were induced in hearts from RAPA-treated db/db mice ( Fig.B ). To further elucidate their role in RAPA-induced protection in diabetes, wild type (WT:MCM:NTG:miR-17-92 flox/flox ) and cardiac-specific miR-17-92-deficient (miR-17-92-def:MCM:TG:miR-17-92 flox/flox ) mice were fed with high-fat-diet (HFD) for 16 weeks. HFD-fed mice exhibited impaired glucose tolerance ( Fig. C ). Treatment with RAPA improved blood glucose level, cardiac function and reduced infarct size following I/R in diabetic WT mice, which were abolished in diabetic tamoxifen-inducible miR-17-92-deficient mice ( Fig. D, E, F ). In addition, miR-17-92-deficient mice had larger infarct size after I/R compared to WT controls (Fig F) . Conclusion: Cardiac miR-17-92 plays a critical role in RAPA-induced protection against I/R injury in diabetic mice. Future studies are required to identify downstream targets of miR-17-92 responsible for cardioprotection.

Liraglutide relieves cardiac dilated function than DPP-4 inhibitors.

IntroductionDiabetes mellitus is a progressive disease with cardiovascular complications. This study evaluated the effects of liraglutide, a glucagon‐like peptide‐1 analogue and the dipeptidyl peptidase 4 inhibitors sitagliptin and linagliptin on cardiac function in type 2 diabetes patients with renal impairment.Materials and MethodsA total of 139 patients who were referred because of suboptimal glycaemic control were randomly assigned to liraglutide 0.9 mg/d (n = 45), sitagliptin 50 mg/d, (n = 49) or linagliptin 5 mg/d (n = 45) at enrolment and were evaluated. Blood glucose, glycosylated haemoglobin and serum creatinine were assayed every 3 months for 48 months. Echocardiography was performed every 12 months for 48 months.ResultsCompared with baseline, fasting glucose, postprandial glucose, and systolic and diastolic pressure, but not estimated glomerular filtration rate, significantly decreased in all three groups. Albuminuria decreased from 24 to 48 months with liraglutide, but only from 24 to 30 months with sitagliptin and linagliptin. Diastolic function, assessed by E/e′ or left atrial dimension improved only with liraglutide.ConclusionsLiraglutide was effective for glucose and blood pressure control, reduced albuminuria and improved diastolic function. Diastolic function was not improved by sitagliptin and linagliptin.

Randomised Placebo Controlled Trial to Assess the Effect of Liraglutide on Cardiac Function in Type 2 Diabetes Mellitus Patients

Background: Diabetic cardiomyopathy is hallmarked by impaired left ventricular relaxation and increased left ventricular filling pressure (E/Ea). Liraglutide is an antidiabetic agent with cardioprotective effect. The aim of this study was to test liraglutide's efficacy to improve diabetic cardiomyopathy in diabetes mellitus type 2 (DM2) patients. Methods: A 26 week double-blind, placebo-controlled trial was performed. DM2 patients without prior cardiovascular disease were randomly assigned to liraglutide 1.8mg (LIRA) or placebo (PLB) added to standard care. Primary outcome measures were LV diastolic and systolic function assessed with MRI. Diastolic function indices were: early (E) and late (A) transmitral peak flow rate, E/A ratio, early decelaration peak (Edec), peak mitral annular septal velocity (Ea) and E/Ea. Systolic function indices were: stroke volume (SV), ejection fraction (EF), cardiac output (CO), cardiac index (CI) and peak ejection rate (PER). Intention-to-treat analysis of between group differences was performed using ANCOVA. Mean estimated treatment differences (95% confidence intervals) are reported. Findings: 23 patients were randomised to LIRA and 26 to PLB. As compared with PLB, LIRA significantly reduced E (-56 ml/s (-91 to -21)), E/A ratio (-0·17 (-0·27 to -0·06)), Edec (-0·9 ml/s2*10-3 (-1·3 to -0·2)) and E/Ea (-1·8 (-3·0 to -0·6)), without affecting A (3 ml/s (-35 to 41)) and Ea (0·4 cm/s (-0·9 to 1·4)). LIRA reduced SV (-9 ml (-16 to -2)) and EF (-3% (-6 to -0·1)), but did not change CO (-0·4 L/min (-0·9 to 0·2)), CI (-0·1 L/min/m2 (-0·4 to 0·1)) and PER (-46 ml/s (-95 to 3)), as compared to PLB. Interpretation: In DM2 patients without prior cardiovascular disease, liraglutide improved E/Ea. Systolic function reduced and remained within normal range. Future studies are needed to investigate if liraglutide-induced left ventricular unloading can slow progression of diabetic cardiomyopathy into symptomatic stages. Trial Registration Number: The trial was registered with ClinicalTrials.gov, number NCT01761318 Funding: MAGNA VICTORIA Competing Declaration of Interest: All authors have no conflict of interest. Ethical Approval Statement: The trial was approved by the local ethics committee and performed in accordance with the principles of the revised Declaration of Helsinki. Written informed consent was obtained from all participants before study entry.

All‐Extremity High‐Intensity Interval Training and Moderate‐Intensity Continuous Training Improve Aerobic Fitness and Cardiac Function in Type 2 Diabetes

High‐intensity interval training (HIIT) on the treadmill has been reported to be more effective in improving aerobic fitness and cardiac function compared with moderate‐intensity continuous training (MICT) in adults with cardiometabolic disorders. However, middle‐aged and older adults with type 2 diabetes (T2D) are often unable to tolerate weight‐bearing exercise which may hinder HIIT and MICT on the treadmill. Therefore, the purpose of this randomized clinical trial was twofold: 1) to test if non‐weight bearing all‐extremity HIIT and MICT are feasible in adults with T2D aged 50 to 79 yrs; and 2) to test whether HIIT is more effective in improving aerobic fitness and cardiac function than MICT. Fifty‐three sedentary adults with T2D (age: 63±1 yrs), free of cardiovascular disease, were randomized to HIIT (n=21), MICT (n=18) or non‐exercise control (CONT; n=14). HIIT (4×4‐min intervals at 90% of peak heart rate; HRpeak) and isocaloric MICT (70% of HRpeak) were performed on an all‐extremity ergometer, 4 times/week for 8 weeks under supervision. Aerobic fitness was assessed by oxygen consumption during an incremental maximal exercise test. Left ventricular (LV) function was assessed during rest by two‐dimensional echocardiography including conventional and tissue Doppler. All measures were obtained at pre‐ and post‐intervention. Approximately 80% of participants randomized to all‐extremity HIIT and MICT completed the exercise intervention. Aerobic fitness improved by 11% in HIIT (22.4±1.2 vs. 24.9±1.4 ml/kg/min, pre‐ vs. post‐intervention; P&lt;0.0001) and 7% in MICT (21.4±1.3 vs. 23.0±1.3 ml/kg/min; P=0.004 and P=0.4 for HIIT vs. MICT), whereas it did not change in CONT (21.4±1.5 vs. 21.3±1.2 ml/kg/min; P=0.9). Ejection fraction, a measure of LV systolic function, increased in both HIIT and MICT by ~2% (HIIT: 54.7±0.7 vs. 56.6±0.9%; P=0.007 and MICT: 54.6±1.4 vs. 56.4±1.2%; P=0.04), whereas it remained unchanged in CONT (56.0±1.2 vs. 54.9±1.1%; P=0.2). Diastolic function was not significantly affected by the intervention (P≥0.06). In conclusion, all‐extremity HIIT and MICT are feasible in middle‐aged and older adults with T2D and are equally effective in improving aerobic fitness and LV systolic function.Support or Funding InformationThis work was supported by the National Institutes of Health (NIA AG 050203).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.