glucagon-like-peptide-1 and Diabetic-Cardiomyopathies

The field of type 2 diabetes is undergoing a major transformation. Recent cardiovascular outcomes trials of glucose-lowering agents - including EMPA-REG, IRIS and LEADER, have all demonstrated convincing cardiovascular benefits within a relatively short period of time - all likely driven via non-glycemic effects of compounds under study. The implications of these studies (with primary focus on the LEADER trial) - and how their result may be paradigm shifting for type 2 diabetes management, are discussed in this article.

Topics: Cardiotonic Agents; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Precision Medicine; Risk Factors

Individuals with diabetes are not only at high risk of developing heart failure but are also at increased risk of dying from it. Fortunately, antiheart failure therapies such as angiotensin-converting-enzyme inhibitors, β blockers and mineralocorticoid-receptor antagonists work similarly well in individuals with diabetes as in individuals without the disease. Response to intensive glycaemic control and the various classes of antihyperglycaemic agent therapy is substantially less well understood. Insulin, for example, induces sodium retention and thiazolidinediones increase the risk of heart failure. The need for new glucose-lowering drugs to show cardiovascular safety has led to the unexpected finding of an increase in the risk of admission to hospital for heart failure in patients treated with the dipeptidylpeptidase-4 (DPP4) inhibitor, saxagliptin, compared with placebo. Here we review the relation between glycaemic control and heart failure risk, focusing on the state of knowledge for the various types of antihyperglycaemic drugs that are used at present.

Topics: Adult; Age Distribution; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Heart Failure; Humans; Hypoglycemic Agents; Insulin; Middle Aged; Observational Studies as Topic; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds; Thiazolidinediones

The glucagon-like peptide-1 receptor agonists (GLP-1RAs) exenatide, liraglutide and lixisenatide have been shown to improve glycaemic control and beta-cell function with a low risk of hypoglycaemia in people with type 2 diabetes. GLP-1 receptors are also expressed in extra-pancreatic tissues and trial data suggest that GLP-1RAs also have effects beyond their glycaemic actions. Preclinical studies using native GLP-1 or GLP-1RAs provide substantial evidence for cardioprotective effects, while clinical trial data have shown beneficial actions on hypertension and dyslipidaemia in people with type 2 diabetes. Significant weight loss has been reported with GLP-1RAs in both people with type 2 diabetes and obese people without diabetes. GLP-1RAs also slow down gastric emptying, but preclinical data suggest that the main mechanism behind GLP-1RA-induced weight loss is more likely to involve their effects on appetite signalling in the brain. GLP-1RAs have also been shown to exert a neuroprotective role in rodent models of stroke, Alzheimer's disease and Parkinson's disease. These extra-pancreatic effects of GLP-1RAs could provide multi-factorial benefits to people with type 2 diabetes. Potential adverse effects of GLP-1RA treatment are usually manageable but may include gastrointestinal effects, increased heart rate and renal injury. While extensive further research is still required, early data suggest that GLP-1RAs may also have the potential to favourably impact cardiovascular disease, obesity or neurological disorders in people without diabetes in the future.

Topics: Animals; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diabetic Neuropathies; Evidence-Based Medicine; Exenatide; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Obesity; Peptides; Receptors, Glucagon; Venoms

Glucagon-like peptide-1 receptor agonists and inhibitors of dipeptidyl peptidase-4 that increase glucagon-like peptide-1 plasma concentrations are current treatment options for patients with diabetes mellitus. As patients with diabetes are a high-risk population for the development of a severe and diffuse atherosclerosis, we aim to review the potential action of these drugs on cardiovascular disease and to summarize the potential role of present glucagon-like peptide-1-based therapies from a cardiologist's point of view.. Using a PubMed/MEDLINE search without language restriction, studies were identified and evaluated in order to review the effects of glucagon-like peptide-1-based therapy on different stages of the cardiovascular continuum.. Recent experimental as well as clinical data suggest that dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists--in addition to their metabolic effects--may have beneficial effects on the cardiovascular continuum at multiple stages, including: (1) cardiovascular risk factors; (2) molecular mechanisms involved in atherogenesis; (3) ischaemic heart disease; and (4) heart failure. Furthermore, retrospective analysis suggested decreased cardiovascular events in patients with glucagon-like peptide-1-based therapies.. There are ample data to suggest beneficial effects of glucagon-like peptide-1-based therapies on the cardiovascular continuum and large-scale clinical trials are warranted to determine whether these effects translate into improved cardiovascular endpoints in humans.

Topics: Animals; Atherosclerosis; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Dogs; Endothelium, Vascular; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Failure; Humans; Hypoglycemic Agents; Mice; Myocardium; Obesity; Rats; Receptors, Glucagon; Risk Factors; Swine

Exercise is recommended as a cornerstone of treatment for type 2 diabetes mellitus (T2DM), however, it is often poorly adopted by patients. Even in the absence of apparent cardiovascular disease, persons with T2DM have an impaired ability to carry out maximal and submaximal exercise and these impairments are correlated with cardiac and endothelial dysfunction. Glucagon-like pepetide-1 (GLP-1) augments endothelial and cardiac function in T2DM. We hypothesized that administration of a GLP-1 agonist (exenatide) would improve exercise capacity in T2DM.. Administration of exenatide improved cardiac function and reduced arterial stiffness, however, these changes were not accompanied by improved functional exercise capacity. In order to realize the benefits of this drug on exercise capacity, combining exenatide with aerobic exercise training in participants with T2DM may be warranted.

Topics: Aged; Arteries; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Double-Blind Method; Endothelium, Vascular; Exenatide; Exercise Tolerance; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Heart Ventricles; Humans; Hypoglycemic Agents; Male; Middle Aged; Oxygen Consumption; Peptides; Pulse Wave Analysis; Sedentary Behavior; Vascular Stiffness; Venoms; Ventricular Dysfunction, Left

Enhancement of myocardial glucose uptake may reduce fatty acid oxidation and improve tolerance to ischemia. Hyperglycemia, in association with hyperinsulinemia, stimulates this metabolic change but may have deleterious effects on left ventricular (LV) function. The incretin hormone, glucagon-like peptide-1 (GLP-1), also has favorable cardiovascular effects, and has emerged as an alternative method of altering myocardial substrate utilization. In patients with coronary artery disease (CAD), we investigated: (1) the effect of a hyperinsulinemic hyperglycemic clamp (HHC) on myocardial performance during dobutamine stress echocardiography (DSE), and (2) whether an infusion of GLP-1(7-36) at the time of HHC protects against ischemic LV dysfunction during DSE in patients with type 2 diabetes mellitus (T2DM).. In study 1, twelve patients underwent two DSEs with tissue Doppler imaging (TDI)-one during the steady-state phase of a HHC. In study 2, ten patients with T2DM underwent two DSEs with TDI during the steady-state phase of a HHC. GLP-1(7-36) was infused intravenously at 1.2 pmol/kg/min during one of the scans. In both studies, global LV function was assessed by ejection fraction and mitral annular systolic velocity, and regional wall LV function was assessed using peak systolic velocity, strain and strain rate from 12 paired non-apical segments.. In study 1, the HHC (compared with control) increased glucose (13.0 ± 1.9 versus 4.8 ± 0.5 mmol/l, p < 0.0001) and insulin (1,212 ± 514 versus 114 ± 47 pmol/l, p = 0.01) concentrations, and reduced FFA levels (249 ± 175 versus 1,001 ± 333 μmol/l, p < 0.0001), but had no net effect on either global or regional LV function. In study 2, GLP-1 enhanced both global (ejection fraction, 77.5 ± 5.0 versus 71.3 ± 4.3%, p = 0.004) and regional (peak systolic strain -18.1 ± 6.6 versus -15.5 ± 5.4%, p < 0.0001) myocardial performance at peak stress and at 30 min recovery. These effects were predominantly driven by a reduction in contractile dysfunction in regions subject to demand ischemia.. In patients with CAD, hyperinsulinemic hyperglycemia has a neutral effect on LV function during DSE. However, GLP-1 at the time of hyperglycemia improves myocardial tolerance to demand ischemia in patients with T2DM.. http://www.isrctn.org . Unique identifier ISRCTN69686930.

Topics: Aged; Biomarkers; Biomechanical Phenomena; Blood Glucose; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Echocardiography, Doppler, Color; Echocardiography, Stress; Female; Glucagon-Like Peptide 1; Glucose Clamp Technique; Humans; Hyperglycemia; Incretins; Infusions, Intravenous; Insulin; Male; Middle Aged; Myocardial Contraction; Peptide Fragments; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Function, Left

Glucagon-like peptide-1 (GLP-1) can improve cardiac function and cardiovascular outcomes in diabetic cardiomyopathy; however, the beneficial effect of GLP-1 on human diabetic cardiomyocytes (DCMs) and its mechanism have not been fully elucidated. Here, the DCMs model by human-induced pluripotent stem cells-derived cardiomyocytes is developed. Two subtypes of GLP-1, GLP-1

Topics: Diabetes Mellitus; Diabetic Cardiomyopathies; Glucagon-Like Peptide 1; Humans; Induced Pluripotent Stem Cells; Myocytes, Cardiac

Ultrasound-targeted microbubble destruction, UTMD; glucagon-like peptide-1 receptor, GLP-1R; diabetic cardiomyopathy, DCM; Goto-Kakizaki, GK; velocity vector imaging, VVI; left ventricular end-diastolic diameter LVIDd; left ventricular end-systolic diameter, LvIDs; left ventricular end-diastolic pressure, LVEDP; fractional shortening, LVFs; left ventricular ejection fraction, LVEF; mean peak radial velocity, Vs; radial strain, Sr; radial strain rate, SRr; superoxide dismutase, SOD; malondialdehyde, MDA; glutathione peroxidase, GSH-Px; peroxisome proliferator-activated receptor-γ, PPAR-γ; nuclear transcription factor κB, NF-κB; insulin resistance, IR; total cholesterol, TC; total triglycerides, TG; creatine kinase, CK; lactate dehydrogenase, LDH; cardiac troponin I, cTnI; collagen volume fraction, CVF; Hematoxylin eosin, H&E.

Topics: Animals; Diabetic Cardiomyopathies; Glucagon-Like Peptide 1; Male; Microbubbles; Myocardium; Oxidative Stress; Rats; Ultrasonic Therapy

This study intended to explore the hypoglycemic and cardioprotective effects of 8-week aerobic interval training combined with liraglutide and elucidate the underlying mechanisms.. Male Wistar rats were randomly divided into 5 groups - normal control group (CON), diabetic cardiomyopathy group (DCM), high-dose liraglutide group (DH), low-dose liraglutide group (DL), and aerobic interval training combined with liraglutide group (DLE). High-fat diet and streptozotocin (STZ) were used to induce the DCM model, and both the liraglutide administration group and combination therapy group allocated to 8 weeks of either liraglutide or liraglutide and exercise intervention. Cardiac functions were analyzed by electrocardiography. Blood biochemical parameters were measured to judge glycemic control conditions. Hematoxylin and eosin (HE) staining and Sirus red staining was used to identify cardiac morphology and collagen accumulation, respectively. Advanced glycation end products (AGEs) were determined by enzymatic methods. The mRNA expression of myocardial remodeling genes (BNP, GSK3β, α-MHC, β-MHC and PPARα) and the protein expression of GLP-1, GLP-1R were analyzed.. DCM rats developed hyperglycemia, impaired cardiac function with accumulation of AGEs and collagen (P < 0.05). The development of hyperglycemia and cardiac dysfunction was significantly attenuated with all interventions, as reduced cardiac fibrosis and improved cardiac function (P < 0.05). Cardiac remodeling genes were normalized after all interventions, these positive modifications were due to increased GLP-1 and GLP-1R expression in DCM heart (P < 0.05). Liraglutide combined with AIT significantly increased the diameters of cardiomyocytes, increased the α-MHC expressionx, reduced PPARαexpression and reduced the fluctuation of blood glucose level, which showed the safety and effective of medicine combined with exercise.. Liraglutide combined with AIT intervention normalized blood glucose alleviates myocardial fibrosis and improves cardiac contractile function in DCM rats, supporting the efficacy and safety of the combination therapy.

Topics: Animals; Blood Glucose; Diabetic Cardiomyopathies; Eosine Yellowish-(YS); Glucagon-Like Peptide 1; Glycation End Products, Advanced; Glycemic Control; Glycogen Synthase Kinase 3 beta; Hematoxylin; Hyperglycemia; Hypoglycemic Agents; Liraglutide; Male; Myocytes, Cardiac; PPAR alpha; Rats; Rats, Wistar; RNA, Messenger; Streptozocin

Diabetic cardiomyopathy is an important contributor to morbidity and mortality of diabetic patients by causing heart failure. Interstitial and perivascular fibrosis plays a crucial role in diabetic cardiomyopathy. However, there is a lack of effective specific treatments available for diabetic cardiomyopathy. In the present study, we aim to explore the effects of Liraglutide, a GLP-1 analogue, on diabetic cardiomyopathy in STZ-induced diabetic rats fed with high-fat diet. A total of 60 male Wistar rats were randomly assigned to three groups, i.e. normal group, model group, and Liraglutide group, with 20 rats in each group. Serum levels of TC, TG, LDL-C, NEFA, and hydroxyproline were measured using commercial kits. Cardiac function was evaluated by QRS waves, LVEDd, LVESd, and LVEF. Myocardial fibrosis was measured by immunohistochemistry. Our results demonstrated that chronic administration of Liraglutide decreased the level of blood glucose and significantly alleviated lipid metabolic disturbance compared with the model group. Furthermore, Liraglutide was found to improve the damaged cardiac function. In line with this, we also found that the alleviation of cardiac dysfunction was associated with the decreased fibrosis in diabetic myocardial tissues, which was reflected by the decreased expressions of P4hα-1, COL-1, COL-3, MMP-1, and MMP-9. Our results thus suggest that Liraglutide might have a myocardial protective effect by inhibiting P4hα-1-mediated myocardial fibrosis.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Fibrosis; Glucagon-Like Peptide 1; Lipid Metabolism; Liraglutide; Male; Myocardium; Procollagen-Proline Dioxygenase; Rats; Rats, Wistar; Streptozocin

The distribution of glucose and fatty-acid transporters in the heart is crucial for energy consecution and myocardial function. In this sense, the glucagon-like peptide-1 (GLP-1) enhancer, sitagliptin, improves glucose homeostasis but it could also trigger direct cardioprotective actions, including regulation of energy substrate utilization.. Type-II diabetic GK (Goto-Kakizaki), sitagliptin-treated GK (10 mg/kg/day) and wistar rats (n = 10, each) underwent echocardiographic evaluation, and positron emission tomography scanning for [. Besides of its anti-hyperglycemic effect, sitagliptin-enhanced GLP-1 may ameliorate diastolic dysfunction in type-II diabetes by shifting fatty acid to glucose utilization in the cardiomyocyte, and thus, improving cardiac efficiency and reducing lipolysis.

Topics: Animals; Blood Glucose; Cells, Cultured; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Energy Metabolism; Fatty Acids; Glucagon-Like Peptide 1; Glucose Transporter Type 4; Incretins; Male; Mice; Myocytes, Cardiac; Protein Transport; Rats, Wistar; Signal Transduction; Sitagliptin Phosphate

Lipotoxicity cardiomyopathy is the result of excessive accumulation and oxidation of toxic lipids in the heart. It is a major threat to patients with diabetes. Glucagon-like peptide-1 (GLP-1) has aroused considerable interest as a novel therapeutic target for diabetes mellitus because it stimulates insulin secretion. Here, we investigated the effects and mechanisms of the GLP-1 analog exendin-4 and the dipeptidyl peptidase-4 inhibitor saxagliptin on cardiac lipid metabolism in diabetic mice (DM). The increased myocardial lipid accumulation, oxidative stress, apoptosis, and cardiac remodeling and dysfunction induced in DM by low streptozotocin doses and high-fat diets were significantly reversed by exendin-4 and saxagliptin treatments for 8 weeks. We found that exendin-4 inhibited abnormal activation of the (PPARα)-CD36 pathway by stimulating protein kinase A (PKA) but suppressing the Rho-associated protein kinase (ROCK) pathway in DM hearts, palmitic acid (PA)-treated rat h9c2 cardiomyocytes (CMs), and isolated adult mouse CMs. Cardioprotection in DM mediated by exendin-4 was abolished by combination therapy with the PPARα agonist wy-14643 but mimicked by PPARα gene deficiency. Therefore, the PPARα pathway accounted for the effects of exendin-4. This conclusion was confirmed in cardiac-restricted overexpression of PPARα mediated by adeno-associated virus serotype-9 containing a cardiac troponin T promoter. Our results provide the first direct evidence that GLP-1 protects cardiac function by inhibiting the ROCK/PPARα pathway, thereby ameliorating lipotoxicity in diabetic cardiomyopathy.

Topics: Adamantane; Animals; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Dipeptides; Exenatide; Glucagon-Like Peptide 1; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; PPAR alpha

The present study aimed to investigate the protective effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on diabetic cardiomyopathy (DCM)-associated apoptosis and if this effect is mediated via modulating the activity of the survival kinases; AMP-activated protein kinase (AMPK) and Akt & the apoptotic kinases; glycogen synthase kinase-3 β (GSK-3β) and p38 mitogen-activated protein kinase (p38MAPK). Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg/kg). Diabetic rats were treated with sitagliptin (10 mg/kg/day, p.o.) and metformin (200 mg/kg/day, p.o. as positive control) for six weeks. Chronic hyperglycemia resulted in elevation of serum cardiac biomarkers reflecting cardiac damage which was supported by H&E stain. The mRNA levels of collagen types I and III were augmented reflecting cardiac fibrosis and hypertrophy which was supported by Masson trichome stain and enhanced phosphorylation of p38MAPK. Cardiac protein levels of cleaved casapse-3, BAX were elevated, whereas, the levels of Bcl-2 and p-BAD were reduced indicating cardiac apoptosis which could be attributed to the diabetes-induced reduced phosphorylation of Akt and AMPK with concomitant augmented activation of GSK-3β and p38MAPK. Protein levels of liver kinase B-1, the upstream kinase of AMPK were also supressed. Sitagliptin administration alleviated the decreased phosphorylation of AMPK and Akt, inactivated the GSK-3β and p38 AMPK, therefore, attenuating the apoptosis and hypertrophy induced by hyperglycemia in the diabetic heart. In conclusion, sitagliptin exhibits valuable therapeutic potential in the management of DCM by attenuating apoptosis. The underlying mechanism may involve the modulating activity of AMPK, Akt, GSK-3β and p38MAPK.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Animals; Apoptosis; Biomarkers; Blood Glucose; Body Weight; Collagen; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Disease Models, Animal; Fatty Acids; Glucagon-Like Peptide 1; Glycogen Synthase Kinase 3 beta; Male; Metformin; Mitogen-Activated Protein Kinase 14; Myocardium; Organ Size; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Rats, Wistar; RNA, Messenger; Signal Transduction; Sitagliptin Phosphate

Cardiomyocyte apoptosis is a major event in the pathogenesis of diabetic cardiomyopathy. Currently, no single effective treatment for diabetic cardiomyopathy exists. The present study investigated whether advanced oxidative protein products (AOPPs) have a detrimental role in the survival of cardiomyocytes and if glucagon-like peptide-1 (GLP-1) exerts a cardioprotective effect under these circumstances. The present study also aimed to determine the underlying mechanisms. H9c2 cells were exposed to increasing concentrations of AOPPs in the presence or absence of GLP-1, and the viability and apoptotic rate were detected using a cell counting kit-8 assay and flow cytometry, respectively. In addition, a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor, LY294002, was employed to illustrate the mechanism of the antiapoptotic effect of GLP-1. The expression levels of the apoptotic-associated proteins, Akt, B-cell lymphoma (Bcl)-2, Bcl-2-associated death promoter (Bad), Bcl-2-associated X protein (Bax) and caspase-3 were measured by western blotting. It was revealed that GLP-1 significantly attenuated AOPP-induced cell toxicity and apoptosis. AOPPs inactivated the phosphorylation of Akt, reduced the phosphorylation of Bad, decreased the expression of Bcl-2, increased the expression of Bax and the activation of caspase-3 in H9c2 cells. GLP-1 reversed the above changes induced by AOPPs and the protective effects of GLP-1 were abolished by the PI3K inhibitor, LY294002. In conclusion, the present data suggested that GLP-1 protected cardiomyocytes against AOPP-induced apoptosis, predominantly via the PI3K/Akt/Bad pathway. These results provided a conceivable mechanism for the development of diabetic cardiomyopathy and rendered a novel application of GLP-1 exerting favorable cardiac effects for the treatment of diabetic cardiomyopathy.

Topics: Advanced Oxidation Protein Products; Animals; Apoptosis; bcl-Associated Death Protein; Chromones; Diabetic Cardiomyopathies; Glucagon-Like Peptide 1; Humans; Morpholines; Myocytes, Cardiac; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Rats

To determine whether the use of incretin-based drugs, including GLP-1 analogs and dipeptidyl peptidase-4 inhibitors, is associated with an increased risk of congestive heart failure (CHF) among patients with type 2 diabetes.. The U.K. Clinical Practice Research Datalink, linked to the Hospital Episode Statistics database, was used to conduct a cohort study with a nested case-control analysis among patients newly prescribed antidiabetic drugs between 1 January 2007 and 31 March 2012 and no prior history of CHF. Case subjects were defined as patients hospitalized for a first CHF and matched with up to 20 control subjects on age, duration of treated diabetes, calendar year, and time since cohort entry. Conditional logistic regression was used to estimate odds ratios (ORs) with corresponding 95% CIs of incident CHF comparing current use of incretin-based drugs with current use of two or more oral antidiabetic drugs.. The cohort consisted of 57,737 patients followed for a mean 2.4 years, during which time 1,118 incident cases of hospitalized CHF were identified (incidence rate 8.1/1,000 person-years). Current use of incretin-based drugs was not associated with an increased risk of CHF (adjusted OR 0.85 [95% CI 0.62-1.16]). Secondary analyses revealed no duration-response relationship (P trend = 0.39).. In our population-based study, incretin-based drug use was not associated with an increased risk of CHF among patients with type 2 diabetes. These findings provide some reassurance, but will need to be replicated in other large-scale studies.

Topics: Aged; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Epidemiologic Methods; Female; Glucagon-Like Peptide 1; Heart Failure; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged

Topics: Biomarkers; Blood Glucose; Diabetic Cardiomyopathies; Glucagon-Like Peptide 1; Humans

Clinically, diabetes mellitus is closely associated with and induces certain cardiovascular diseases. The aim of this study was to investigate endoplasmic reticulum (ER) stress-associated apoptosis of diabetic cardiomyopathy (DCM), and explore the protective mechanism of liraglutide. The DCM model was established with a high-fat diet and streptozotocin (STZ). Cardiac function was detected by echocardiogram examination and hematoxylin-eosin staining. ER stress unfolded protein response (UPR) hallmarks [inositol-requiring enzyme-α (IRE-α), p-Perk and ATF6] and transcription factors were detected with western blotting. Apoptosis inducers CHOP, c-Jun amino terminal kinase (JNK) and casapse-12 were also examined with western blotting. The results indicated that liraglutide is capable of improving cardiac function in DCM rats (P<0.05). IRE-α expression was significantly increased in the DCM group compared with the control group (P<0.05), and liraglutide is capable of decreasing IRE-α expression. X-box transcription factor-1 (XBP-1) was significantly spliced in the model group, and downregulated in the liraglutide-treated group. CHOP protein was upregulated in the DCM group, but inactivated by liraglutide treatment. In conclusion, liraglutide is capable of protecting DCM and blocking CHOP-mediated ER stress by inhibiting the IRE-α UPR pathway.

Topics: Animals; Apoptosis; Blood Glucose; Diabetic Cardiomyopathies; Disease Models, Animal; Electrocardiography; Endoplasmic Reticulum Stress; Endoribonucleases; Fasting; Glucagon-Like Peptide 1; Liraglutide; Male; Mice; Multienzyme Complexes; Myocardium; Myocytes, Cardiac; Protein Serine-Threonine Kinases; Rats; Rats, Wistar; Signal Transduction; Transcription Factor CHOP; Ultrasonography

Myocardial fibrosis is a key process in diabetic cardiomyopathy. However, their underlying mechanisms have not been elucidated, leading to a lack of therapy. The glucagon-like peptide-1 (GLP-1) enhancer, sitagliptin, reduces hyperglycemia but may also trigger direct effects on the heart.. Goto-Kakizaki (GK) rats developed type-II diabetes and received sitagliptin, an anti-hyperglycemic drug (metformin) or vehicle (n=10, each). After cardiac structure and function assessment, plasma and left ventricles were isolated for biochemical studies. Cultured cardiomyocytes and fibroblasts were used for in vitro assays.. Untreated GK rats exhibited hyperglycemia, hyperlipidemia, plasma GLP-1 decrease, and cardiac cell-death, hypertrophy, fibrosis and prolonged deceleration time. Moreover, cardiac pro-apoptotic/necrotic, hypertrophic and fibrotic factors were up-regulated. Importantly, both sitagliptin and metformin lessened all these parameters. In cultured cardiomyocytes and cardiac fibroblasts, high-concentration of palmitate or glucose induced cell-death, hypertrophy and fibrosis. Interestingly, GLP-1 and its insulinotropic-inactive metabolite, GLP-1(9-36), alleviated these responses. In addition, despite a specific GLP-1 receptor was only detected in cardiomyocytes, GLP-1 isoforms attenuated the pro-fibrotic expression in cardiomyocytes and fibroblasts. In addition, GLP-1 receptor signalling may be linked to PPARδ activation, and metformin may also exhibit anti-apoptotic/necrotic and anti-fibrotic direct effects in cardiac cells.. Sitagliptin, via GLP-1 stabilization, promoted cardioprotection in type-II diabetic hearts primarily by limiting hyperglycemia e hyperlipidemia. However, GLP-1 and GLP-1(9-36) promoted survival and anti-hypertrophic/fibrotic effects on cultured cardiac cells, suggesting cell-autonomous cardioprotective actions.

Topics: Animals; Apoptosis; Cardiomegaly; Cardiotonic Agents; Cells, Cultured; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Disease Models, Animal; Drug Evaluation, Preclinical; Fibroblasts; Fibronectins; Fibrosis; Glucagon-Like Peptide 1; Glucose Intolerance; Hypoglycemic Agents; Insulin; Male; Metformin; Myocardium; Myocytes, Cardiac; PPAR delta; Protein Isoforms; Pyrazines; Rats; Sitagliptin Phosphate; Triazoles

Impaired cardiac microvascular function contributes to cardiovascular complications in diabetes. Glucagon-like peptide-1 (GLP-1) exhibits potential cardioprotective properties in addition to its glucose-lowering effect. This study was designed to evaluate the impact of GLP-1 on cardiac microvascular injury in diabetes and the underlying mechanism involved. Experimental diabetes was induced using streptozotocin in rats. Cohorts of diabetic rats received a 12-week treatment of vildagliptin (dipeptidyl peptidase-4 inhibitor) or exenatide (GLP-1 analog). Experimental diabetes attenuated cardiac function, glucose uptake, and microvascular barrier function, which were significantly improved by vildagliptin or exenatide treatment. Cardiac microvascular endothelial cells (CMECs) were isolated and cultured in normal or high glucose medium with or without GLP-1. GLP-1 decreased high-glucose-induced reactive oxygen species production and apoptotic index, as well as the levels of NADPH oxidase such as p47(phox) and gp91(phox). Furthermore, cAMP/PKA (cAMP-dependent protein kinase activity) was increased and Rho-expression was decreased in high-glucose-induced CMECs after GLP-1 treatment. In conclusion, GLP-1 could protect the cardiac microvessels against oxidative stress, apoptosis, and the resultant microvascular barrier dysfunction in diabetes, which may contribute to the improvement of cardiac function and cardiac glucose metabolism in diabetes. The protective effects of GLP-1 are dependent on downstream inhibition of Rho through a cAMP/PKA-mediated pathway.

Topics: AMP-Activated Protein Kinases; Animals; Cardiotonic Agents; Cells, Cultured; Cyclic AMP; Diabetic Angiopathies; Diabetic Cardiomyopathies; Disease Models, Animal; Endothelium, Vascular; Exenatide; Glucagon-Like Peptide 1; Heart Ventricles; Hyperglycemia; Hypoglycemic Agents; Male; Microvessels; Oxidative Stress; Peptides; Random Allocation; Rats; Rats, Sprague-Dawley; rho GTP-Binding Proteins; Second Messenger Systems; Venoms