glucagon-like-peptide-1 and Hypertension

Obesity affects approximately 42% of US adults and is associated with increased rates of type 2 diabetes, hypertension, cardiovascular disease, sleep disorders, osteoarthritis, and premature death.. A body mass index (BMI) of 25 or greater is commonly used to define overweight, and a BMI of 30 or greater to define obesity, with lower thresholds for Asian populations (BMI ≥25-27.5), although use of BMI alone is not recommended to determine individual risk. Individuals with obesity have higher rates of incident cardiovascular disease. In men with a BMI of 30 to 39, cardiovascular event rates are 20.21 per 1000 person-years compared with 13.72 per 1000 person-years in men with a normal BMI. In women with a BMI of 30 to 39.9, cardiovascular event rates are 9.97 per 1000 person-years compared with 6.37 per 1000 person-years in women with a normal BMI. Among people with obesity, 5% to 10% weight loss improves systolic blood pressure by about 3 mm Hg for those with hypertension, and may decrease hemoglobin A1c by 0.6% to 1% for those with type 2 diabetes. Evidence-based obesity treatment includes interventions addressing 5 major categories: behavioral interventions, nutrition, physical activity, pharmacotherapy, and metabolic/bariatric procedures. Comprehensive obesity care plans combine appropriate interventions for individual patients. Multicomponent behavioral interventions, ideally consisting of at least 14 sessions in 6 months to promote lifestyle changes, including components such as weight self-monitoring, dietary and physical activity counseling, and problem solving, often produce 5% to 10% weight loss, although weight regain occurs in 25% or more of participants at 2-year follow-up. Effective nutritional approaches focus on reducing total caloric intake and dietary strategies based on patient preferences. Physical activity without calorie reduction typically causes less weight loss (2-3 kg) but is important for weight-loss maintenance. Commonly prescribed medications such as antidepressants (eg, mirtazapine, amitriptyline) and antihyperglycemics such as glyburide or insulin cause weight gain, and clinicians should review and consider alternatives. Antiobesity medications are recommended for nonpregnant patients with obesity or overweight and weight-related comorbidities in conjunction with lifestyle modifications. Six medications are currently approved by the US Food and Drug Administration for long-term use: glucagon-like peptide receptor 1 (GLP-1) agonists (semaglutide and liraglutide only), tirzepatide (a glucose-dependent insulinotropic polypeptide/GLP-1 agonist), phentermine-topiramate, naltrexone-bupropion, and orlistat. Of these, tirzepatide. Obesity affects approximately 42% of adults in the US. Behavioral interventions can attain approximately 5% to 10% weight loss, GLP-1 agonists and glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonists can attain approximately 8% to 21% weight loss, and bariatric surgery can attain approximately 25% to 30% weight loss. Comprehensive, evidence-based obesity treatment combines behavioral interventions, nutrition, physical activity, pharmacotherapy, and metabolic/bariatric procedures as appropriate for individual patients.

Topics: Adult; Anti-Obesity Agents; Body Mass Index; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Gastric Balloon; Glucagon-Like Peptide 1; Glucose; Humans; Hypertension; Male; Obesity; Obesity Management; Overweight; Peptides; United States; Weight Loss

GLP-1 is derived from intestinal L cells, which takes effect through binding to GLP-1R and is inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4). Since its discovery, GLP-1 has emerged as an incretin hormone for its facilitation in insulin release and reduction of insulin resistance (IR). However, GLP-1 possesses broader pharmacological effects including anti-inflammation, neuro-protection, regulating blood pressure (BP), and reducing lipotoxicity. These effects are interconnected to the physiological and pathological processes of Alzheimer's disease (AD), hypertension, and non-alcoholic steatohepatitis (NASH). Currently, the underlying mechanism of these effects is still not fully illustrated and a better understanding of them may help identify promising therapeutic targets of AD, hypertension, and NASH. Therefore, we focus on the biological characteristics of GLP-1, render an overview of the mechanism of GLP-1 effects in diseases, and investigate the potential of GLP-1 analogues for the treatment of related diseases in this review.

Topics: Alzheimer Disease; Animals; Glucagon-Like Peptide 1; Humans; Hypertension; Incretins; Metabolic Networks and Pathways; Non-alcoholic Fatty Liver Disease

Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease. The presence of concomitant hypertension in diabetics is a major driver of excess cardiovascular risk. Glucagon-like peptide-1 receptor agonists (GLP-1a) act on numerous pathways that intersect glycemic, weight, and blood pressure (BP) control. BP-lowering effects have been observed in mouse models of hypertension with a variety of GLP-1a. Acute administration of GLP-1a in humans has been shown to no effects and sometimes increased BP in humans. Chronic administration of GLP-1a, however, reduces clinic systolic BP (≈2 mmHg) at least when evaluated as a secondary end point in glycemia-lowering studies while simultaneously increasing heart rate. BP lowering has not been consistently observed in two recent double-blind controlled clinical trials evaluating ambulatory BP as the primary end point. While a number of mechanisms including vascular, myocardial, renal, and central nervous system pathways have been suggested in animal studies, these mechanistic pathways have not been sufficiently detailed in humans and it is unclear if the same pathways are operational. Further studies need to be conducted to unravel the full spectrum of effects of this drug class. An understanding of their effects on BP may help provide an explanation for the ability of GLP-1a to influence cardiovascular (CV) events in ongoing event-driven CV trials.

Topics: Animals; Blood Pressure; Cardiovascular Diseases; Glucagon-Like Peptide 1; Heart Rate; Humans; Hypertension; Risk Factors

Obesity is a major public health problem worldwide. Obesity-related illnesses, such as coronary heart disease, type 2 diabetes, hypertension, dyslipidemia, stroke, sleep apnea, and several forms of cancer (endometrial, breast, and colon), contribute to a significant number of deaths in the USA. Bariatric surgery, including the Roux-en-Y gastric bypass (RYGB) procedure, has demonstrated significant improvements in obesity and obesity-related co-morbidities and is becoming more popular as the number of obese individuals rises. Despite the reported benefits of bariatric surgery, there are potential complications that physicians need to be aware of as the number of patients undergoing these procedures continues to increase. One challenging and potentially life-threatening complication that to date is not well understood is post-RYGB surgery hypoglycemia (PGBH). In this review, we will present the definition, historical perspective, diagnostic approach, currently available treatment options, and anecdotal assessment and treatment algorithm for this disorder.

Topics: Gastric Bypass; Glucagon-Like Peptide 1; Humans; Hypertension; Hypoglycemia; Incretins; Obesity

Vascular endothelial cells play a major role in maintaining cardiovascular homeostasis. Endothelial dysfunction, characterized by reduced endothelium-dependent relaxations or accompanied by enhanced endothelium-dependent contractions, is a hallmark of and plays a pivotal role in the pathogenesis of hypertension. Endothelial dysfunction in hypertension has been linked to decreases in nitric oxide (NO) bioavailability, reflecting the impaired generation of NO and/or the enhanced inactivation of NO by reactive oxygen species. Many of these conditions can be improved by glucagon-like peptide 1 (GLP-1), a proglucagon-derived hormone secreted by intestinal endocrine L-type cells, which is rapidly inactivated by an enzyme dipeptidyl peptidase 4 in circulation. On one hand, GLP-1 analogues or dipeptidyl peptidase 4 inhibitors upregulate endothelial nitric oxide synthase expression and increase endothelial nitric oxide synthase phosphorylation, resulting in improved production of NO and thus endothelium-dependent relaxations. On the other hand, GLP-1 and related agents attenuate endothelium-dependent contractions by reducing reactive oxygen species generation and cyclooxygenase-2 expression. GLP-1 elevating agents and GLP-1 receptor agonists improve endothelial function in hypertension, suggesting that GLP-1 signaling could be a therapeutic target in hypertension-related vascular events.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Cyclooxygenase 2; Endothelium, Vascular; Glucagon-Like Peptide 1; Humans; Hypertension; Nitric Oxide; Nitric Oxide Synthase Type III; Reactive Oxygen Species; Signal Transduction; Vasodilation; Vasodilator Agents

To evaluate current evidence of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on blood pressure, heart rate, and hypertension in patients with type 2 diabetes.. Medline, Embase, the Cochrane library, and the website www.clinicaltrials.gov were searched on April 5th, 2014. Randomized-controlled trials with available data were included if they compared GLP-1RAs with placebo and traditional antidiabetic drugs in patients with type 2 diabetes with duration ≥ 12 weeks. Weighted mean difference for blood pressure and heart rate, odds ratio (OR) for hypertension were calculated by random-effect model. Network meta-analysis was performed to supplement direct comparisons.. Sixty trials with 14 treatments were included. Compared with placebo, insulin, and sulfonylureas, GLP-1RAs decreased systolic blood pressure with range from -1.84 mmHg (95% CI: -3.48 to -0.20) to -4.60 mmHg (95% CI: -7.18 to -2.03). Compared with placebo, a reduction in diastolic blood pressure was detected significantly only for exenatide-10 μg-twice-daily (-1.08 mmHg, 95% CI: -1.78 to -0.33). Exenatide (2 mg once weekly), liraglutide 1.2 mg once daily), and liraglutide (1.8 mg once daily) increased heart rate by 3.35 (95% CI: 1.23-5.50), 2.06 (95% CI: 0.43, 3.74), and 2.35 (95% CI: 0.94-3.76) beats/min versus placebo. This effect was evident compared with active control (range: 2.22-3.62). No significant association between incident hypertension and GLP-1RAs was detected, except for the association between exenatide-10 μg-twice-daily and sulfonylureas (OR, 0.40, 95% CI: 0.16, 0.82).. GLP-1RAs were associated with modest reduction on blood pressure, a slight increase in heart rate, yet no significant association with hypertension. Further investigation to explore mechanisms is warranted.

Topics: Blood Pressure; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Rate; Humans; Hypertension; Hypoglycemic Agents; Insulin; Liraglutide; Peptides; Randomized Controlled Trials as Topic; Sulfonylurea Compounds; Venoms

The present opinion article provides an overview of the key improvements in metabolic and cardiovascular health following Roux-en-Y Gastric Bypass (RYGB). Some clinically important long-term complications of RYGB are also briefly described to contextualise the potential value of finding selective non-surgical means of replicating only the beneficial aspects of RYGB. Three biological responses linked to changes in gastrointestinal tract structure and function post-RYGB, that are implicated in the clinical efficacy of RYGB and that have actual or potential applications as non-surgical mimetic based approaches are addressed. These are (1) exaggerated post-prandial gut hormone responses; (2) local increases in undiluted bile in the gut lumen and augmented circulating bile acid and FGF19 concentrations and (3) compositional changes in the gut microbiota.

Topics: Adaptation, Physiological; Bile Acids and Salts; Fibroblast Growth Factors; Gastric Bypass; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Humans; Hypertension; Peptide Fragments; Peptide YY; Postprandial Period

Incretin-based therapies are now well established for diabetes management and are among the frontline agents for control of hyperglycemia. In addition to their antihyperglycemic effects, evidence is emerging on the role of these agents on blood pressure regulation, cardioprotective and renoprotective properties. Because of the pleiotropic nature of these affects, these agents could offer significant benefits with regards to the cardiorenal metabolic complications that are part of the diabetes and obesity epidemic in the United States and worldwide. We review the various known mechanisms or pathways by which incretin based therapy exerts its regulation of blood pressure with emphasis on novel mechanisms such as inflammation/immunomodulation and oxidative stress.

Topics: Animals; Blood Pressure; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Hypertension; Incretins; Oxidative Stress; Peptides; Pyrazines; Renin-Angiotensin System; Sitagliptin Phosphate; T-Lymphocytes, Regulatory; Triazoles; Venoms

The growing number of obese patients with a high risk of developing hypertension and type 2 diabetes mellitus requires several drugs to treat all the associated morbidities. Ideally, one drug would help to tackle several health problems at the same time. We review available information on the blood pressure-reducing effects of the new antidiabetic drug classes, glucagon-like peptide 1 analogues and sodium glucose transporter 2 inhibitors.. Blood pressure reduction with glucagon-like peptide 1 analogues or sodium glucose transporter 2 inhibitors ranges between 1 and 7 mmHg, both systolic and diastolic. As these drugs have not been sufficiently investigated in studies with office or ambulatory blood pressure as the primary efficacy measure or in prespecified hypertensive patient populations, their true efficacy in reducing blood pressure remains unclear. These studies are needed because the blood pressure-lowering effects of metabolic drugs may help to improve the clinical management of hypertensive patients with type 2 diabetes mellitus.. Obese patients with type 2 diabetes mellitus and difficult to control arterial hypertension represent a clinically important patient group at high cardiovascular risk that may profit from combined cardiovascular and metabolic actions of a drug.

Topics: Animals; Antihypertensive Agents; Arterial Pressure; Blood Glucose; Diabetes Mellitus, Type 2; Drug Design; Glucagon-Like Peptide 1; Humans; Hypertension; Hypoglycemic Agents; Obesity; Risk Factors; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Aside from lowering blood glucose, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) attract much attention because of their cardioprotective effects. The aim of this study was to assess the blood pressure-lowering effects of the GLP-1 RAs exenatide and liraglutide compared with other common drugs used to treat type 2 diabetes (T2DM) based on randomized controlled trials (RCTs) including data describing complete blood pressure (BP) changes from baseline.. We searched the major databases for published or unpublished RCTs that had been performed in patients with T2DM and compared the effects of exenatide and liraglutide to those of other common drugs used to treat T2DM. The RCTs that included data describing BP changes between the baseline and the end of the study were selected for further analysis.. A total of 16 RCTs that enrolled 3443 patients in the GLP-1 RA treatment group and 2417 subjects in the control group were included in this meta-analysis. The GLP-1 RA exenatide reduced systolic blood pressure (SBP) when compared with both placebo and insulin glargine, with mean differences of -5.24 and -3.46 mmHg, respectively, and with 95% confidence intervals (CI) of -6.88 to -3.59, p < 0.00001 and -3.63 to -3.29, p < 0.00001, respectively. Meanwhile, in the exenatide-treated group, diastolic blood pressure (DBP) was reduced by -5.91 mmHg, with a 95% CI of -7.53 to -4.28, p < 0.00001 compared with the placebo group, and -0.99 mmHg with a 95% CI of -1.12 to -0.87, p < 0.00001 compared with the sitagliptin group. SBP changes in this meta-analysis were assessed in the groups treated with 1.2 or 1.8 mg liraglutide per day. In the 1.2 mg-treated group, liraglutide treatment reduced SBP compared with placebo and glimepiride treatment, with mean differences of -5.60 and -2.38 mmHg, and 95% CIs of -5.84 to -5.36, p < 0.00001 and -4.75 to -0.01, p = 0.05, respectively. In the 1.8-mg-treated group, liraglutide also reduced SBP compared with placebo and glimepiride treatment with mean differences of -4.49 and -2.62 mmHg, and a 95% CI of -4.73 to -4.26, p < 0.00001, and -2.91 to -2.33, p < 0.00001, respectively.. Treatment with the GLP-1 RAs exenatide and liraglutide reduced SBP and DBP by 1 to 5 mmHg compared with some other anti-diabetic drugs including insulin, glimepiride and placebo for patients with T2DM. GLP-1 RAs may offer an alternative therapy for these patients and will help provide extra cardiovascular benefits.

Topics: Blood Glucose; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypertension; Hypoglycemic Agents; Insulin; Liraglutide; Male; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Sulfonylurea Compounds; Treatment Outcome; Venoms

Anti-diabetic drugs have, in addition to their well-known glucose lowering-effect, different effects in the rest of cardiovascular factors that are associated with diabetes mellitus. Glucagon-like peptide-1 (GLP-1) receptor agonists have recently been incorporated to the therapeutic arsenal of type 2 diabetes mellitus. The objective of this review is to summarize the available evidence on the effect of the GLP-1 receptor agonists on different cardiovascular risk factors, mediated by the effect of GLP-1 receptor agonists on the control of hyperglycaemia and the GLP-1 receptor agonists effect on other cardiovascular risk factors (weight control, blood pressure control, lipid profile and all other cardiovascular risk biomarkers). In addition, we present the emerging evidence with regards to the impact that GLP-1 receptor agonists therapy could have in the reduction of cardiovascular events and the currently ongoing studies addressing this issue.

Topics: Blood Glucose; Brain; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dyslipidemias; Exenatide; Gastric Emptying; Glucagon-Like Peptide 1; Heart; Humans; Hypertension; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Liraglutide; Liver; Meta-Analysis as Topic; Obesity; Peptides; Risk; Venoms; Weight Loss

The glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide and exenatide can improve glycaemic control by stimulating insulin release through pancreatic β-cells in a glucose-dependent manner. GLP-1 receptors are not restricted to the pancreas; therefore, GLP-1 RAs cause additional non-glycaemic effects. Preclinical and clinical trial data suggest a multitude of additional beneficial effects related to GLP-1 RA therapy, including improvements in β-cell function, systolic blood pressure and body weight. These effects are of a particular advantage to patients with type 2 diabetes, as most are affected by β-cell dysfunction, obesity and hypertension. Transient gastrointestinal adverse events, such as nausea and diarrhoea, are also common. To improve gastrointestinal tolerability, an incremental dosing approach is used with liraglutide and exenatide twice daily. A potential protective role for GLP-1 RAs in the cardiovascular and central nervous systems has been suggested from animal studies and short-term clinical trials. These effects and other safety aspects of GLP-1 therapy are currently being investigated in ongoing long-term clinical studies.

Topics: Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypertension; Incretins; Insulin-Secreting Cells; Liraglutide; Male; Neuroprotective Agents; Receptors, Glucagon; Weight Loss

Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel drugs for the treatment of type 2 diabetes mellitus. They exert their action through inhibition of the catabolism of locally secreted incretins such as glucagon-like peptide-4 (GLP-4) and glucose-dependent insulinotropic polypeptide (GIP) by inhibiting enzyme DPP-4. GLP-1 and GIP are secreted from the gastrointestinal tract in response to food intake. GLP-1 is secreted from L cells present in the mucosa of the small intestine and colon, whereas GIP is secreted from K cells of the jejunum. These 2 incretins lower blood glucose levels and postprandial hyperglycemia by stimulating insulin release from b cells of the pancreas, thus increasing insulin sensitivity, delaying gastrointestinal emptying, decreasing food intake through early satiety, and causing weight loss in the long term. However, their action is short-lived (2 to 3 minutes) because of catabolism by the DPP-4 enzyme. The importance of DPP-4 inhibitors lies in their blockade of the DPP-4 enzyme leading to the prevention of their catabolism and thus increasing their blood levels, extending the duration of their action, and improving their blood glucose-lowering effect. In addition to their antidiabetic action, recent experimental and clinical studies have demonstrated a pleiotropic cardiovascular protective effect of these agents independent of their antidiabetic action. They prevent atherosclerosis, improve endothelial dysfunction, lower blood pressure, and prevent myocardial injury. All these actions are discussed in this concise review. In conclusion, DPP-4 inhibitors are novel antidiabetic agents with pleiotropic cardiovascular protective effects in addition to their antidiabetic action.

Topics: Animals; Cardiotonic Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Endothelium, Vascular; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Heart; Humans; Hypertension; Incretins; Receptors, Glucagon

Incretin-based therapies are currently being used in the treatment of type 2 diabetes mellitus (T2DM). Apart from glycemic control, these agents have been shown to have multiple extra-pancreatic effects, including their role in blood pressure (BP) regulation. This article will review the origins of incretins, the incretin axis, possible mechanisms of antihypertensive effect of these agents, as well as the recent evidence.. Preclinical and clinical studies demonstrate the antihypertensive effects of glucagon-like peptide-1 (GLP-1) and its analogs in patients with T2DM and hypertension. This effect seems to be mediated through vasodilatation as well as modulation of renal sodium handling causing natriuresis, although the exact mechanisms are not fully known.. Incretin-based therapies are emerging as a novel class of hypoglycemic agents that display antihypertensive properties. Given the small decreases in BP, it is unlikely that these agents will be used as stand-alone antihypertensive agents, but they may be an attractive option in patients with T2DM and hypertension.

Topics: Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypertension; Incretins

Type 2 diabetes mellitus (DM) affects an estimated 25.8 million people in the United States and is the 7th leading cause of death. While effective therapy can prevent or delay the complications that are associated with diabetes, according to the Center for Disease Control, 35% of Americans with DM are undiagnosed, and another 79 million Americans have blood glucose levels that greatly increase their risk of developing DM in the next several years. One of the Healthy People 2020 goals is to reduce the disease and economic burden of DM and improve the quality of life for all persons who have, or are at risk for, DM. Achieving this goal requires a concentrated focus on improving the management of diabetes and in targeting prevention of macrovascular complications. This article reviews established and emerging therapeutic approaches for managing DM and prevention of macrovascular complications.

Topics: Algorithms; Cardiomyopathy, Hypertrophic; Cerebrovascular Disorders; Diabetes Mellitus; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Dyslipidemias; Glucagon-Like Peptide 1; Glycated Hemoglobin; Healthy People Programs; Humans; Hyperglycemia; Hypertension; Life Style; Myocardial Infarction; Risk Factors

The prevalence of diabetes is expected to rise together with an increase in morbidity and a reduction in life expectancy. A leading cause of death is cardiovascular disease, and hypertension and diabetes are additive risk factors for this complication. Selected treatment options should neither increase cardiovascular risk in patients with diabetes, nor increase risk of hyperglycaemia in patients with hypertension. The efficacy of present antihyperglycaemic agents is limited and new therapies, such as incretin-targeted agents, are under development. Even though most patients do not achieve glycated haemoglobin targets, trial data show that such interventions reduce the incidence of macrovascular events; however, intensive lowering may be detrimental in patients with existing cardiovascular disease. Currently available oral drugs do not address the key driver of type 2 diabetes--loss of functional beta-cell mass. In the future, new oral treatments must improve this, whilst providing durable blood glucose control and long-term tolerability.

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Disease Outbreaks; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypertension; Hypoglycemic Agents; Incretins; Male

Recently, the European Medicines Agency (EMEA) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending to grant a marketing authorization for liraglutide for the treatment of type 2 diabetes mellitus. Liraglutide is the first human glucagon-like peptide-1 (GLP-1) analog, based on the structure of native GLP-1, with pharmacokinetic properties suitable for once-daily dosing. In the phase III Liraglutide Effect and Action in Diabetes (LEAD) program, liraglutide has been shown to lower glycated hemoglobin to the same extent or more than other antidiabetic drugs including insulin. Liraglutide determines favorable changes in the global cardiovascular risk profile because its use is associated with weight loss, blood pressure reduction, as well as improvements of several cardiovascular risk biomarkers. Liraglutide is generally well tolerated, the most frequently reported adverse effect is transient nausea, and it does not seems to have significant interactions with medications commonly used for cardiovascular prevention. This article reviews, for the practicing cardiologist, the results of the LEAD program and explores liraglutide potentials for cardiovascular prevention in type 2 diabetes mellitus.

Topics: Algorithms; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Complications; Diabetes Mellitus, Type 2; Evidence-Based Medicine; Glucagon-Like Peptide 1; Humans; Hypertension; Hypoglycemic Agents; Liraglutide; Obesity; Practice Guidelines as Topic; Risk Factors; Treatment Outcome

GLP-1 receptor (GLP-1R) agonists induce natriuresis and reduce blood pressure (BP) through incompletely understood mechanisms. We examined the effects of acute and 21-day administration of liraglutide on plasma atrial natriuretic peptide (ANP), urinary sodium excretion, office and 24-h BP, and heart rate (HR).. Liraglutide or placebo was administered for 3 weeks to hypertensive subjects with type 2 diabetes in a double-blinded, randomized, placebo-controlled crossover clinical trial in the ambulatory setting. End points included within-subject change from baseline in plasma ANP, Nt-proBNP, office BP, and HR at baseline and over 4 h following a single dose of liraglutide (0.6 mg) and after 21 days of liraglutide (titrated to 1.8 mg) versus placebo administration. Simultaneous 24-h ambulatory BP and HR monitoring and 24-h urine collections were measured at baseline and following 21 days of treatment.. Plasma ANP levels did not change significantly after acute (+16.72 pg/mL, P = 0.24, 95% CI [-12.1, +45.5] at 2 h) or chronic (-17.42 pg/mL, 95% CI [-36.0, +1.21] at 2 h) liraglutide administration. Liraglutide significantly increased 24-h and nighttime urinary sodium excretion; however, 24-h systolic BP was not significantly different. Small but significant increases in 24-h and nighttime diastolic BP and HR were observed with liraglutide. Body weight, HbA1c, and cholesterol were lower, and office-measured HR was transiently increased (for up to 4 h) with liraglutide administration.. Sustained liraglutide administration for 3 weeks increases urinary sodium excretion independent of changes in ANP or BP in overweight and obese hypertensive patients with type 2 diabetes.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Endpoint Determination; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Rate; Humans; Hypertension; Liraglutide; Male; Middle Aged; Natriuresis; Natriuretic Peptide, Brain; Obesity; Peptide Fragments; Receptors, Glucagon; Sodium

Diet composition may affect blood pressure (BP), but the mechanisms are unclear. The aim of the present study was to compare postprandial BP-related responses to the ingestion of pea protein, milk protein and egg-white protein. In addition, postprandial BP-related responses to the ingestion of maltodextrin were compared with those to the ingestion of sucrose and a protein mix. We hypothesised that lower postprandial total peripheral resistance (TPR) and BP levels would be accompanied by higher plasma concentrations of nitric oxide, insulin, glucagon-like peptide 1 (GLP-1) and glucagon. On separate occasions, six meals were tested in a randomised order in forty-eight overweight or obese adults with untreated elevated BP. Postprandial responses of TPR, BP and plasma concentrations of insulin, glucagon, GLP-1 and nitrite, nitroso compounds (RXNO) and S-nitrosothiols (NO(x)) were measured for 4 h. No differences were observed in TPR responses. Postprandial BP levels were higher after the ingestion of the egg-white-protein meal than after that of meals containing the other two proteins (P≤ 0·01). The ingestion of the pea-protein meal induced the highest NO(x) response (P≤ 0·006). Insulin and glucagon concentrations were lowest after the ingestion of the egg-white-protein meal (P≤ 0·009). Postprandial BP levels were lower after the ingestion of the maltodextrin meal than after that of the protein mix and sucrose meals (P≤ 0·004), while postprandial insulin concentrations were higher after the ingestion of the maltodextrin meal than after that of the sucrose and protein mix meals after 1-2 h (P≤ 0·0001). Postprandial NO(x), GLP-1 and glucagon concentrations were lower after the ingestion of the maltodextrin meal than after that of the protein mix meal (P≤ 0·008). In conclusion, different protein and carbohydrate sources induce different postprandial BP-related responses, which may be important for BP management. Lower postprandial BP levels are not necessarily accompanied by higher NO(x), insulin, glucagon or GLP-1 responses.

Topics: Blood Pressure; Body Mass Index; Cross-Over Studies; Dietary Carbohydrates; Dietary Sucrose; Double-Blind Method; Egg Proteins, Dietary; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Hypertension; Insulin; Insulin Secretion; Male; Meals; Middle Aged; Milk Proteins; Nitric Oxide; Overweight; Pisum sativum; Plant Proteins, Dietary; Polysaccharides; Postprandial Period; Seeds

Hypertension is a significant risk factor of cardiovascular diseases (CVDs) with high prevalence worldwide, the current treatment has multiple adverse effects and requires continuous administration. The glucagon-like peptide-1 receptor (GLP-1R) agonists have shown great potential in treating diabetes mellitus, neurodegenerative diseases, obesity and hypertension. Butyric acid is a potential target in treating hypertension. Yet, the application of GLP-1 analogue and butyric acid in reducing blood pressure and reversing ventricular hypertrophy remains untapped. In this study, we combined the therapeutic capability of GLP-1 and butyric acid by transforming Clostridium butyricum (CB) with recombinant plasmid pMTL007 encoded with hGLP gene to construct the engineered probiotics Clostridium butyricum-pMTL007-GLP-1 (CB-GLP-1). We used spontaneous hypertensive rat (SHR) models to evaluate the positive effect of this strain in treating hypertension. The results revealed that the intragastric administration of CB-GLP-1 had markedly reduced blood pressure and improved cardiac marker ACE2, AT2R, AT1R, ANP, BNP, β-MHC, α-SMA and activating AMPK/mTOR/p70S6K/4EBP1 signalling pathway. The high-throughput sequencing further demonstrated that CB-GLP-1 treatments significantly improved the dysbiosis in the SHR rats via downregulating the relative abundance of Porphyromonadaceae at the family level and upregulating Lactobacillus at the genus level. Hence, we concluded that the CB-GLP-1 greatly improves blood pressure and cardiomegaly by restoring the gut microbiome and reducing ventricular hypertrophy in rat models. This is the first time using engineered CB in treating hypertension, which provides a new idea for the clinical treatment of hypertension.

Topics: Animals; Blood Pressure; Butyric Acid; Clostridium butyricum; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Hypertension; Hypertrophy; Probiotics; Rats; Rats, Inbred SHR

Hypertension is the most common cardiovascular disease, and its main harmful effect is chronic damage to target organs. In some patients with well-controlled blood pressure, target organ damage still occurs. GLP-1 agonists have significant cardiovascular benefits, but their antihypertensive effect is limited. The cardiovascular protective effect of GLP-1 is worth studying.. The ambulatory blood pressure of spontaneously hypertensive rats (SHRs) was detected by ambulatory blood pressure monitoring, and the characteristics of blood pressure and the effect of subcutaneous intervention with a GLP-1R agonist on blood pressure were observed. To explore the mechanism of the cardiovascular benefit of GLP-1R agonists in SHRs, we evaluated the effects of GLP-1R agonists on vasomotor function and calcium homeostasis in vascular smooth muscle cells (VSMCs) in vitro.. Although the blood pressure of SHRs was significantly higher than that of WKY rats, the blood pressure variability of SHRs was also significantly higher than that of the control group. The GLP-1R agonist significantly reduced blood pressure variability in SHRs, but the antihypertensive effect was not obvious. GLP-1R agonists can significantly improve the cytoplasmic calcium overload of VSMCs in SHRs by upregulating the expression of NCX1, improving the systolic and diastolic functions of arterioles, and reducing blood pressure variability.. Taken together, these results provide evidence that GLP-1R agonists improved VSMC cytoplasmic Ca2+ homeostasis through upregulated NCX1 expression in SHRs, which plays a key role in blood pressure stability and broad cardiovascular benefits.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium; Glucagon-Like Peptide 1; Homeostasis; Hypertension; Hypotension; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY

The current research was designed to explore the relationship between the lipid accumulation index (LAP), coronary artery disease (CAD), and the triglyceride-glucose (TyG) index in patient with H-type hypertension.. From June 2021 to January 2022, our hospital's information management system collected data on 186 patients with essential hypertension. The participants were categorized into two groups (H-type hypertension (. There were statistically significant differences (. In conclusion, the LAP and TyG indexes were observed to be closely related to the degree of CAD in H-type individuals with hypertension, which can better understand the pathogenesis of coronary artery disease in patients with H-type hypertension and is of great significance for guiding clinical doctors to carry out personalized treatment and management.

Topics: Cholesterol, HDL; Constriction, Pathologic; Coronary Artery Disease; Glucagon-Like Peptide 1; Glucose; Homocysteine; Humans; Hypertension

Topics: Chemoreceptor Cells; Glucagon-Like Peptide 1; Humans; Hypertension

This study aims to investigate whether stabilization of glucagon-like peptide-1 (GLP-1) level reduces angiotensin II (Ang II)-induced cardiac fibrosis and -elevated blood pressure accompanying with inhibition of NADPH oxidase (NOX) expression and preservation of mitochondrial integrity. The study was performed in Sprague-Dawley rat model of Ang II infusion (500 ng/kg/min) using osmotic minipumps for 4 weeks. GLP-1 receptor agonist liraglutide (0.3 mg/kg, injected subcutaneously twice daily) and dipeptidyl peptides-4 inhibitor, linagliptin (8 mg/kg, administered via oral gavage) were selected to preserve GLP-1 level. Blood pressure was measured noninvasively. Heart and aorta were saved for histological analysis. Relative to the animals with Ang II infusion, in the heart, liraglutide and linagliptin comparatively reduced the protein levels of NOX4 and TGFβ1 and expression of monocyte chemoattractant protein 1, and attenuated the proliferation of myofibroblasts (15 ± 4 and 13 ± 3 vs. 42 ± 22/HPF in Ang II group). The number of distorted mitochondria in both groups was significantly reduced (8 ± 4 and 10 ± 6 vs. 27 ± 13/HPF in Ang II group), in company with a significant reduction in cardiac fibrosis. In the aorta, treatment with liraglutide and linagliptin significantly downregulated the expression of NOX4 and intercellular adhesion molecule 1, and enhanced endothelial NOS expression. Aortic wall thickness was reduced comparatively (267 ± 22 and 286 ± 25 vs. 339 ± 40 μm in Ang II group). The area of fibrotic aorta was also reduced (13 ± 6 and 14 ± 5 vs. 38 ± 24 mm

Topics: Angiotensin II; Animals; Cardiomyopathies; Fibrosis; Glucagon-Like Peptide 1; Hypertension; Linagliptin; Liraglutide; Mitochondria; NADPH Oxidase 4; Rats; Rats, Sprague-Dawley

Glucagon-like peptide-1 (GLP-1), a novel type of glucose-lowering agent, has been reported to exert cardioprotective effects. However, the cardioprotective mechanism of GLP-1 on spontaneous hypertension-induced cardiac hypertrophy has not been fully elucidated. In this study, we revealed that liraglutide or alogliptin treatment ameliorated spontaneous hypertension-induced cardiac hypertrophy, as evidenced by decreased levels of cardiac hypertrophic markers (atrial natriuretic peptide, brain natriuretic peptide, and β-myosin heavy chain), as well as systolic blood pressure, diastolic blood pressure, mean arterial pressure, and histological changes. Both drugs significantly reduced the levels of angiotensin II (AngII) and AngII type 1 receptor (AT1R) and upregulated the levels of AngII type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2), as indicated by a reduced AT1R/AT2R ratio. Simultaneously, treatment with liraglutide or alogliptin significantly increased GLP-1 receptor expression and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and downregulated the phosphorylation of mammalian target of rapamycin (mTOR), p70 ribosomal S6 protein kinase, and eukaryotic translation initiation factor 4E binding protein 1 in spontaneous hypertension rats. Furthermore, our data demonstrated that the AMPK inhibitor compound C or mTOR activator MHY1485 inhibited the anti-hypertrophic effect of GLP-1. In summary, our study suggests that liraglutide or alogliptin protects the heart against cardiac hypertrophy by regulating the expression of AngII/AT1R/ACE2 and activating the AMPK/mTOR pathway, and GLP-1 agonist can be used in the treatment of patients with cardiac hypertrophy.

Topics: Adenylate Kinase; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Blood Pressure; Cardiomegaly; Cardiotonic Agents; Cell Line; Disease Models, Animal; Glucagon-Like Peptide 1; Hypertension; Liraglutide; Male; Morpholines; Myocytes, Cardiac; Piperidines; Rats; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; TOR Serine-Threonine Kinases; Triazines; Uracil

In addition to serving as an incretin-based treatment of type 2 diabetes mellitus (T2DM), glucagon-like peptide 1 (GLP-1) can also reverse cardiovascular diseases caused by vascular remodelling. However, a detailed mechanism underlying how GLP-1 reverses vascular remodelling remains unclear. Here, Spontaneous hypertension rats (SHR) were used as an in vivo model of vascular remodelling. Treatment with a GLP-1 receptor (GLP-1R) agonist Liraglutide or dipeptidyl peptidase 4 (DPP4) inhibitor Alogliptin decreased systolic blood pressure (SBP), diastolic blood pressure (DBP), thickness of vascular wall, and overall collagen levels in SHR. In vitro vascular remodelling can be induced by exposing rat aortic smooth muscle cells (RASMC) to angiotensin II (Ang II); GLP-1 treatment attenuated AngII induction of RASMC proliferation, migration, and excessive extracellular matrix (ECM) degradation. Downregulation of matrix metalloproteinase 1 (MMP1) enhanced the inhibitory effects of GLP-1, and extracellular regulated protein kinase 1/2 (ERK1/2) and nuclear factor kappa-B (NF-κB) signalling participated in these processes. These results provide a new mechanistic understanding of key therapeutic strategies for the treatment of vascular remodelling-related diseases.

Topics: Animals; Blood Pressure; Cells, Cultured; Dipeptidyl-Peptidase IV Inhibitors; Down-Regulation; Gene Expression Regulation, Enzymologic; Glucagon-Like Peptide 1; Hypertension; Liraglutide; Male; MAP Kinase Signaling System; Matrix Metalloproteinase 1; Myocytes, Smooth Muscle; NF-kappa B; Piperidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Uracil; Vascular Remodeling

Angiotensin-1 converting enzyme inhibitors (ACEIs) improve insulin sensitivity. Inhibitors of dipeptidyl peptidase-4 (DPP-4) are anti-diabetic drugs with several cardio-renal effects. Both ACE and DPP-4 share common features. Thus, we tested if they could be inhibited by one inhibitor. First, in silico screening was used to investigate the ability of different DPP-4 inhibitors or ACEIs to interact with DPP-4 and ACE. The results of screening were then extrapolated into animal study. Fifty Sprague Dawley rats were randomly assigned into 5 groups treated with vehicle, captopril, enalapril, linagliptin or sitagliptin. Both low and high doses of each drug were tested. Baseline blood samples and samples at days 1, 8, 10, 14 were used to measure plasma DPP-4 and ACE activities and angiotensin II levels. Active glucagon-like peptide-1 (GLP-1) levels were measured after oral glucose challenge. All tested DPP-4 inhibitors could interact with ACE at a relatively reasonable binding energy while most of the ACEIs only interacted with DPP-4 at a predicted high inhibition constant. In rats, high dose of sitagliptin was able to inhibit ACE activity and reduce angiotensin II levels while linagliptin had only a mild effect. ACEIs did not significantly affect DPP-4 activity or prevent GLP-1 degradation. It seems that some DPP-4 inhibitors could inhibit ACE and this could partially explain the cardio-renal effects of these drugs. Further studies are required to determine if such inhibition could take place in clinical settings.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enalapril; Female; Glucagon-Like Peptide 1; Humans; Hypertension; Linagliptin; Peptidyl-Dipeptidase A; Protein Binding; Rats; Rats, Sprague-Dawley; Sitagliptin Phosphate

Cardiovascular diseases frequently coexist with chronic kidney disease that constitutes a major determinant of outcome in patients with heart failure. Dysfunction of both organs is related to chronic inflammation, endothelial dysfunction, oxidative stress, and fibrosis. Widespread expression of serine protease DPP4 that degrades varieties of substrates suggests its involvement in numerous physiological processes. In this study, we tested the effects of selective DPP4 inhibition on the progression of renal disease in a nondiabetic model of hypertensive heart disease using Dahl salt-sensitive rats. Chronic DPP4 inhibition positively affected renal function with a significant reduction in albuminuria and serum creatinine. DPP4 inhibition attenuated the inflammatory component by reducing the expression of NF-

Topics: Animals; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Endothelial Cells; Fibrosis; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypertension; Inflammation; Kidney; Kidney Function Tests; Models, Biological; Nitrosative Stress; Oxidative Stress; Phenotype; Rats, Inbred Dahl; Renal Insufficiency, Chronic; Signal Transduction; Sodium Chloride, Dietary

Pancreatic lipidosis (nonalcoholic fatty pancreas disease, NAFPD) causes insulin resistance and dysfunction of pancreatic β-cells, with the risk of type 2 diabetes mellitus (T2DM). However, the prevalence and pathogenic factors associated with NAFPD are not clear. The aim of the study was to explore the prevalence of NAFPD in a Chinese adult population, and investigate factors associated with NAFPD aggravation.This was a cross-sectional study; 4419 subjects were enrolled for NAFPD screening and were divided into NAFPD (n = 488) and without NAFPD (n = 3930) groups. The sex, age, related concomitant diseases, general physical parameters, and serum glucose and lipid metabolism were compared between the 2 groups.The overall NAFPD prevalence was 11.05%, but increased with age. In those <55 years NAFPD prevalence was lower in females than males (P < .05), but prevalence was similar >55 years. Nonalcoholic fatty liver disease (NAFLD), T2DM, homeostasis model assessment-insulin resistance index, total cholesterol, triglyceride, lipoprotein, adiponectin, and glucagon-like peptide 1 (GLP-1) were the independent risk factors for NAFPD (P < .05). Analaysis of mild NAFPD (MN) and severe NAFPD (SN) subgroups, according to the extent of fat deposition, suggested that NAFLD, triglyceride, lipoprotein, and adiponectin were independent risk factors for NAFPD aggravation (P < .05).The NAFPD prevalence was about 11% in Chinese adults. Its development and progression was related to NAFLD, T2DM, insulin resistance, dyslipidemia, and GLP-1 levels. Severe NAFPD was associated with NAFLD and dyslipidemia.

Topics: Adiponectin; Adult; Age Factors; China; Comorbidity; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Dyslipidemias; Female; Glucagon-Like Peptide 1; Humans; Hypertension; Insulin Resistance; Lipoproteins; Male; Middle Aged; Overweight; Pancreatic Diseases; Prevalence; Risk Factors; Sex Factors; Triglycerides

To reveal potential association between glucagon-like peptide 1 (GLP-1) concentration in serum and mild cognitive function impairment (MCI) in type 2 diabetes mellitus (T2DM) patients.. A total of 106 T2DM patients and 47 normal controls were recruited in this study. Montreal Cognitive Assessment (MoCA) was performed in all subjects. Among the 106 patients, 52 presented with MCI. Fasting blood glucose (FBG), total cholesterol (TC), low-density cholesterol (LDL-C), high-density cholesterol (HDL-C), triglyceride (TG), uric acid (UA) and GLP-1 levels were also assessed in all subjects.. Patients with MCI had higher serum concentrations of FBG and TC and lower concentrations of GLP-1 and HDL-C than controls. Bivariate correlation analysis showed that MCI in T2DM patients closely correlated with FBG, HDL-C, and GLP-1 levels. Moreover, ordinal regression analysis showed that GLP-1 concentration in serum was protective for MCI in T2DM patients (OR = 0.025; 95%CI: 0.005-3.934).. Our results indicated that low concentration of GLP-1 may play a role in the pathogenesis of MCI in T2DM patients.

Topics: Adult; Biomarkers; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hypertension; Hypoglycemic Agents; Male; Middle Aged; Risk Factors

Accumulating evidence from clinical and experimental studies indicates that the incretin glucagon-like peptide-1 (GLP-1) elicits blood-pressure lowering effects via its diuretic, natriuretic and vasodilatory properties. The present study investigated whether acute infusion of GLP-1 induces diuresis and natriuresis in spontaneously hypertensive rats (SHRs). Additionally, we examined whether GLP-1 influences the vascular reactivity of the renal arteries of normotensive and hypertensive rats and elucidated the underlying mechanisms. We found that the increase in urinary output and urinary sodium excretion in response to systemic infusion of GLP-1 for 30min in SHRs was much less pronounced than in normotensive rats. The diuretic and natriuretic actions of GLP-1 in normotensive rats were accompanied by increases in GFR and RBF and a reduction in RVR through activation of the cAMP signaling pathway. However, no changes in renal hemodynamics were observed in SHRs. Similarly, GLP-1 induced an endothelium-independent relaxation effect in the renal arteries of normotensive rats, whereas the renal vasculature of SHRs was unresponsive to this vasodilator. The absence of a GLP-1-induced renal artery vasodilator effect in SHRs was associated with lower expression of the GLP-1 receptor, blunted GLP-1-induced increases in cAMP production and higher activity and expression of the GLP-1 inactivating enzyme dipeptidyl peptidase IV relative to the renal arteries of normotensive rats. Collectively, these results demonstrate that the renal acute responses to GLP-1 are attenuated in SHRs. Thus, chronic treatment with incretin-based agents may rely upon the upregulation of GLP-1/GLP-1 receptor signaling in the kidneys of hypertensive patients and experimental models.

Topics: Animals; Cyclic AMP; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypertension; Male; Natriuresis; Rats; Renal Artery; Signal Transduction

Glucagon-like peptide-1 (GLP-1) is an incretin hormone increasing postprandial insulin release. GLP-1 also induces diuresis and natriuresis in humans and rodents. The GLP-1 receptor is extensively expressed in the renal vascular tree in normotensive rats where acute GLP-1 treatment leads to increased mean arterial pressure (MAP) and increased renal blood flow (RBF). In hypertensive animal models, GLP-1 has been reported both to increase and decrease MAP. The aim of this study was to examine expression of renal GLP-1 receptors in spontaneously hypertensive rats (SHR) and to assess the effect of acute intrarenal infusion of GLP-1. We hypothesized that GLP-1 would increase diuresis and natriuresis and reduce MAP in SHR. Immunohistochemical staining and in situ hybridization for the GLP-1 receptor were used to localize GLP-1 receptors in the kidney. Sevoflurane-anesthetized normotensive Sprague-Dawley rats and SHR received a 20 min intrarenal infusion of GLP-1 and changes in MAP, RBF, heart rate, dieresis, and natriuresis were measured. The vasodilatory effect of GLP-1 was assessed in isolated interlobar arteries from normo- and hypertensive rats. We found no expression of GLP-1 receptors in the kidney from SHR. However, acute intrarenal infusion of GLP-1 increased MAP, RBF, dieresis, and natriuresis without affecting heart rate in both rat strains. These results suggest that the acute renal effects of GLP-1 in SHR are caused either by extrarenal GLP-1 receptors activating other mechanisms (e.g., insulin) to induce the renal changes observed or possibly by an alternative renal GLP-1 receptor.

Topics: Animals; Blood Pressure; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypertension; Kidney; Male; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Renal Circulation; Urodynamics; Vasodilation

Rapid gastric emptying has been proposed to justify the increase in glucagon-like polypeptide-1 (GLP-1) after laparoscopic sleeve gastrectomy (LSG).. To assess gastric emptying changes after LSG and their relationship with GLP-1 secretion.. San Salvatore Hospital general surgery unit, University of L'Aquila, Italy.. 52 patients underwent gastric emptying scintigraphy for liquid and solid foods, before and 3 months after LSG. Twenty-six patients were in the liquid group (L group) and the remaining in the solid group (S group). We evaluated the half time of gastric emptying (T. The rapid gastric emptying 3 months after LSG upregulates the production of GLP-1 in the distal bowel. Further studies are needed to confirm these findings.

Topics: Adult; Analysis of Variance; Bariatric Surgery; Female; Gastrectomy; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Hypertension; Hypothyroidism; Laparoscopy; Male; Obesity, Morbid; Sleep Apnea Syndromes; Up-Regulation

Because the effects of dipeptidyl peptidase 4 (DPP4) inhibitors on blood pressure are controversial, we examined the long-term effects of sitagliptin (80 mg/kg per day) on blood pressure (radiotelemetry) in spontaneously hypertensive rats (SHR), Wistar-Kyoto rats, and Zucker Diabetic-Sprague Dawley rats (metabolic syndrome model). In SHR, chronic (3 weeks) sitagliptin significantly increased systolic, mean, and diastolic blood pressures by 10.3, 9.2, and 7.9 mm Hg, respectively, a response abolished by coadministration of BIBP3226 (2 mg/kg per day; selective Y1-receptor antagonist). Sitagliptin also significantly increased blood pressure in SHR treated with hydralazine (vasodilator; 25 mg/kg per day) or enalapril (angiotensin-converting enzyme inhibitor; 10 mg/kg per day). In Wistar-Kyoto rats, chronic sitagliptin slightly decreased systolic, mean, and diastolic blood pressures (-1.8, -1.1, and -0.4 mm Hg, respectively). In Zucker Diabetic-Sprague Dawley rats, chronic sitagliptin decreased systolic, mean, and diastolic blood pressures by -7.7, -5.8, and -4.3 mm Hg, respectively, and did not alter the antihypertensive effects of chronic enalapril. Because DPP4 inhibitors impair the metabolism of neuropeptide Y1-36 (NPY1-36; Y1-receptor agonist) and glucagon-like peptide (GLP)-1(7-36)NH2 (GLP-1 receptor agonist), we examined renovascular responses to NPY1-36 and GLP-1(7-36)NH2 in isolated perfused SHR and Zucker Diabetic-Sprague Dawley kidneys pretreated with norepinephrine (to induce basal tone). In Zucker Diabetic-Sprague Dawley kidneys, NPY1-36 and GLP-1(7-36)NH2 exerted little, if any, effect on renovascular tone. In contrast, in SHR kidneys, both NPY1-36 and GLP-1(7-36)NH2 elicited potent and efficacious vasoconstriction.. (1) The effects of DPP4 inhibitors on blood pressure are context dependent; (2) The context-dependent effects of DPP4 inhibitors are due in part to differential renovascular responses to DPP4’s most important substrates (NPY1–36 and GLP-1(7–36)NH2) [corrected]; (3) Y1 receptor antagonists may prevent the prohypertensive and possibly augment the antihypertensive effects of DPP4 inhibitors.

Topics: Animals; Blood Pressure; Blood Pressure Determination; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Glucagon-Like Peptide 1; Hypertension; Male; Pyrazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sitagliptin Phosphate; Treatment Outcome; Triazoles

A growing body of evidence has indicated that dipeptidyl peptidase-4 (DPP-4) inhibitors have antihypertensive effects. Here, we aim to examine the effect of vildagliptin, a DPP-4-specific inhibitor, on blood pressure and its circadian-dipping pattern during the development of salt-dependent hypertension in Dahl salt-sensitive (DSS) rats. DSS rats were treated with a high-salt diet (8% NaCl) plus vehicle or vildagliptin (3 or 10 mg kg(-1) twice daily by oral gavage) for 7 days. Blood pressure was measured by the telemetry system. High-salt diet for 7 days significantly increased the mean arterial pressure (MAP), systolic blood pressure (SBP) and were also associated with an extreme dipping pattern of blood pressure in DSS rats. Treatment with vildagliptin dose-dependently decreased plasma DPP-4 activity, increased plasma glucagon-like peptide 1 (GLP-1) levels and attenuated the development of salt-induced hypertension. Furthermore, vildagliptin significantly increased urine sodium excretion and normalized the dipping pattern of blood pressure. In contrast, intracerebroventricular infusion of vildagliptin (50, 500 or 2500 μg) did not alter MAP and heart rate in DSS rats. These data suggest that salt-dependent hypertension initially develops with an extreme blood pressure dipping pattern. The DPP-4 inhibitor, vildagliptin, may elicit beneficial antihypertensive effects, including the improvement of abnormal circadian blood pressure pattern, by enhancing urinary sodium excretion.

Topics: Adamantane; Animals; Antihypertensive Agents; Arterial Pressure; Blood Pressure; Circadian Rhythm; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Glucagon-Like Peptide 1; Heart Rate; Hypertension; Injections, Intraventricular; Male; Nitriles; Pyrrolidines; Rats; Rats, Inbred Dahl; Sodium; Sodium Chloride, Dietary; Telemetry; Vildagliptin

Topics: Antihypertensive Agents; Blood Pressure; Cross-Cultural Comparison; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Guideline Adherence; Humans; Hypertension; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors

Topics: Aged; Body Mass Index; Dyslipidemias; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypertension; Hypoglycemic Agents; Insulin; Middle Aged; Obesity, Morbid; Sleep Apnea, Obstructive; Treatment Outcome; Weight Loss

The present study was undertaken to assess the possible protective effects of sitagliptin, a dipeptidyl peptidase 4-inhibitor (DPP4), against Nω-nitro-L-arginine methyl ester (L-NAME) induced hypertensive nephropathy in rats. Hypertension was induced in adult rats by administration of L-NAME for 6 weeks. Rats were treated with sitagliptin (10mg/kg/day or 30 mg/kg/day) for six weeks. Chronic L-NAME administration resulted in depletion of serum nitric oxide (NO) associated with elevation in the mean arterial pressure. When compared with the control group; serum urea, serum creatinine, albuminuria, urinary N-acetyl-ß-d-glucosaminidase (NAG) level and renal tissue malondialdhyde (MDA) content were significantly elevated, while creatinine clearance, serum level of glucagon like peptide-1 (GLP-1) as well as renal tissue superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were signifcantly decreased in L-NAME treated group. Renal expression of mRNA for eNOS and GLP-1 receptors were reduced in the L-NAME treated group as compared with the control group. Treatment with sitagliptin (10mg/kg or 30 mg/kg) successfully ameliorated the deleterious effects of L-NAME on the all tested parameters. Our study indicates a novel protective effect of sitagliptin against L-NAME induced hypertensive nephropathy. An effect which is mediated through, increasing serum level of GLP-1, upregulation of GLP-1 receptors, which in turn, lead to induction of expression eNOS, increased serum NO level, tandem with decreased lipid perodixation and restore the antioxidant defense mechanisms. It is worth mentioning that the effects produced by sitaglipin (30 mg/kg) were superior to the effects obtained by the lower dose.

Topics: Animals; Blood Glucose; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glutathione Peroxidase; Hypertension; Hypertension, Renal; Hypoglycemic Agents; Kidney; Lipid Peroxidation; Male; Nephritis; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type III; Pyrazines; Rats; Rats, Wistar; Receptors, Glucagon; Sitagliptin Phosphate; Superoxide Dismutase; Triazoles

The aims of this study were designed to determine whether liraglutide, a long-acting glucagon-like peptide, could reverse the adverse effects of a diet high in fat that also contained trans-fat and high-fructose corn syrup (ALIOS diet). Specifically, we examined whether treatment with liraglutide could reduce hepatic insulin resistance and steatosis as well as improve cardiac function. Male C57BL/6J mice were pair fed or fed ad libitum either standard chow or the ALIOS diet. After 8 wk the mice were further subdivided and received daily injections of either liraglutide or saline for 4 wk. Hyperinsulinemic-euglycemic clamp studies were performed after 6 wk, revealing hepatic insulin resistance. Glucose tolerance and insulin resistance tests were performed at 8 and 12 wk prior to and following liraglutide treatment. Liver pathology, cardiac measurements, blood chemistry, and RNA and protein analyses were performed. Clamp studies revealed hepatic insulin resistance after 6 wk of ALIOS diet. Liraglutide reduced visceral adiposity and liver weight (P < 0.001). As expected, liraglutide improved glucose and insulin tolerance. Liraglutide improved hypertension (P < 0.05) and reduced cardiac hypertrophy. Surprisingly, liver from liraglutide-treated mice had significantly higher levels of fatty acid binding protein, acyl-CoA oxidase II, very long-chain acyl-CoA dehydrogenase, and microsomal triglyceride transfer protein. We conclude that liraglutide reduces the harmful effects of an ALIOS diet by improving insulin sensitivity and by reducing lipid accumulation in liver through multiple mechanisms including, transport, and increase β-oxidation.

Topics: Adiposity; Animals; Cardiomegaly; Diet, High-Fat; Fatty Liver; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hypertension; Insulin Resistance; Liraglutide; Liver; Male; Mice; Mice, Inbred C57BL

Topics: Blood Pressure; Cardiovascular System; Diabetes Mellitus; Drug Therapy, Combination; Glucagon-Like Peptide 1; Humans; Hypertension; Incretins; Liraglutide; Practice Guidelines as Topic; Societies, Medical; South Africa

Sitagliptin, a selective dipeptidyl peptidase 4 inhibitor, inhibits the inactivation and degradation of glucagon like peptide 1 (GLP-1), which is used for the treatment of type 2 diabetes mellitus. However, little is known about the role of GLP-1 in hypertension. This study investigated whether the activation of GLP-1 signaling protects endothelial function in hypertension. Two-week sitagliptin treatment (10 mg/kg per day, oral gavage) improved endothelium-dependent relaxation in renal arteries, restored renal blood flow, and reduced systolic blood pressure in spontaneously hypertensive rats. In vivo sitagliptin treatment elevated GLP-1 and GLP-1 receptor expressions, increased cAMP level, and subsequently activated protein kinase A, liver kinase B1, AMP-activated protein kinase-α and endothelial NO synthase in spontaneously hypertensive rat renal arteries. Inhibition of GLP-1 receptor, adenylyl cyclase, protein kinase A, AMP-activated protein kinase-α, or NO synthase reversed the protective effects of sitagliptin. We also demonstrate that GLP-1 receptor agonist exendin 4 in vitro treatment had similar vasoprotective effects in spontaneously hypertensive rat renal arteries and increased NO production in spontaneously hypertensive rat aortic endothelial cells. Studies using transient expressions of wild-type and dominant-negative AMP-activated protein kinase-α2 support the critical role of AMP-activated protein kinase-α in mediating the effect of GLP-1 in endothelial cells. Ex vivo exendin 4 treatment also improved endothelial function of renal arteries from hypertensive patients. Our results elucidate that upregulation of GLP-1 and related agents improve endothelial function in hypertension by restoring NO bioavailability, suggesting that GLP-1 signaling could be a therapeutic target in hypertension-related vascular events.

Topics: Aged; Aged, 80 and over; Animals; Blood Pressure; Cells, Cultured; Cyclic AMP; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Endothelium, Vascular; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypertension; In Vitro Techniques; Kidney; Magnetic Resonance Imaging; Male; Middle Aged; Nitric Oxide; Peptides; Pyrazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Glucagon; Regional Blood Flow; Renal Artery; Signal Transduction; Sitagliptin Phosphate; Triazoles; Venoms

The majority of patients with type 2 diabetes mellitus have blood pressure (BP) exceeding the recommended value of <130/80 mm Hg. Optimal control of hyperglycemia and hypertension has been shown to reduce the incidence of macrovascular and microvascular complications due to diabetes. Treatment with the GLP-1 receptor agonist exenatide, previously demonstrated to reduce hemoglobin A(1C) and weight in subjects with type 2 diabetes, was associated with BP reduction in several studies.. This analysis explored the effects of exenatide vs. placebo or insulin on BP measurements in pooled data from six trials including 2,171 subjects studied for at least 6 months.. Overall, 6 months of exenatide treatment was associated with a significantly greater reduction in systolic BP (SBP) compared with placebo (least squares mean (s.e.): difference of -2.8 mm Hg (0.75); P = 0.0002) or insulin (difference of -3.7 mm Hg (0.85); P < 0.0001). No significant intergroup differences in diastolic BP (DBP) were observed. The majority of the intergroup difference was observed in subjects with SBP > or = 130 mm Hg (difference of -3.8 mm Hg (1.08) from placebo: P = 0.0004; difference of -4.0 mm Hg (1.01) from insulin; P < 0.0001). The largest intertreatment differences between exenatide and comparators were observed in subjects with SBP >/=150 mm Hg. Similar responses were observed in African-American subjects. A weak correlation between the amount of weight lost and reduction in SBP was found (r = 0.09, P = 0.002) for exenatide-treated subjects.. These results support the need for a prospective, randomized, controlled study of BP changes during exenatide treatment in patients with hypertension and type 2 diabetes.

Topics: Blood Pressure; Databases, Factual; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypertension; Hypoglycemic Agents; Male; Middle Aged; Peptides; Randomized Controlled Trials as Topic; Retrospective Studies; Venoms

Exenatide is a peptide incretin mimetic that has glucoregulatory actions associated with weight reduction. Previous reports demonstrated acute increases in blood pressure after systemic or intracerebroventricular administration of exenatide or glucagon like peptide 1 (GLP 1) in rats. However, there are limited studies testing the chronic effects of these peptides on arterial pressure and no reports showing the effects of these peptides to reverse hypertension in the context of the metabolic syndrome.. Thus, we examined the response to peripheral exenatide using telemetry in conscious, unrestrained rats under normotensive conditions and in a model of hypertension/metabolic syndrome induced by corticosterone. Rats were implanted with either corticosterone or wax (control) pellets, followed 14 days later by the additional implantation of pumps to deliver exenatide (1 microg/kg per day) or vehicle for 7 days.. The 21-day corticosterone treatment produced hypertriglyceridemia, visceral fat deposition, hyperglycemia, insulin resistance, and an elevation of mean arterial blood pressure (MAP) by 14 +/- 1 mmHg. Exenatide significantly reversed corticosterone-induced increases in blood pressure and this normalization occurred independently from change in body weight. Additionally, exenatide reduced MAP by 5 +/- 3 mmHg in normotensive control rats.. These results are the first demonstration of a durable antihypertensive effect of exenatide in a glucocorticoid-induced model of the metabolic syndrome.

Topics: Animals; Blood Pressure; Body Weight; Corticosterone; Disease Models, Animal; Exenatide; Glucagon-Like Peptide 1; Hypertension; Hypoglycemic Agents; Injections, Intraventricular; Male; Metabolic Syndrome; Peptides; Rats; Rats, Sprague-Dawley; Telemetry; Time Factors; Venoms

Topics: Animals; Cardiovascular Agents; Disease Models, Animal; Dogs; Glucagon-Like Peptide 1; Glucose Transporter Type 4; Heart Failure; Hypertension; Infusions, Parenteral; Insulin; Myocardium; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred SHR; Signal Transduction; Systole; Ventricular Function, Left

Compared with Caucasians, obese African-American adolescents have a higher risk for type 2 diabetes. Subclinical inflammation and reduced glucagon-like peptide 1 (GLP-1) concentration are linked to the pathogenesis of the disease. We determined the relationship between insulin resistance, beta-cell activity, and subclinical inflammation with GLP-1 concentrations and whether racial disparities in GLP-1 response were present in 49 obese adolescents (14 +/- 3 years; 76% African American; 71% female).. Subjects underwent physical examination and an oral glucose tolerance test. We measured levels of high-sensitivity CRP (CRP(hs)), fibrinogen, glucose, GLP-1(total), GLP-1(active), and insulin. Insulin and glucose area under the curve (AUC), insulinogenic index (DeltaI30/DeltaG30), and composite insulin sensitivity index (CISI) were computed. Subjects were categorized by race and as inflammation positive (INF+) if CRP(hs) or fibrinogen were elevated.. No racial differences were seen in mean or relative BMI. Thirty-five percent of subjects had altered fasting or 2-h glucose levels (African American vs. Caucasian, NS), and 75% were INF+ (African American vs. Caucasian, P = 0.046). Glucose and insulin, CISI, and DeltaI30/DeltaG30 values were similar; African Americans had lower GLP-1(total) AUC (P = 0.01), GLP-1(active) at 15 min (P = 0.03), and GLP-1(active) AUC (P = 0.06) and higher fibrinogen (P = 0.01) and CRP(hs) (NS) compared with Caucasians.. African Americans exhibited lower GLP-1 concentrations and increased inflammatory response. Both mechanisms may act synergistically to enhance the predisposition of obese African Americans to type 2 diabetes. Our findings might be relevant to effective deployment of emerging GLP-1-based treatments across ethnicities.

Topics: Adolescent; Biomarkers; Black People; Blood Pressure; C-Reactive Protein; Child; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hypertension; Inflammation; Insulin Resistance; Male; Obesity; White People

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glipizide; Glucagon-Like Peptide 1; Humans; Hypertension; Hypoglycemic Agents; Insulin; Metformin; Middle Aged; Obesity; Pioglitazone; Thiazolidinediones

Topics: Animals; Blood Pressure; Glucagon; Glucagon-Like Peptide 1; Hypertension; Peptide Fragments; Protein Precursors; Rats; Rats, Inbred Dahl

Dahl salt-sensitive (Dahl S) rats exhibit many phenotypic traits associated with salt-sensitive hypertension in man. Specifically, they are salt-sensitive, insulin-resistant and hyperlipidemic. They also develop endothelial dysfunction, cardiac injury and glomerulosclerosis. Insulin resistance is linked to hypertension, renal and cardiac damage and endothelial dysfunction. Thus, an agent that has diuretic action and can improve insulin resistance, like recombinant glucagon-like peptide-1(7-36)amide (rGLP-1), may have an antihypertensive effect.. To determine whether chronic administration of rGLP-1 attenuates the development of hypertension, endothelial dysfunction and/or hypertension-induced renal and cardiac end organ damage in Dahl S rats.. Mean arterial pressure (MAP) and urinary excretion of protein and albumin were measured in Dahl S rats before and after they were fed a 8% NaCl diet and infused with rGLP-1 (1 micro g/kg per min, i.v.) or vehicle for 14 days. At the end of the study, the degree of renal and cardiac injury was histologically assessed and endothelium-dependent relaxing function was studied using aortic rings. In other rats, the effects of rGLP-1 on sodium and water balance and plasma glucose and insulin levels for the first 3 days following a step change in sodium intake from a 0.1% NaCl diet to 7.5 mEq/day were determined.. rGLP-1 significantly attenuated the development of hypertension in Dahl S rats (136 +/- 7 versus 174 +/- 6 mmHg). This was associated with reduction in proteinuria (46 +/- 7 versus 128 +/- 15 mg/day) and albuminuria (46 +/- 7 versus 86 +/- 18 mg/day) and improvement of endothelial function and renal and cardiac damage. rGLP-1 markedly increased urine flow and sodium excretion for the first 3 days following elevation in sodium intake. It had no significant effects on plasma glucose and insulin concentrations.. rGLP-1 has antihypertensive and cardiac and renoprotective effects in Dahl S rats fed a high salt diet. The antihypertensive effect of rGLP-1 in Dahl S rats is due mainly to its diuretic and natriuretic effects, rather than an effect to improve insulin-resistance.

Topics: Animals; Antihypertensive Agents; Aorta; Blood Glucose; Diuresis; Endothelium, Vascular; Glucagon; Glucagon-Like Peptide 1; Heart Diseases; Hypertension; Insulin; Kidney Diseases; Male; Natriuresis; Peptide Fragments; Protein Precursors; Rats; Rats, Inbred Dahl; Sodium; Sodium Chloride, Dietary; Water-Electrolyte Balance

The present study was designed to compare the effects of glucagon-like peptide-1 (7-36) amide (GLP-1) injected centrally or systemically in a dose range of 10-10000 ng on the vasopressin and oxytocin release as well as the blood pressure in the rat. The urethane-anaesthetised Wistar male and female rats were fitted with venous as well as arterial catheters and, in the second study, additionally with the intracerebroventricular cannula. The arterial blood pressure was monitored throughout the experiment. The plasma vasopressin/oxytocin concentrations were measured in blood samples taken 15 min before and 5, 15 and 30 min after the intravenous or intracerebroventricular GLP-1 injection. No gender-dependent differences were seen as to the GLP-1 effect on the blood pressure or the hormone release. GLP-1 administered centrally or systemically at low doses (10 or 100 ng) either showed a hypertensive or biphasic (an increase followed by a decrease in the blood pressure) effect. On the other hand, 1000 or 10000 ng GLP-1 caused a clear increase of the blood pressure regarding the way of injection. When injected systemically, GLP-1 increased the release of both neurohypophysial hormones. When injected centrally, however, GLP-1 either enhanced or, at low doses, significantly reduced the plasma vasopressin/oxytocin levels. The effect on the blood pressure seems to be independent of the possible pressor effect of endogenous vasopressin. It is concluded that GLP-1 may modulate the function of the hypothalamo-neurohypophysial system as well as the cardiovascular system through both the central and systemic mechanisms.

Topics: Animals; Blood Pressure; Dose-Response Relationship, Drug; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Hypertension; Injections, Intravenous; Male; Neurotransmitter Agents; Oxytocin; Peptide Fragments; Radioimmunoassay; Rats; Rats, Wistar; Sex Factors; Time Factors; Vasopressins