incretins and Hypertension

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

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

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

In addition to its effects on reproductive health, it is now well recognized that polycystic ovary syndrome (PCOS) is a metabolic disorder, characterized by decreased insulin sensitivity which leads to an excess lifetime risk of type 2 diabetes and cardiovascular disease. PCOS patients are often obese, hypertensive, dyslipidemic and insulin resistant; they have obstructive sleep apnea and have been reported to have higher aldosterone levels in comparison to normal healthy controls. These are all components of an adverse cardiovascular risk profile. Many studies exploring subclinical atherosclerosis using different methods (flow-mediated dilatation, intima media thickness, arterial stiffness, coronary artery calcification) as well as assessing circulating cardiovascular risk markers, point toward an increased cardiovascular risk and early atherogenesis in PCOS. The risk and early features of subclinical atherosclerosis can be reversed by non-medical (normalization of weight, healthy lifestyle) and medical (metformin, thiazolidinediones, spironolactone, and statins) interventions. However, the long-term risk for cardiovascular morbidity and mortality as well as the clinical significance of different interventions still need to be properly addressed in a large prospective study.

Topics: Adolescent; Adult; Androstenes; Atherosclerosis; Cardiovascular Diseases; Carotid Intima-Media Thickness; Coronary Artery Disease; Female; Humans; Hypertension; Incretins; Insulin Resistance; Life Style; Metformin; Middle Aged; Obesity; Polycystic Ovary Syndrome; Postmenopause; Renin-Angiotensin System; Risk Factors; Sleep Apnea, Obstructive; Thiazolidinediones; Vascular Stiffness; Weight Reduction Programs

The prevalence of type 2 diabetes mellitus (T2DM) has increased markedly worldwide. A recent epidemiological study reported that approximately 63% of T2DM patients also have high blood pressure (>130/80 mmHg), which doubles their risk of cardiac events. Of the medications used to treat T2DM, the incretins are a group of peptides that not only regulate blood glucose effectively and moderately, but also protect patients against cardiovascular events and improve several cardiovascular parameters. Here were review data from preclinical and short- and long-term clinical studies investigating the antihypertensive effects of incretins. We also elucidate four possible mechanisms underlying the antihypertensive effects of incretins. We conclude that incretins can lower blood pressure of T2DM patients, independent of weight loss, and will surely improve the prognosis of these patients.

Topics: Animals; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Hypertension; Incretins

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

Incretin mimetics, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), as well as dipeptidyl peptidase-IV (DPP-IV) inhibitors, are used in the treatment of type 2 diabetes mellitus (T2DM). In addition to stimulating insulin secretion from pancreatic β cells, incretins have apparent extrapancreatic functions beyond glycemic control. This review summarizes the recent findings regarding the blood-pressure-lowering effects of incretins and DPP-IV inhibitors in patients who are obese, diabetic, or have metabolic syndrome.. Clinical studies have indicated that GLP-1 and its analogues lower blood pressure in patients with T2DM, particularly in patients with moderate-to-severe hypertension. DPP-IV inhibitors also appear to elicit a similar blood-pressure-lowering effect. In animal models of salt-sensitive hypertension, incretins appear to induce their antihypertensive effects by inhibiting the proximal tubular sodium reabsorption, and thereby increasing urinary excretion of sodium. These data suggest that the local actions of incretins may be via their key role in regulating natriuresis and lowering blood pressure.. Incretin mimetics and DPP-IV inhibitors are a novel class of antihypertensive drugs with natriuretic properties. They can be used in the treatment of salt-sensitive hypertension, which is characterized by edema.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Humans; Hypertension; Incretins; Kidney Tubules, Proximal; Molecular Mimicry; Natriuresis; Sodium; Sodium Chloride, Dietary; Treatment Outcome

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

Topics: Adrenergic beta-Antagonists; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Blood Pressure; Calcium Channel Blockers; Cats; COVID-19; COVID-19 Serotherapy; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dogs; Drug Combinations; Gastric Inhibitory Polypeptide; Heart Sounds; History, 20th Century; Humans; Hypertension; Immunization, Passive; Incretins; Insulin Glargine; Meta-Analysis as Topic; Randomized Controlled Trials as Topic; SARS-CoV-2; Thiazides; Valsartan

Obesity, hypertension and prediabetes contribute greatly to coronary artery disease, heart failure and vascular events, and are the leading cause of mortality and morbidity in developed societies. Salt sensitivity exacerbates endothelial dysfunction. Herein, we investigated the effect of chronic glucagon like peptide-1 (GLP-1) receptor activation on the coronary microcirculation and cardiac remodeling in Zucker rats on a high-salt diet (6% NaCl).. Eight-week old Zucker lean (+/+) and obese (fa/fa) rats were treated with vehicle or liraglutide (LIRA) (0.1 mg/kg/day, s.c.) for 8 weeks. Systolic blood pressure (SBP) was measured using tail-cuff method in conscious rats. Myocardial function was assessed by echocardiography. Synchrotron contrast microangiography was then used to investigate coronary arterial vessel function (vessels 50-350 µm internal diameter) in vivo in anesthetized rats. Myocardial gene and protein expression levels of vasoactive factors, inflammatory, oxidative stress and remodeling markers were determined by real-time PCR and Western blotting.. We found that in comparison to the vehicle-treated fa/fa rats, rats treated with LIRA showed significant improvement in acetylcholine-mediated vasodilation in the small arteries and arterioles (< 150 µm diameter). Neither soluble guanylyl cyclase or endothelial NO synthase (eNOS) mRNA levels or total eNOS protein expression in the myocardium were significantly altered by LIRA. However, LIRA downregulated Nox-1 mRNA (p = 0.030) and reduced ET-1 protein (p = 0.044) expression. LIRA significantly attenuated the expressions of proinflammatory and profibrotic associated biomarkers (NF-κB, CD68, IL-1β, TGF-β1, osteopontin) and nitrotyrosine in comparison to fa/fa-Veh rats, but did not attenuate perivascular fibrosis appreciably.. In a rat model of metabolic syndrome, chronic LIRA treatment improved the capacity for NO-mediated dilation throughout the coronary macro and microcirculations and partially normalized myocardial remodeling independent of changes in body mass or blood glucose.

Topics: Animals; Coronary Artery Disease; Coronary Circulation; Disease Models, Animal; Glucagon-Like Peptide-1 Receptor; Hypertension; Hypoglycemic Agents; Incretins; Insulin Resistance; Liraglutide; Male; Microcirculation; Nitric Oxide; Obesity; Oxidative Stress; Rats, Zucker; Sodium Chloride, Dietary; Ventricular Remodeling

Glucagon-like peptide-1 receptor agonists may have a role in modulation of cardiac fibrosis. Our study aimed to determine the effect of the glucagon-like peptide-1 receptor agonist liraglutide in obesity, hypertension and age-induced murine models of cardiac fibrosis and identify associated molecular mechanisms.. C57Bl/6J mice on a high-fat diet and C57Bl/6J mice on a normal chow diet treated with angiotensin II were used to induce obesity and hypertension-mediated cardiac fibrosis, respectively. C57Bl/6J mice 20 months old were used to study age-induced cardiac fibrosis. Liraglutide treatment of 30 µg/kg/day-300 µg/kg s.c. twice daily was administered for 4 weeks.. Liraglutide treatment attenuated obesity, hypertension and age-induced increases in interstitial cardiac fibrosis and expression of inflammatory and oxidative stress markers.. These observations identify a potential role for liraglutide in the prevention of cardiac fibrosis and identify molecular mechanisms associated with these effects.

Topics: Aging; Angiotensin II; Animals; Aorta; Blood Pressure; Body Weight; Chemokine CCL2; Diet, High-Fat; Disease Models, Animal; Endothelium, Vascular; Fibrosis; Glucagon-Like Peptide-1 Receptor; Heart; Heart Diseases; Hypertension; I-kappa B Proteins; Immunohistochemistry; Incretins; Inflammation; Interleukin-10; Liraglutide; Macrophages; Male; Mice; Mice, Inbred C57BL; Myocardium; NF-kappa B p50 Subunit; Obesity; Oxidative Stress; Real-Time Polymerase Chain Reaction; Vasoconstrictor Agents; Vimentin

Despite its high prevalence among patients suffering myocardial infarction, the significance of left ventricle hypertrophy for infarct size is not known. We asked whether infarct size might be increased by this condition, and whether any such increase might be associated with an increased mitochondrial damage following coronary occlusion.. Occlusion of the left descending artery in isolated, perfused hearts of SHR-SP (spontaneously hypertensive rat stroke-prone) (left ventricular hypertrophy) or Wistar-Kyoto (WKY) (control) rats was used, followed by reperfusion with or without exendin-4 (Exe-4), a glucagon-like peptide-1 receptor agonist. Infarct size relative to area-at-risk was determined. Separately, mitochondria were isolated after global ischemia. Activities of complexes III and IV and amounts of selected complex subunits and cytochromes a, b, c, and c1 were determined.. Infarct size (ischemia 35  min and 120  min reperfusion) was 65.8% (±3.3%) and 37.1% (±3.4%) in the SHR-SP and WKY hearts, respectively (P < 0.05). Exe-4 significantly decreased infarct size and hypercontracture in WKY, but not in SHR-SP, hearts. After ischemia 15  min in SHR-SP hearts, Exe-4 reduced the infarct (26.6%, ±3.8% to 9.3% ± 1.5%; P < 0.05). Mitochondria from postischemic SHR-SP hearts showed a reduction of complex III (368.1 ± 37.5 to 175.8 ± 23.0  nmoles/min × mg; P < 0.05) and complex IV (14.4 ± 0.22 to 5.8 ± 0.8 1/s × mg; P < 0.05) activities and decreased amounts of cytochromes a, b, and c.. Hearts from hypertensive (SHR-SP) rats with left ventricle hypertrophy appeared more vulnerable to ischemia-reperfusion injury, as supported by a more profound infarct development and an earlier loss of postconditioning by Exe-4. Mitochondrial complexes III and IV were identified among possible loci of this increased, hypertrophy-associated vulnerability.

Topics: Animals; Cytochromes; Electron Transport Complex III; Electron Transport Complex IV; Exenatide; Heart; Hypertension; Hypertrophy, Left Ventricular; Incretins; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Peptides; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Severity of Illness Index; Venoms

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

In recent years, the number of patients with type 2 diabetes in Japan is increasing. It is assumed that two core defects which are insulin resistance as an environmental factor caused by accumulation of fat in adipose cells, liver, and muscles, and insulin deficiency to glucose spike as a genetic factor contribute to the epidemic of type 2 diabetes. It is obvious that type 2 diabetes is closely correlated with a variety of underlying disorders of atherosclerosis. Therefore, it is critical to reduce the development of macrovascular events by integrated treatment which consists of a combination of tight glycemic control with appropriate lipid and hypertension control. In treatment of hypertension, a combination use of antihypertensive agents is common for patients with type 2 diabetes. A couple of fixed dose combinations (FDC) of ARB and thiazide diuretic agent are already in practice for better hypertension management by reduction of the pill burdens on patients to improve drug adherence. In addition, another FDC of ARB and CCB will be also available soon. In treatment of type 2 diabetes, incretin mimetics are drawing physicians' attentions and a novel oral anti-diabetic agent DPP-4 inhibitor is more promising and expected as the first-line therapy. However, further clinical experiences finding out safety and efficacy in a cautious manner are required so that appropriate roles of this agent in treatment algorithm can be built.

Topics: Diabetes Complications; Diabetes Mellitus, Type 2; Humans; Hypertension; Incretins

Obesity has reached epidemic proportions in the USA with a nearly fourfold rise in the prevalence of childhood obesity. There are many possible etiologies of obesity as the adipose tissue plays a significant, complex role in the physiology of fuel metabolism and hormone regulation. The development of obesity represents a pathophysiologic increase in fat mass in which multiple metabolic pathways are deranged. The consequences of these metabolic derangements, including insulin resistance and inflammation, are reflected in obesity-related comorbidities and can be seen in the setting of pediatric obesity. Obese adolescents demonstrate increased rates of early maturation, orthopedic growth abnormalities, diabetes mellitus, obstructive sleep apnea, hypertension, steatosis, and polycystic ovarian syndrome, placing this group of children at risk for long-term health problems and reduced quality of life. Given the negative short- and long-term impact of obesity on children, careful attention should be paid to the unique health issues of this "at-risk" population with both prevention and early intervention strategies.

Topics: Adipocytes; Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Adolescent; Animals; Body Mass Index; Diabetes Mellitus; Evidence-Based Medicine; Female; Humans; Hypercholesterolemia; Hypertension; Incretins; Metabolic Syndrome; Obesity; Ohio; Polycystic Ovary Syndrome; Prevalence; Quality of Life; Risk Factors; Sleep Apnea, Obstructive

Topics: Blood Glucose; Clinical Trials as Topic; Congresses as Topic; Consensus; Diabetes Mellitus; Diabetic Angiopathies; Humans; Hypertension; Incretins; Obesity; Weight Gain