Angiotensin-(1-7) for Metabolic Effects in High Blood Pressure, Insulin Resistance, Metabolic Syndrome, and Obesity

Recruiting at 1 trial location

Overseen By Cynthia Laws, MS

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Vanderbilt University

Must not be taking: SNRIs, NET inhibitors, Anticoagulants, others

Disqualifiers: Diabetes, Cardiovascular disease, Renal impairment, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 2 weeks

26 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The overall purpose of this study is to learn more about the metabolic effects of angiotensin-(1-7) in the insulin resistant state associated with obesity. Pharmacologic approaches to increase angiotensin-(1-7) levels or its actions are currently in development for treatment of metabolic-related diseases such as obesity and type II diabetes, based on findings from animal studies. It is unclear if this peptide contributes to the regulation of metabolism in humans. The investigators will test if angiotensin-(1-7) infusion can improve insulin sensitivity measured by hyperinsulinemic-euglycemic clamp methods in individuals with obesity and insulin resistance. The investigators will also examine for changes in blood pressure and related hemodynamic and hormonal changes following angiotensin-(1-7) infusion.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on certain medications like SNRIs, NET inhibitors, phosphodiesterase 5 inhibitors, anticoagulants, or chronic systemic glucocorticoids. It's best to discuss your specific medications with the trial team.

Is Angiotensin-(1-7) safe for humans?

The research articles provided do not contain specific safety data for Angiotensin-(1-7) in humans, but they discuss its potential therapeutic roles and effects in animal studies and cellular models. ^{1 2 3 4 5}

How is the drug Angiotensin-(1-7) different from other treatments for high blood pressure and metabolic disorders?

Angiotensin-(1-7) is unique because it works by activating a specific pathway (ACE2/Ang-(1-7)/Mas) that helps regulate blood pressure and improve insulin sensitivity, counteracting the negative effects of another hormone, Angiotensin II, which is often increased in conditions like obesity and diabetes. This makes it a novel option for treating metabolic disorders and high blood pressure, especially in cases where traditional treatments may not address these underlying mechanisms. ^{1 3 6 7 8}

What evidence supports the effectiveness of the drug Angiotensin-(1-7) for metabolic effects in high blood pressure, insulin resistance, metabolic syndrome, and obesity?

Research shows that Angiotensin-(1-7) can help regulate blood pressure and improve insulin sensitivity, which is important for managing conditions like high blood pressure and metabolic syndrome. It also counteracts negative effects of another hormone, Angiotensin II, which is linked to obesity and diabetes. ^{1 3 5 9 10}

Who Is on the Research Team?

Alfredo Gamboa, MD

Principal Investigator

Vanderbilt University Medical Center

Are You a Good Fit for This Trial?

This trial is for adults aged 18-60 with obesity (BMI of 30-40), high blood pressure, and insulin resistance but not diabetes. Participants should not be pregnant, breastfeeding, or have a history of serious health issues like heart disease or drug abuse. They mustn't be on certain medications like anticoagulants or antidepressants.

Inclusion Criteria

I have high blood pressure or am taking medication for it.

Able and willing to provide informed consent

You are very overweight, with a body mass index between 30 and 40.

Exclusion Criteria

I am unable to understand or decide about participating in this study.

Pregnancy or breast-feeding

You have a history of drinking too much alcohol or using drugs.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive intravenous angiotensin-(1-7) or saline infusion on two separate study days, with each study day lasting approximately four hours

2 weeks

2 visits (in-person)

Washout

A washout period of at least one week between study days

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Angiotensin-(1-7)

Trial Overview The study investigates the effects of angiotensin-(1-7) on metabolism in obese individuals with insulin resistance. It involves infusing this peptide to see if it improves insulin sensitivity using a special test called hyperinsulinemic-euglycemic clamp and monitors changes in blood pressure and other related body functions.

How Is the Trial Designed?

Group I: Angiotensin-(1-7) Experimental Treatment 1 Intervention

Subjects will receive intravenous infusion of three ascending doses of Angiotensin-(1-7). The doses are 4, 8, and 16 ng/kg/min. Each dose will be maintained for 10 minutes. The highest dose of Angiotensin-(1-7) will be maintained for an additional 120 minutes during the hyperinsulinemic-euglycemic clamp, for a total of 150 minutes of infusion.

Group II: Saline Placebo Group 1 Intervention

Subjects will receive an intravenous infusion of saline that is matched in volume to the Angiotensin-(1-7) study day. The saline infusion will also be maintained for a total of 150 minutes.

Angiotensin-(1-7) is already approved in United States, European Union for the following indications:

Approved in United States as TXA127 for:

• Duchenne muscular dystrophy (DMD)
• Limb-girdle muscular dystrophy (LGMD)
• Congenital muscular dystrophy MDC1A
• Marfan syndrome
• Dystrophic Epidermolysis Bullosa (DEB)
• Pulmonary arterial hypertension
• Myelodysplastic Syndrome (MDS)

Approved in European Union as TXA127 for:

• Duchenne muscular dystrophy (DMD)

Who Is Running the Clinical Trial?

Vanderbilt University

Lead Sponsor

Trials

714

Recruited

6,143,000+

Published Research Related to This Trial

Angiotensin-(1-7) has shown potential as a therapeutic agent for treating and preventing metabolic disorders, particularly in the context of rising obesity and metabolic syndrome rates worldwide.

The activation of the ACE2/Ang-(1-7)/Mas pathway may counteract the negative effects of Angiotensin II, which is linked to appetite regulation and fat metabolism, suggesting a promising approach for managing metabolic diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin 1-7: a peptide for preventing and treating metabolic syndrome. Santos, SH., Andrade, JM.[2020]

The renin-angiotensin system is linked to obesity and metabolic diseases, influencing appetite, metabolism, and fat tissue growth, as shown by various animal and human studies.

New pharmaceuticals that inhibit the renin-angiotensin system, originally designed for treating hypertension and heart failure, may also be effective in addressing obesity and metabolic disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of angiotensin in obesity and metabolic disease. Mathai, ML., Chen, N., Cornall, L., et al.[2019]

Chronic infusion of angiotensin-(1-7) in obese female mice improved glucose tolerance, highlighting a significant sex difference in response to this treatment compared to male mice, who showed similar insulin sensitivity but did not experience the same level of improvement in glucose tolerance.

Both male and female obese mice experienced reduced body mass and adiposity with angiotensin-(1-7) treatment, suggesting its potential as a therapeutic target for obesity-related insulin resistance, particularly in females.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sex differences in metabolic effects of angiotensin-(1-7) treatment in obese mice. White, MC., Miller, AJ., Loloi, J., et al.[2020]

Angiotensin II (Ang II) plays a significant role in metabolism and may contribute to obesity-related conditions like hypertension and type 2 diabetes by acting through its receptors in adipose tissue.

The review discusses how Ang II is produced and its signaling pathways, as well as the potential of pharmaceutical agents targeting the renin-angiotensin system (RAS) to treat obesity-related disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Possible involvement of the adipose tissue renin-angiotensin system in the pathophysiology of obesity and obesity-related disorders. Goossens, GH., Blaak, EE., van Baak, MA.[2019]

Insulin resistance is a key factor in the development of Type 2 diabetes and is linked to metabolic syndrome, which includes obesity and hypertension, highlighting the need for effective treatments.

Angiotensin-(1-7) has been shown to improve insulin action and counteract the negative effects of angiotensin II, suggesting that targeting the ACE2/Ang-(1-7)/Mas receptor pathway could be a promising therapeutic strategy for managing diabetes and metabolic syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of the action of insulin by angiotensin-(1-7). Dominici, FP., Burghi, V., Muñoz, MC., et al.[2021]

Angiotensin-(1-7) (Ang-[1-7]) protects heart cells from high glucose-induced damage by inhibiting the reactive oxygen species-leptin-p38 MAPK/ERK1/2 pathways, which are activated during diabetic conditions.

In laboratory tests on H9c2 heart cells, Ang-(1-7) treatment led to increased cell viability, reduced apoptosis, and lower reactive oxygen species production, demonstrating its potential as a therapeutic agent in diabetic cardiovascular diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) protects cardiomyocytes against high glucose-induced injuries through inhibiting reactive oxygen species-activated leptin-p38 mitogen-activated protein kinase/extracellular signal-regulated protein kinase 1/2 pathways, but not the leptin-c-Jun N-terminal kinase pathway in vitro. Lei, Y., Xu, Q., Zeng, B., et al.[2022]

Oral Angiotensin (Ang)-(1-7) treatment significantly improved metabolic syndrome (MetS) in rats by reducing mean arterial pressure (MAP), insulin resistance, and inflammation in white adipose tissue (WAT) after 6 weeks of treatment following a 13-week high-fat diet.

The treatment led to a decrease in body mass and adiposity, normalization of fasting plasma glucose and insulin levels, and improved expression of uncoupling proteins in muscle and brown adipose tissue, indicating a restoration of metabolic health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Ang-(1-7) treatment improves white adipose tissue remodeling and hypertension in rats with metabolic syndrome. Barbosa, MA., de Sousa, GG., de Castro, UGM., et al.[2021]

In a study involving 34 male Wistar rats with diabetes induced by streptozotocin, treatment with angiotensin-(1-7) (Ang-(1-7)) significantly improved glucose metabolism and insulin resistance, reversing many of the negative effects of diabetes.

Ang-(1-7) treatment enhanced the expression of key proteins involved in insulin secretion and glucose transport, such as Pdx1, Glut2, and glucokinase, indicating its potential as a protective agent against diabetes-related pancreatic damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) Improves Islet Function in a Rat Model of Streptozotocin- Induced Diabetes Mellitus by Up-Regulating the Expression of Pdx1/Glut2. Li, J., Zhu, R., Liu, Y., et al.[2021]

Angiotensin (1-7) can counteract the negative effects of angiotensin II on insulin signaling in human umbilical vein endothelial cells, restoring insulin-induced activation of key enzymes like eNOS and promoting nitric oxide production.

The beneficial effects of angiotensin (1-7) are mediated through the Mas receptor, suggesting that the balance between angiotensin II and angiotensin (1-7) is crucial in preventing endothelial dysfunction and insulin resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin (1-7) counteracts the negative effect of angiotensin II on insulin signalling in HUVECs. Tassone, EJ., Sciacqua, A., Andreozzi, F., et al.[2021]

Chronic treatment with Angiotensin (Ang)-(1-7) significantly lowered blood pressure in aged mice, indicating its potential as a therapeutic option for managing age-related hypertension.

Ang-(1-7) improved insulin sensitivity in aged mice to levels comparable to young mice, suggesting it may help mitigate metabolic issues associated with aging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) Improves Integrated Cardiometabolic Function in Aged Mice. Miller, AJ., Bingaman, SS., Mehay, D., et al.[2021]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

Angiotensin 1-7: a peptide for preventing and treating metabolic syndrome. [2020]

2. United Arab Emirates pubmed.ncbi.nlm.nih.gov

The role of angiotensin in obesity and metabolic disease. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Sex differences in metabolic effects of angiotensin-(1-7) treatment in obese mice. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Possible involvement of the adipose tissue renin-angiotensin system in the pathophysiology of obesity and obesity-related disorders. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Modulation of the action of insulin by angiotensin-(1-7). [2021]

6. Japan pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) protects cardiomyocytes against high glucose-induced injuries through inhibiting reactive oxygen species-activated leptin-p38 mitogen-activated protein kinase/extracellular signal-regulated protein kinase 1/2 pathways, but not the leptin-c-Jun N-terminal kinase pathway in vitro. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Oral Ang-(1-7) treatment improves white adipose tissue remodeling and hypertension in rats with metabolic syndrome. [2021]

8. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) Improves Islet Function in a Rat Model of Streptozotocin- Induced Diabetes Mellitus by Up-Regulating the Expression of Pdx1/Glut2. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Angiotensin (1-7) counteracts the negative effect of angiotensin II on insulin signalling in HUVECs. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) Improves Integrated Cardiometabolic Function in Aged Mice. [2021]