NCT05216042

GENESIS: Genotype Guided - Natriuretic Peptides - Cardiometabolic Health Study

Atrial Natriuretic Peptide and Regulation of Cardiometabolic Health: A Genotype-Guided Human Physiological Study

• Status: Recruiting
• Phase: N/A
• Study type: Interventional
• Enrollment: 200 (estimated)
• Sponsor: University of Alabama at Birmingham · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Accepted

Summary

Natriuretic Peptides (NP) are hormones produced by the heart, and they have a wide range of favorable metabolic benefits. Lower levels of these hormones are associated with an increased likelihood of the development of diabetes and poor cardiometabolic health. Obese and Black individuals have \~30% lower levels of NP and are at a greater risk of developing cardiovascular (CV) events as compared to lean and White counterparts. Some people have common genetic variations that cause them to have \~20% lower NP levels. Similar to other low NP populations, these individuals with low NP genotype (i.e., carrying a common genetic variation called rs5068) are at a greater risk of developing cardiometabolic diseases. By understanding the NP response following the exercise challenge and the glucose challenge in individuals with genetically lower NP levels will help us understand how to improve cardiometabolic health in them.

Detailed description

The heart plays an endocrine role by secreting hormones called Natriuretic Peptides (NPs). NPs directly regulates blood pressure (BP) by causing dilation of blood vessels and removing sodium and water from the body. Apart from blood pressure regulation, previous experimental data suggest that NPs has a wide range of favorable metabolic effects and regulates energy homeostasis, fatty acid oxidation, lipid metabolism, glucose intolerance, insulin sensitivity, and obesity. Investigators have demonstrated that low levels of NPs can increase the risk of developing cardiovascular (CV) events (such as heart failure \[HF\], stroke, myocardial infarction \[MI\], or heart attack). Former studies by the investigators have shown that the NP deficient states such as obese and black individuals contributes to lower energy expenditure, poor metabolic profile and promotes the onset of diabetes. Certain genetic factors contribute to the higher predisposition to cardiometabolic disease in individuals with relative atrial natriuretic peptide (ANP) deficiency. PI and others have identified a common genetic variant, rs5068 is associated with higher plasma ANP levels. The lack of the rs5068 variant has a comparable effect on ANP levels as seen in obese and black individuals and plays a causal role in cardiometabolic health regulation. The rs5068 variant is only present in 10-12% of the population, thereby leaving nearly 90% of adults vulnerable to the potential adverse cardiometabolic impact of having a relative ANP deficiency. This indicates that a low ANP genotype is associated with a poor metabolic health profile. Our earlier study, in normotensive healthy young adults, demonstrated that a high glucose meal results in reduce ANP levels by 20-30%, which indicates that ANP is a glucose-responsive hormone. The preliminary data from our ongoing clinical trial has shown increased ANP levels with response to the exercise. The impact of genetically determined low ANP levels on the differences in exercise-induced ANP (beneficial) increase and glucose load-induced suppression of ANP (detrimental) is not known in humans. Micro-RNA-425 (miR-425) is a negative regulator of ANP and acts in a genotype-specific manner. In our previous study, the investigators have demonstrated that miR-425 levels decreased by 71% following one week on a high-salt diet compared with a low-salt diet in individuals with low ANP genotype, and no change was seen in high ANP genotype individuals. In vitro experiments in animals showed an increase in cardiac miR-425 levels by 22-30%. The negative regulator of ANP also independently negatively regulates the control of energy expenditure. The responsiveness of mir-425 to glucose challenge and exercise challenge (metabolic perturbations) has not been previously evaluated in humans. Individuals with genetically reduced amounts of ANP will be the focus of our present genotype-guided physiological investigation. Following the glucose and exercise challenges, the investigators will additionally investigate the extent to which miR-425 mediated control of ANP suppression occurs. This study will help in understanding how ANP regulates cardiometabolic health in individuals with genetically lower ANP levels.

Conditions

• Cardiovascular Diseases
• Natriuretic Peptides
• Cardiometabolic Diseases
• Energy Expenditure
• Glucose Metabolism
• Exercise
• Obesity

Interventions

Type	Name	Description
DIETARY_SUPPLEMENT	Study diet	Participants will consume the study diet for 5 days provided by the clinical research unit's metabolic kitchen (at UAB)
OTHER	Exercise capacity VO2 max determination	Each participant's maximal oxygen capacity will be determined using a modified Bruce treadmill protocol and will also undergo a DEXA scan to determine the body mass.
OTHER	Exercise Challenge	Each participant will walk at 70 % of his/her VO2max for 20 minutes on treadmill and will also undergo a resting energy expenditure test.
OTHER	Glucose Challenge	Participants will come in fasting state on day 6th and will be given 75 gm oral glucose solution to drink, followed by blood collection every hour for next 8 hours.

Timeline

• Start date: 2022-04-01
• Primary completion: 2026-09-30
• Completion: 2027-04-30
• First posted: 2022-01-31
• Last updated: 2026-04-09

Locations

1 site across 1 country: United States