Effects of Autonomic Nervous System Modulation by Heart Rate Variability Biofeedback Training With Resonant Frequency Breathing on Glucose Metabolism in Individuals With Prediabetes

NCT ID: NCT06739993

Last Updated: 2025-05-25

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-05-14
• Study Completion Date: 2027-03-31

Brief Summary

Approximately 20% of adults have prediabetes in Germany. Prediabetes is defined as a condition with glucose levels outside the normal range but not yet meeting the criteria for type 2 diabetes. The pathogenesis of prediabetes, as well as of type 2 diabetes, involves whole-body insulin resistance associated with inadequate insulin secretion. These two central processes of glucose regulation are modulated by the brain. The brain communicates via the autonomic nervous system (ANS) with metabolically important organs in the periphery to modulate insulin sensitivity and insulin secretion. These processes are impaired in individuals with prediabetes and diabetes. An ANS sympathovagal imbalance has also been observed in individuals with prediabetes. There are no specific therapeutic approaches to improve ANS sympathovagal imbalance. It is assumed that resonant frequency breathing (RFB) maximizes heart rate variability (HRV) through rhythmization of breathing, heartbeat, and blood pressure. Through this state of coherence, the activity of the parasympathetic nervous system is upregulated, and the activity of the sympathetic nervous system is suppressed, leading to an increase in modulation of ANS activity. Several studies have demonstrated that heart rate variability-biofeedback (HRV-BF) interventions improve HRV, reduce stress and anxiety, and alleviate symptoms in patients with various medical conditions. To the best of current knowledge, no study has investigated the effect of HRV-BF-RFB on glucose metabolism. Therefore, the proposed randomized controlled non-blinded trial aims to gain evidence about the effect of HRV-BF-RFB compared to an anti-stress program on glucose metabolism in individuals with prediabetes. Glucose metabolism is characterized using the 75 g oral glucose tolerance test. There are two potential mechanisms by which HRV-BF-RFB may improve glucose metabolism in individuals with prediabetes: (a) a 0°-phase relationship between heart oscillations and breathing, maximizing the amplitude of respiratory sinus arrhythmia (RSA), and (b) activation of the cholinergic anti-inflammatory pathway. The investigators hypothesized that in individuals with prediabetes, the HRV-BF-RFB intervention will improve glucose metabolism and glucose variability.

Conditions

Prediabetes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Resonance frequency breathing with heart rate variability biofeedback training (RFB-HRV-BF)

The mobile system "eSense Pulse" by Mindfield Biosystems Ltd. (Gronau, Germany) was used for RFB-HRV-BF training. The participants sat in an upright position, started the training via the eSense app on their smartphone, and were instructed to practice breathing at their individually determined resonance frequency.During training, a ball that expands (breathe in) and shrinks (breathe out) on the screen specified the breathing frequency goal to a value of six cycles per minute (five seconds inspiration, five seconds expiration). The HRV was visualized by new symbols varying in color depending on the respectively measured values, which appeared every ten seconds.

Group Type: EXPERIMENTAL

Resonance frequency breathing with heart rate variability biofeedback training

Intervention Type: BEHAVIORAL

During training, a ball that expands (breathe in) and shrinks (breathe out) on the screen specified the breathing frequency goal to a value of six cycles per minute (five seconds inspiration, five seconds expiration). The HRV was visualized by new symbols varying in color depending on the respectively measured values, which appeared every ten seconds. When the participants achieved the specified breathing frequency, resulting in an increased sinus arrhythmia, the symbols appearing on the smartphone display were green. When the participants did not achieve the specified breathing frequency, the symbols appeared in yellow (non-significant deviation), orange (significant deviation), or red (very significant deviation). The participants were instructed to adjust their breathing frequency to reach emergence of as many green symbols as possible for the entire training session.

Anti-Stress program

The mobile system eSense Pulse from Mindfield Biosystems is used for the digital anti-stress program. To do this, the participants put on a chest strap with a sensor and can start training via the eSense app. The anti-stress program is carried out using a procedure generated for the study. During the anti-stress program units, the participants receive application-related information and tips to better understand the topic of stress, identify stressors in their own lives and reduce stress. The active control intervention of the anti-stress program was selected to investigate the effect of a specific stress level reduction without the direct modulation of physiological mechanisms of action as with HRV-BF-RFA.

Group Type: ACTIVE_COMPARATOR

Anti-Stress program

Intervention Type: BEHAVIORAL

The mobile system eSense Pulse from Mindfield Biosystems is used for the digital anti-stress program. To do this, the participants put on a chest strap with a sensor and can start training via the eSense app. The anti-stress program is carried out using a procedure generated for the study. During the anti-stress program units, the participants receive application-related information and tips to better understand the topic of stress, identify stressors in their own lives and reduce stress. The active control intervention of the anti-stress program was selected to investigate the effect of a specific stress level reduction without the direct modulation of physiological mechanisms of action as with HRV-BF-RFA.

Interventions

Resonance frequency breathing with heart rate variability biofeedback training

During training, a ball that expands (breathe in) and shrinks (breathe out) on the screen specified the breathing frequency goal to a value of six cycles per minute (five seconds inspiration, five seconds expiration). The HRV was visualized by new symbols varying in color depending on the respectively measured values, which appeared every ten seconds. When the participants achieved the specified breathing frequency, resulting in an increased sinus arrhythmia, the symbols appearing on the smartphone display were green. When the participants did not achieve the specified breathing frequency, the symbols appeared in yellow (non-significant deviation), orange (significant deviation), or red (very significant deviation). The participants were instructed to adjust their breathing frequency to reach emergence of as many green symbols as possible for the entire training session.

Intervention Type: BEHAVIORAL

Anti-Stress program

The mobile system eSense Pulse from Mindfield Biosystems is used for the digital anti-stress program. To do this, the participants put on a chest strap with a sensor and can start training via the eSense app. The anti-stress program is carried out using a procedure generated for the study. During the anti-stress program units, the participants receive application-related information and tips to better understand the topic of stress, identify stressors in their own lives and reduce stress. The active control intervention of the anti-stress program was selected to investigate the effect of a specific stress level reduction without the direct modulation of physiological mechanisms of action as with HRV-BF-RFA.

Intervention Type: BEHAVIORAL

Other Intervention Names

RFB-HRV-BF; ASP

Eligibility Criteria

Inclusion Criteria

• Presence of prediabetes Fasting glucose: 100-125 mg/dl (5.6-6.9 mmol/L) and/or HbA1c in %: 5.7-6.4 (39-47 mmol/mol Hb) and/or 2-hour value of the 75 g OGTT: 140-199 mg/dl (7.8-11.0 mmol/L)

• This is checked using a 75 g OGTT in a screening visit.
• Age between 18 and 65 years
• BMI between 20 and 40 kg/m²

Exclusion Criteria

• Diabetes mellitus
• Malignant diseases within the last 5 years before randomization
• History of gastrointestinal surgery
• Pancreatic diseases other than pancreatic lipomatosis
• Acute diseases or infections
• Regular intake of cardiac drugs that affect heart rate within the last 4 weeks before the first measurement (e.g. beta-receptor blockers, antiarrhythmics, etc.)
• Intake of centrally acting drugs
• Medical contraindications to a meaningful interpretation of the heart rate analysis (e.g. patients with pacemakers, atrial fibrillation or other arrhythmias)
• Chronic diseases (particularly metabolic diseases, heart diseases, blood diseases)
• Endocrinological disease other than substituted hypothyroidism
• Mental illnesses
• Intake of drugs that can affect blood sugar metabolism (e.g. steroids)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Johannes Gutenberg University Mainz

OTHER

Sponsor Role: lead

Responsible Party

Benedict Herhaus

Ph.D.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

University Medical Center Mainz - Medical Psychology and Medical Sociology

Mainz, Mainz, Germany

Site Status: RECRUITING

University Medical Center of the Johannes-Gutenberg University, Department of Medical Psychology and Medical Sociology

Mainz, Rhineland-Palatinate, Germany

Site Status: NOT_YET_RECRUITING

Countries

Germany

Central Contacts

Benedict Herhaus, Ph.D.

Role: CONTACT

bherhaus@uni-mainz.de

004961313929140

Martin Heni, Prof. Dr. med.

Role: CONTACT

Facility Contacts

Benedict Herhaus, Ph.D.

Role: primary

bherhaus@uni-mainz.de

+4961313929140

Benedict Herhaus, Ph.D.

Role: primary

bherhaus@uni-mainz.de

004961313929140

References

Herhaus B, Thesing G, Conrad R, Petrowski K. Alterations in heart rate variability and pro-inflammatory cytokine TNF-alpha in individuals with panic disorder. Psychiatry Res. 2023 Apr;322:115107. doi: 10.1016/j.psychres.2023.115107. Epub 2023 Feb 12.

Reference Type: BACKGROUND

PMID: 36796202 (View on PubMed)

Herhaus B, Siepmann M, Kahaly GJ, Conrad R, Petrowski K. Effect of a Biofeedback Intervention on Heart Rate Variability in Individuals With Panic Disorder: A Randomized Controlled Trial. Psychosom Med. 2022 Feb-Mar 01;84(2):199-209. doi: 10.1097/PSY.0000000000001031.

Reference Type: BACKGROUND

PMID: 34654028 (View on PubMed)

Herhaus B, Kalin A, Gouveris H, Petrowski K. Mobile Heart Rate Variability Biofeedback Improves Autonomic Activation and Subjective Sleep Quality of Healthy Adults - A Pilot Study. Front Physiol. 2022 Feb 17;13:821741. doi: 10.3389/fphys.2022.821741. eCollection 2022.

Reference Type: BACKGROUND

PMID: 35250623 (View on PubMed)

Herhaus B, Conrad R, Petrowski K. Effect of a slow-paced breathing with heart rate variability biofeedback intervention on pro-inflammatory cytokines in individuals with panic disorder - A randomized controlled trial. J Affect Disord. 2023 Apr 1;326:132-138. doi: 10.1016/j.jad.2023.01.091. Epub 2023 Jan 28.

Reference Type: BACKGROUND

PMID: 36720404 (View on PubMed)

Heni M, Wagner R, Willmann C, Jaghutriz BA, Vosseler A, Kubler C, Hund V, Scheffler K, Peter A, Haring HU, Preissl H, Kullmann S, Fritsche A. Insulin Action in the Hypothalamus Increases Second-Phase Insulin Secretion in Humans. Neuroendocrinology. 2020;110(11-12):929-937. doi: 10.1159/000504551. Epub 2019 Nov 5.

Reference Type: BACKGROUND

PMID: 31689708 (View on PubMed)

Heni M, Wagner R, Kullmann S, Veit R, Mat Husin H, Linder K, Benkendorff C, Peter A, Stefan N, Haring HU, Preissl H, Fritsche A. Central insulin administration improves whole-body insulin sensitivity via hypothalamus and parasympathetic outputs in men. Diabetes. 2014 Dec;63(12):4083-8. doi: 10.2337/db14-0477. Epub 2014 Jul 15.

Reference Type: BACKGROUND

PMID: 25028522 (View on PubMed)

Heni M, Wagner R, Kullmann S, Gancheva S, Roden M, Peter A, Stefan N, Preissl H, Haring HU, Fritsche A. Hypothalamic and Striatal Insulin Action Suppresses Endogenous Glucose Production and May Stimulate Glucose Uptake During Hyperinsulinemia in Lean but Not in Overweight Men. Diabetes. 2017 Jul;66(7):1797-1806. doi: 10.2337/db16-1380. Epub 2017 Feb 7.

Reference Type: BACKGROUND

PMID: 28174292 (View on PubMed)

Other Identifiers

540546352

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

2022-16489

Identifier Type: -

Identifier Source: org_study_id