Diabetic Cardiomyopathy and Heart Failure

NCT ID: NCT05571865

Last Updated: 2025-01-31

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: NA
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-07-31
• Study Completion Date: 2026-06-30

Brief Summary

This study will demonstrate the beneficial effects of ketone bodies in type 1 diabetes (T1D) patients and will have significant translational applications to prevent serious metabolic conditions such as T1D induced diabetic cardiomyopathy (DCM).

Detailed Description

T1D remains the primary cause of DCM. The long-term goal is to understand the mechanism of T1D leading to DCM. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in degrading the low-density lipoprotein receptors (LDLRs) and that increases the circulating LDL cholesterol (LDL-C). Further, PCSK9 increases duringT1D and that, in turn, decreases mitochondrial bioenergetics, transcription factor- mitochondrial (TFAM), and the mitochondrial numbers thus creates an oxidative stress. These changes lead to oxidation of high-density lipoprotein paraoxonase-1 (HDL-Pon1). Because Pon1 hydrolyzes homocysteine (Hcy), the oxidized Pon1 thus causes accumulation of Hcy (i.e. hyperhomocysteinemia; HHcy). Also, the 'metabolic memory' is associated with epigenetic modification (methylation) of genes encoding proteins such as thioredoxin interacting protein (TXNIP). Since methylation/epigenetics inhibits genes, this phenomenon generates even more amounts of Hcy. Investigators have shown that HHcy decreases G-protein coupled receptor (GPCR) Gαs subunit, protein kinase-B (AKT), focal adhesion kinase (FAK) but increases calpain-1, inflammasome and oxidative stress. The central hypothesis is that an increase in PCSK9 causes oxidative stress and decreases TXNIP thus causing oxidation of HDL-Pon1 and subsequent accumulation of Hcy. These alterations lead to decrease in Gαs, AKT, FAK and concomitant increase in PCSK9 and calpain-1 causing metabolic, diastolic, and systolic cardiac dysfunction. Treatment with ketone bodies (the food for mitochondria) will mitigate these changes.

Conditions

Diabetic Cardiomyopathies; Heart Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Control subjects (non-diabetic).

Control subjects (non-diabetic):

10 subjects: No intervention (placebo). 10 subjects: Intervention (probiotic)

Group Type: OTHER

Probiotic

Intervention Type: DIETARY_SUPPLEMENT

Oral administration of a probiotic

Diabetic Subjects

Diabetic subjects:

10 subjects: No intervention (placebo). 10 subjects: Intervention (probiotic)

Group Type: OTHER

Probiotic

Intervention Type: DIETARY_SUPPLEMENT

Oral administration of a probiotic

Interventions

Probiotic

Oral administration of a probiotic

Intervention Type: DIETARY_SUPPLEMENT

Eligibility Criteria

Inclusion Criteria

-Diabetic subjects with high blood glucose levels

Exclusion Criteria

• Comorbidities affecting glucose levels and cardiac function

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

University of Louisville

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mahavir Singh, DVM, MS, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Louisville School of Medicine

Locations

University of Louisville School of Medicine

Louisville, Kentucky, United States

Countries

United States

References

Mishra SP, Wang S, Nagpal R, Miller B, Singh R, Taraphder S, Yadav H. Probiotics and Prebiotics for the Amelioration of Type 1 Diabetes: Present and Future Perspectives. Microorganisms. 2019 Mar 2;7(3):67. doi: 10.3390/microorganisms7030067.

Reference Type: RESULT

PMID: 30832381 (View on PubMed)

Wang CH, Yen HR, Lu WL, Ho HH, Lin WY, Kuo YW, Huang YY, Tsai SY, Lin HC. Adjuvant Probiotics of Lactobacillus salivarius subsp. salicinius AP-32, L. johnsonii MH-68, and Bifidobacterium animalis subsp. lactis CP-9 Attenuate Glycemic Levels and Inflammatory Cytokines in Patients With Type 1 Diabetes Mellitus. Front Endocrinol (Lausanne). 2022 Mar 1;13:754401. doi: 10.3389/fendo.2022.754401. eCollection 2022.

Reference Type: RESULT

PMID: 35299968 (View on PubMed)

Other Identifiers

PA-20-190

Identifier Type: OTHER

Identifier Source: secondary_id

00002

Identifier Type: -

Identifier Source: org_study_id