Diabetic Cardiomyopathy and Heart Failure

NCT05571865 — Not applicable, Withdrawn, University of Louisville

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Preventing Diabetic Cardiomyopathy and Heart Failure by Ketone Bodies

Registry	NCT05571865
Status	Withdrawn - Did not receive funding as anticipated.
Phase	Not applicable
Study type	Interventional; randomized, parallel, masking: none, prevention
Sponsor	University of Louisville (Other); collaborators: National Institutes of Health (NIH)
Conditions	Diabetic Cardiomyopathies, Heart Failure
Interventions	Probiotic (Dietary supplement)
Dates	start 2025-07-01 (estimated), primary completion 2026-06-01 (estimated), completion 2026-06-01 (estimated), first posted 2022-10-07, last updated 2025-01-31
Locations	1 site in United States

-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).

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+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.

+Arms and interventions

Arm	Type	Interventions	Description
Control subjects (non-diabetic).	Other	Dietary Supplement: Probiotic	Control subjects (non-diabetic): 10 subjects: No intervention (placebo). 10 subjects: Intervention (probiotic)
Diabetic Subjects	Other	Dietary Supplement: Probiotic	Diabetic subjects: 10 subjects: No intervention (placebo). 10 subjects: Intervention (probiotic)

Probiotic (Dietary supplement): Oral administration of a probiotic

+Outcome measures

Primary outcomes

Primary Outcome Measure-I [4 years]: Levels of glucose in blood and urine
Primary Outcome Measure-II [4 years]: Cardiac function evaluation by electrocardiogram

Secondary outcomes

Secondary Outcome Measure-I [4 years]: Biochemical estimation of biomarkers from blood samples

+Eligibility

Sex: All, ages: 18 Years to 70 Years, accepts healthy volunteers

Inclusion Criteria:

-Diabetic subjects with high blood glucose levels

Exclusion Criteria:

\- Comorbidities affecting glucose levels and cardiac function

+Locations (1)

Facility	City	Country	Status
University of Louisville School of Medicine	Louisville, Kentucky	United States

+Publications

Results publication: 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. PMID 30832381
Results publication: 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. PMID 35299968

+Investigators

Mahavir Singh, DVM, MS, PhD, Principal investigator, University of Louisville School of Medicine