Clinical trial NCT05571865: Diabetic Cardiomyopathy and Heart Failure
Official title: Preventing Diabetic Cardiomyopathy and Heart Failure by Ketone Bodies
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: NA
Conditions: Diabetic Cardiomyopathies
Heart Failure
Keywords: Diabetic Cardiomyopathy, Metabolic Dysregulation, and Heart Failure.
Lead sponsor: University of Louisville
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
First posted: 2022-10-07
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Diabetic, and non-diabetic subjects.
Primary purpose: PREVENTION

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.

Eligibility criteria: Inclusion Criteria:

-Diabetic subjects with high blood glucose levels

Exclusion Criteria:

- Comorbidities affecting glucose levels and cardiac function

Primary outcomes:
measure: Primary Outcome Measure-I
timeFrame: 4 years
measure: Primary Outcome Measure-II
timeFrame: 4 years
Secondary outcomes:
measure: Secondary Outcome Measure-I
timeFrame: 4 years
Other outcomes:
Locations:
city: Louisville
country: United States
facility: University of Louisville School of Medicine
state: Kentucky
Study officials:
affiliation: University of Louisville School of Medicine
name: Mahavir Singh, DVM, MS, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.