Diabetic Cardiomyopathy and Heart Failure
Study Details
Study Description
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Other: Control subjects (non-diabetic). Control subjects (non-diabetic): 10 subjects: No intervention (placebo). 10 subjects: Intervention (probiotic) |
Dietary Supplement: Probiotic
Oral administration of a probiotic
|
| Other: Diabetic Subjects Diabetic subjects: 10 subjects: No intervention (placebo). 10 subjects: Intervention (probiotic) |
Dietary Supplement: Probiotic
Oral administration of a probiotic
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- Secondary Outcome Measure-I [4 years]
Biochemical estimation of biomarkers from blood samples
Eligibility Criteria
Criteria
Inclusion Criteria:
-Diabetic subjects with high blood glucose levels
Exclusion Criteria:
- Comorbidities affecting glucose levels and cardiac function
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Louisville School of Medicine | Louisville | Kentucky | United States | 40202 |
Sponsors and Collaborators
- Mahavir Singh, DVM, MS, PhD
- National Institutes of Health (NIH)
Investigators
- Principal Investigator: Mahavir Singh, DVM, MS, PhD, University of Louisville School of Medicine
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 00002
- PA-20-190