Diabetic Cardiomyopathy and Heart Failure

Study Overview
=================
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.

Official Title
-----------------
Preventing Diabetic Cardiomyopathy and Heart Failure by Ketone Bodies

Conditions
-----------------
Diabetic Cardiomyopathies, Heart Failure

Intervention / Treatment
-----------------
* Dietary Supplement: Probiotic


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: -Diabetic subjects with high blood glucose levels Exclusion Criteria: - Comorbidities affecting glucose levels and cardiac function

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Diabetic, and non-diabetic subjects.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Control subjects (non-diabetic).<br>Control subjects (non-diabetic): 10 subjects: No intervention (placebo). 10 subjects: Intervention (probiotic) | Dietary Supplement: Probiotic<br>* Oral administration of a probiotic<br>|
| Other: Diabetic Subjects<br>Diabetic subjects: 10 subjects: No intervention (placebo). 10 subjects: Intervention (probiotic) | Dietary Supplement: Probiotic<br>* Oral administration of a probiotic<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Outcome Measure-I | Levels of glucose in blood and urine | 4 years | 
| Primary Outcome Measure-II | Cardiac function evaluation by electrocardiogram | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary Outcome Measure-I | Biochemical estimation of biomarkers from blood samples | 4 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diabetic Cardiomyopathy, Metabolic Dysregulation, and Heart Failure.