Improve Cardiac Substrate Utilization

In Type 2 diabetes mellitus (T2DM) there is a more than 2-fold greater risk of developing heart failure (HF) and a 60%–80% greater probability of death in those with established HF. Evidence suggests that T2DM itself can drive adverse cardiac remodeling and give rise to diabetic cardiomyopathy and is reportedly evident in up to 60% of patients with T2DM. Diabetic cardiomyopathy is characterized by unexplained myocardial hypertrophy and fibrosis, with left ventricular (LV) diastolic impairment. At the cardiomyocyte level various defects including calcium mishandling and increased oxidative stress are present. Mitochondrial dysfunction is associated with abnormal myocardial structure and function in T2DM. Reductions in OXPHOS manifest in decreases in myocardial PhosphoCreatine and ATP content which have been shown in animals and humans with T2DM. [53].

Profound alterations in myocardial substrate metabolism and energetics have been shown. Crucially, these metabolic derangements precede cardiac structural and functional changes. Their early correction in animal models of T2DM aborted the development of diabetic cardiomyopathy. Consequently, metabolic abnormalities of the heart are promising therapeutic targets whose amelioration might improve outcomes in T2DM [53].

The heart is the highest energy consuming organ of the body, needing about 30kg of ATP per day. This is nearly 75-100 times the weight of the heart [53]. The mitochondria in the muscles of the heart produce the required ATP by the process of oxidative phosphorylation or OXPHOS. For continuous ATP generation there should be sufficient functional mitochondria and a continuous supply of oxygen and fuel substrates. Consistent with its high energy demands, the myocardium has the highest mitochondrial density (35% of cardiomyocyte volume versus 3%–8% in skeletal and smooth muscle cells) of any organ, and its mitochondria exhibit the greatest number of cristae which enhance OXPHOS [53].

Fatty Acids (FA) are the preferred fuel substrates and account for 70%–90% of myocardial ATP generation.Glucose oxidation accounts for 10%–30% of cardiac ATP production. In T2DM there is an increase in plasma FA levels as a result of increased lipolysis from insufficient insulin action, increased hepatic triglyceride production and inefficient adipocyte triglyceride storage. This leads to greater myocardial uptake and utilization of FA. Myocardial FA abundance activates PPAR-α which amplifies the reliance on FAs further by upregulating FA uptake, storage and β-oxidation, while suppressing glucose utilization [53].

Excessive FA uptake by myocardium and accumulation of triglycerides lead to generation of more ROS, disrupt signalling and trigger cardiomyocyte apoptosis. Even though FAs generate more ATP than glucose for each molecule metabolized, it comes at much higher oxygen cost. FA oxidation results in approximately 86% greater myocardial oxygen consumption compared to glucose [53].

Despite systemic hyperglycaemia, cardiac glucose oxidation is reduced by 30%–40% in patients with T2DM. Cardiac mitochondria exhibit diminished rates of OXPHOS and a greater uncoupling of respiration from ATP generation in T2DM [53].

Aging is associated with muscle insulin resistance, increased intra-myocellular fat content, and reductions in rates of muscle mitochondrial activity. Aging is also associated with a marked inability of mitochondria to switch from lipid to glucose oxidation on insulin stimulation, which may further contribute to dysregulated glucose and lipid metabolism in the elderly [54].

Mitochondria in resting skeletal muscle of both young lean insulin sensitive healthy control subjects and insulin resistant elderly subjects rely similarly ( about 85%) on fatty acid oxidation to meet their energy requirements despite the presence of muscle insulin resistance in the elderly [54].

Death from HF within 5 years of diagnosis is common despite current opti­mal medical therapy. Mortality and re-hospitalization within 60–90 days after discharge from hospital can be as high as 15% and 35%, respectively. These event rates have largely not changed over the past 15 years, despite implementation of evidence-based therapy.
Commonly prescribed HF medications, although beneficial in promoting some symptom relief, often do not fully address the underlying causes of progressive left ventricular dysfunction [55].

Most standard care pharmacological approaches to HF, act by reducing workload on the failing heart. They attempt to rebalance energy supply and energy demand to a lower level. Although these therapies have improved survival in patients with chronic ambulatory HF over the past 2–3 decades, death and poor qual­ity of life continue to adversely affect this ever-increasing patient population [55].

This unmet need is probably not going to be met by drugs that modulate neurohormonal abnormalities and lower heart rates, because further inter­vention along these axes is likely to be counterproductive as hypotension and bradycardia become limiting factors [55].

The search for more effective and complementary therapy for this patient population must be focused on improv­ing the intrinsic function of the viable, but dysfunctional, cardiac unit — the cardiomyocytes. The novel therapy must be hemodynamically neutral (no decrease in blood pressure or heart rate) and must target the myocardium as the centrepiece of the therapeutic intervention. Stimulating mitochondrial glucose oxidation, either directly or by inhibiting fatty acid catabolism, has been suggested as a viable therapeutic strategy to compensate for the energetically ‘starved’ failing heart [55].

Treatment with Resveratrol decreases the serum level of FFA. Resveratrol treatment increases peripheral glucose utilization as an energy substrate and decreases FFA oxidation, as demonstrated by a greater respiratory quotient (RQ). Resveratrol protects the metabolic shifting in cardiac tissue and hence cellular energy homeostasis and maintenance of the glycolytic pathway. The supplementation of Resveratrol becomes important in controlling cardiac contractility and improves heart function under diabetic conditions [56]. Glycemic control alone may not be sufficient to prevent or manage Diabetic Cardiomyopathy [53].

Resveratrol may act directly by scavenging the ROS or increase the endogenous antioxidant defenses. Resveratrol decreased the concentration of biomarkers of oxidative stress produced in diabetes mellitus. Resveratrol recovered glucose homeostasis, normalized free fatty acid oxidation, enhanced utilization glucose, regulated myocardial metabolic enzymes and calorimetric parameters, and optimized cardiac energy metabolism in diabetes conditions [56].

Resveratrol completely prevented cardiac FA utilization reduction and improved mitochondria-driven energy supply while preserving expression of mitochondrial fusion protein. This suggests that amelioration of energy metabolism may contribute to the regression of HF independent of cardiac hypertrophy [57].

The components of Cresvin Beta reduce excessive Fatty Acid Oxidation in Diabetes. It improves Cardiac Substrate Utilization and therefore increases Cardiac Energy Output. Thus Cresvin Beta and the PROD Initiative will be a valuable means of preventing the progression of Diabetic Cardiomyopathy and other complications of diabetes.

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Disclaimer: Cresvin Beta Team has taken maximum care to ensure that the information is authentic. The information has been extracted from published medical trials and text books. The information is not meant to substitute a Physicians advice, nor is it meant to treat any disease. Members are advised to consult a Physician, Dietician, Physiotherapist or Trainer before taking medication or commencing an exercise program.

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