Page 53 - ITPS-7-2

INNOSC Theranostics and
Pharmacological Sciences Cardiac metabolism in health and disease

resistance to insulin, fibroblast growth factor 21 (FGF21), aligns with the concept described earlier, involving a shift
and leptin, have been observed. 12,40-49 These conditions from mitochondrial FAO to glycolysis or other substrates.
correlate with heightened myocardial FAO and a In addition, during myocardial ischemia, SGLT1
predominant reliance on FAO as the primary myocardial expression increases approximately two to threefold,
metabolism. Moreover, the proportion of FAO is increased promoting increased glucose uptake into cardiomyocytes.
in these pathological states. The impairment of hormonal These alterations are beneficial, protecting cardiomyocytes
signaling pathways in the heart especially disturbs cardiac from irreversible injury, necrosis, and apoptosis. 57-59
insulin signaling pathways and can also contribute In clinical settings, a randomized controlled trial
to decreased GLUT4 vesicle trafficking to the plasma conducted with acute myocardial infarction (MI) patients
membrane, leading to decreased glucose uptake into using glucose–insulin–potassium (GIK) as a supplementary
cells, 48,49 since GLUT4 is the dominant glucose transporter treatment alongside myocardial reperfusion showed no
in the human heart. Therefore, in DM, increased plasma efficacy in cardioprotection. This lack of effectiveness
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FA levels are attributed to elevated glucagon levels in this trial might be attributed to delays in initiating
activating lipolysis and cholesterol synthesis. 23 therapy, which was administered only during reperfusion.
Cardiac insulin resistance in DM involves the However, findings from the IMMEDIATE study revealed
overexpression of FA transporters such as CD36 and FABP that early intravenous GIK for acute coronary syndrome
on cardiomyocyte membranes, augmenting FA uptake. 50,51 (ACS) in out-of-hospital emergency medical service
In addition, high expression levels of peroxisome settings demonstrated an 80% reduction in infarct size at
proliferator-activated receptor alpha and peroxisome 30 days. Although there was no significant reduction in
proliferator-activated receptor-gamma coactivator 1-alpha serious endpoints at 1 year among patients with suspected
(PGC-1α) in insulin resistance and DM contribute to ACS compared to placebo controls, individuals with
elevated mitochondrial FAO levels by regulating genes ST-elevation MI treated with GIK exhibited reduced
involved in FAO, thereby reducing cardiac glycolysis rates of cardiac arrest, 1-year mortality, or heart failure
and mitochondrial glucose oxidation (via the “Randle hospitalization within the year. 60-62
cycle”). 52-54 Insulin resistance leads to impaired cardiac During myocardial reperfusion following ischemia,
mitochondrial function, diminishing cardiac efficiency reperfusion therapy elevates FA levels and reduces malonyl
due to increased mitochondrial FAO, which elevates the CoA, a potent inhibitor of CPT-1, leading to increased
cardiac mitochondrial workload and oxygen demands for cardiac FAO. ATP production during this phase primarily
substrate metabolism. 55,56 arises from mitochondrial FAO. Moreover, there is a

In terms of SGLT1 activity and expression in DM, decrease in glycolysis, increasing cellular oxygen demand
studies have revealed type-dependent effects: SGLT1 for ATP production, as described by the “Randle cycle,”
expression significantly increased in end-stage DCM in which outlines reciprocal changes between mitochondrial
type 2 DM (T2DM) patients and animal models (db/db FAO and glycolysis. This aligns with the second concept
mice), while it decreased in type 1 DM (T1DM) animal mentioned earlier, which involves a shift toward a higher
models (streptozotocin-diabetic mice). The elevated degree of FAO. 8,9
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SGLT1 expression in T2DM might be influenced by In the context of myocardial reperfusion injury,
chronic hyperinsulinemia, as SGLT1 activity is regulated reperfusion therapy contributes to this type of injury.
by insulin. However, the contradictory findings regarding Mitochondrial dysfunction triggers cellular apoptosis and
the effects of DM on SGLT1 expression necessitate further ATP depletion. Despite hyperoxygenation at the onset
investigation, particularly considering the severe insulin of reperfusion, impaired cardiac mitochondrial function
resistance observed in end-stage cardiomyopathy. induces oxidative stress and mediates myocardial injury. 63,64
This impairment intensifies the cardiac mitochondrial
6. Cardiac metabolism in myocardial workload due to a shift from glucose oxidation to FAO,
ischemia and/or reperfusion increasing oxygen demands and potentially accelerating
During myocardial ischemia, the myocardium experiences apoptosis, thereby decreasing cardiac efficiency and
a decrease in oxygen supply, leading to reduced circulating function.
FAs available for FAO. Conversely, there is an increase in 7. Cardiac metabolism in cardiac
glucose derived from glycogen breakdown, facilitated by
enhanced glucose transport through GLUT1 and GLUT4 hypertrophy and heart failure
translocation to the plasma membrane, resulting in a Cardiac hypertrophy is an adaptive response of the
metabolic shift toward glycolysis. This metabolic shift myocardium to pressure or volume stress in the heart

Volume 7 Issue 2 (2024) 4 doi: 10.36922/itps.2302