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Cardio Diabetes Medicine 2017 229

METABOLIC ALTERATIONS: IMPAIRED CALCIUM HOMEOSTASIS:
One of consequences of. Insulin- resistance is the DM is associated with ab-normalites in calcium han-
impaired hormone capacity to inhibit adipose issue dling major changes in DM include a shift in myocin
lipolysis with consequent enhanced free fatty acid isoenzyme composition (from V1-V3 isoforms) and
(FFA) release particularly in subject with visceral the predominance of the fetal (beta) myosin heavy
adiposity, and the reduction in myocardial glucose chain expression with respect to the (alpha) myocin
transporter GLUT-4. Expression and glucose uptake, heavy chain ,leading to depressed ATP ase activity
These metabolic alterations may be firstly related of myofibrils and reduced contractile force. In addi-
to changes in substrate availability (higher availabil- tion, alterations in sarco-endoplasmic reticulum Ca2+
ity FFA and insulin resistant-mediated impairment ATPase (SERCA) 2 activity, inefficient sequestration
in myocyte glucose metabolism) and lead to a shift of Ca2 + in the sacroplasmic reticulum resulting in
from glucose to FFA uptake and utilization in the Ca2 + overload in the cystosol and defects in ryano-
heart (13) dine, receptors activity have been proposed as major
determinants of impaired relaxation and contractile
This metabolic subtract changes lead to dysfunction
of myocardial mitochondria with increased genera- dysfunction. Recently, a perturbation in the function
tion of reactive oxygen species promoting mitochon- of the endoplasmic reticulum, a central organelle en-
drial uncoupling and leading to increase oxygen con- trusted with Ca2 +haemeostasis and protein folding
sumption and reduced myocardial efficiency and maturation has been suggested as the leading
cause of myocytes apoptosis .
Diabetic mitochondrial dysfunction is sustained by
ultrastructural changes (e.g., hyperplasia, reduced HYPERGLYCEMIA INDUCED
organelle size, loss of membranes and cristae) and ALTERATIONS
reduced expression of genes involved in oxidative
phosphorylation .The phoscreatine / ATP ratio, a Hyperglycemia is one of the main pathogenic mech-
surrogate marker of mitochondrial function and car- anism leading to diabetic structural alteration in CHF.
diac energetic, is significantly reduced in patient Important consequences of hyperglycemia- induced
with type I and type. 2 DM without a known history cellular injury are the function of AGE – advanced gly-
of CAD,, and correlates with the degree of diastolic cation end products resulting from the non-enzymat-
dysfunction these metabolic alterations\ characterize ic glycation and oxidation of proteins and lipids, and
the early stages of diabetic cardiomyopathy without the activation of the protein kinase C AGE accumula-
overt functional alteration. As metabolic alterations tion in DM is known to induced myocardial alteration
become long standing, high FFA levels activate myo- primarily via two mechanisms. Advanced glycations
cyte expression of peroxisome proliferator-activated end-product form cross – links within or between
receptor (alpha) that stimulates the transcription of proteins such as myocardial collagen, laminin and
multiple genes responsible for an increase in mito- elastin, thereby impairing the ability of collagen to
chondrial (FFA) transport and oxidation. FFA myo- be degraded,, leading to collagen accumulation and
cardial uptake may exceed FFA oxylation capacity fibrosis with increased myocardial stiffness and im-
leading to triglycerides accumulation in the myocytes paired cardiac relaxation. Secondly, soluble extra
(lipotoxicity) and production of toxic lipid intermedi- cellular advanced glycated end-products bind to
ates such as diacylglycerol and ceramides both pro- their receptors stimulating the upregulation of trans-
moting oxidative stress and cardiomyocytes apop- forming growth factor-and important pro-sclerotic
tosis with consequient mechanical dysfunction and factor that have also been implicated in inflammatory
organ failure. signaling pathways .
Hyperglycaemic–induced protein kinase C activation
There are some data to suggest that the risk of heart
failure could be lessened also contributes to cardiac fibrosis by stimulating
connective tissue growth factor expression
By tight control of HBA1c, Lind and colleagues
demonstrated that patient with a HBA1c of at least The activation of all the above hyperglycaemic – in-
10.5% had a four – fold greater risk of heart failure duced pathways characterise the middle stage of di-
than did those with a HBA1c of less than 6.5% . How- abetic cardiomyopathy associated with myocellular
ever, strict glycemic control has not uniformly been hypertrophy and myocardial fibrosis which contrib-
demonstrated to reduce the onset of heart failure ute to abnormal diastolic dysfunction and normal or
slightly decreased EF.

Cardio Diabetes Medicine