Delaware County Medical Society Summer/Fall 2020 - 30

FEATURE
synthesis and storage occurs. The adipocyte has a
remarkable ability to expand in size to meet its health wise
limited. Once hypoxia ensues in the adipocyte cell, due to
an over-taxed blood supply, typoxia triggers the expression
of pro-inflammatory mediator signaling pathways as the
as the IKK pathway, resulting in the release of cytokines as
TNF alpha (tumor necrosis alpha) from activated platelets;
and which can disrupt the insulin signaling cascade,
resulting in the onset of insulin resistance in the adipocyte;
and which in turn leads to an unhibited lipolysis, as
large quantities of fatty acid enter the circulation. Such a
combination of excessive caloric intake plus an uninhibited
lipolysis from expanded-in-size adipocytes in adipose
tissue, the "supply" side, can readily overcome the lipid
oxidative capacity of down-stream organs as skeletal
muscle and liver; organs not structured for a large amount
of lipid uptake and storage in their tissues - the onset of
lipotoxicity in these tissues.
The development of obesity-associated co-morbidities
resulting from lipid overload (the "supply" side) for
metabolic disposal; a comorbidity of diabetes results in
the accumulation of DAG and its initiation of molecular
activity resulting in breaking the insulin-signaling cascade
in skeletal muscle. In health, skeletal muscle, the largest
organ, in the body, accounts for the majority (75%) of
glucose uptake from the circulation into a cell. However,
with the presence of insulin resistance in skeletal muscle,
insulin is no longer effective to promote glucose uptake.
Hypoglycemia ensues. Beta cells in the pancreas eventually
fall to produce enough insulin to maintain normoglycemia,
and at this point diabetes is established (Kwon and Pessin
2013, Kragen and Cooney 2008, Guilherme 2008, Wisse
2004).
Non-alcoholic fatty liver develops as a co-morbidity in an
insulin-resistant liver in obesity, again due to an excessive
uptake of fatty acid from the circulation into the liver,
and its subsequent accumulation intracellulary of DAG.
Vanter (2015) explains why there is continued synthesis
of triglyceride in an insulin-resistant organ as the liver, as
insulin action; but fails to suppress glucose production,
an action insulin normally suppresses. The explanation
Vatner (2015) finds is that fatty acid uptake in an insulinresistantant liver is independent of insulin action. Fatty
acid uptake into the liver is related more to the large
amount of fatty acid delivery to the liver. The continued
large uptake of fatty acid and subsequent synthesis of
triglyceride and deposition leads to hepatic inflammation,
fibrosis, cirrhosis and hepatocellular carcinoa (Fruci 2013).
While non-alcoholic liver disease, found in 20-30% of

28 DELAWARE COUNTY MEDICINE & HEALTH

the general population, it is present in 75-90% in obese
individuals and 90% in obese type 2 diabetics (Sears and
Perry).
Abel (2010) describes the process for the development of
obese-associated co-morbidity, lipotoxic cardiomyopathy.
In health, fatty acid is the usual fuel substrate for the
adult myocardium but its fuel selection is flexible. Given
clinical circumstances, the myocardium may select an
alternative substrate as glucose, lactate or ketone bodies in
order to preserve its function. In the fetal heart glucose is
the preferred substrate for energy production, as oxygen
supply here is low. Glucose for energy ATP production
requires less oxygen consumption than does fatty acid.
With the onset of insulin resistance in organs of the
body, the myocardium receives a continued excessive
fatty acid uptake. The result is the myocardium looses
its flexibility for substrate selection. This obligatory use
of fatty acid as a fuel source, however, comes at a higher
oxygen consumption cost, and with it a predisposition for
congestive heart failure.
Lipid oxidative metabolism imbalance arises from a
depressed oxidative capacity in mitochondria themselves
or gene variation. Houmard (2008) reports the finding of
a depressed lipid oxidation in the skeletal muscle of obese
individuals; due to, he reports, a depressed activity in
the enzymes that catalyze the steps in the beta-oxidation
pathway for fatty acid metabolic degradation.
Petersen (2004) reports on a gene mitochondrial variation,
an impaired oxidative function in the mitochondria of
young, insulin-resistant offspring from parents with type
2 diabetes. These young offspring were found to have a
mitochondrial content in their skeletal muscle of only
55%, compared to matched controls. In addition was
found a decreased type 1/type 2 muscle fiber ration in
their skeletal muscle. Type 1 skeletal muscle fibers contain
a high mitochondrial content and a high aerobic energy
production. In contrast type 2 skeletal muscle fibers use a
non-oxidative (glycolytic) pathway for energy production.
This later pathway make teleologic sense when a quick
burst of energy, as in fight or flight situation, is required.
Glycogen breakdown to glucose is a quicker source of
energy than via fatty acid metabolism.
Tsushmi (2008), a former lab assistant for Dr. Abel reports
that further on the entity, lipotoxic cardiomyopathy, reports
that the myocardial mitochondria may become oxidatively
defective in obesity. Prolonged lipid overload of the

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Delaware County Medical Society Summer/Fall 2020

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