Delaware County Medical Society Summer/Fall 2020 - 31

myocardial mitochondria leads to mis-shaped, shrunkenin-size mitochondria, due to the generation of damaging
reactive oxygen species (ROS) which can disrupt the
activity of the myocardial proteins that control the size and
shape of the mitochondria.

A prescription for both dietary restriction and exercise
should reverse the lipid metabolic imbalance.

The Insulin Signaling Cascade
and Method of it's Disruption

Rationale for therapy prescription to diminish the comorbidities associated with obesity: a prescription for both
diet restriction and exercise to reduce the lipid metabolic
mismatch.
Dietary Prescription: a dietary prescription to reduce
the metabolic imbalance on the "supply" side of lipid
metabolism. Adipocyte inflammation will be reduced
along with unrestricted lipolysis, reduced DAG
accumulation in critical organs, and myocardial substrate
flexibility restored. For example, Petersen (2005) reported
a moderate weight reduction was only required, less than
10% of body weight, in patients with non-alcoholic fatty
liver disease with type 2 diabetes, was associated with
a hepatic insulin resistance reduction, a reduction in
gluconeogenesis, a normalization of fasting blood glucose,
and an 80% reduction in liver triglyceride content. The diet
prescribed for a period of three months was 3% low fat diet
with 800 calories.
Prescriptions for Exercise: the body's skeletal muscle is
unique in its ability to increase mitochondrial oxidative
capacity with physical exercise. Resistance exercise or
submaximal intensity physical exercise is very effective. In
promoting oxidation of fat, and more so than high intensity
physical exercise, the thought here being due to less fatty
acid delivery for oxidation in high-intensity exercise, which
uses more glucose. An advantage of performing resistance
exercise is it can be done effectively while sitting in a chair.
Horowitz and Klein (2000) report mitochondrial content
(density) can be increased with exercise in skeletal muscle,
increased proliferation of capillaries into skeletal muscle,
increased membrane-binding proteins that regulate fatty
acid uptake increased carnitine palmitoyltransferase
(CPT-1) activity, the enzyme that escorts fatty acid across
a mitochondrial membrane for oxidation. Strasser and
Pestal (2013) reported a single bout of exercise will increase
the enzymes that catalyze triglyceride synthesis in skeletal
muscle, with a simultaneous intracellular reduction I DAG.
In summary, as Strasses and Pesta (2013) observe the
depressed oxidative capacity associated with obesity, type
2 diabetes or aging, is not an irreversible condition. Either
aerobic or resistance, but not the weight loss alone, will
improve mitochondrial content.

Figure 1 - adapted with permission
from 12/7/13 lecture by G. Boden, MD

Legend for Figure 1 in health insulin binds to its receptor,
a transmembrance tyrosine kinase. The receptor is autophosphorylated on the inside of the cell membrane and
in turn affects the next protein in line , IRS ½ (insulin
receptor proteins) to be tyrosine phosphorylated. Next the
IRS1 ½ proteins associated with P13 K (phosphoinostitide3-kinase) to GLUT 4 to migrate from the interior of the cell
in cytoplasm to the cell membrane, where it facilitates the
uptake of glucose from the circulation into the cell.
The insulin-signaling cascade is broken at the IRS ½ step
when a serine-threonine kinase protein, Kinase C, activated
by DAG signaling, migrates to the position of the IRS ½
protein and phosphorylates IRS ½. This breaks the insulinsignaling cascade at this point, being phosphorylated not
by a tyrosine kinase.
Definitions: a kinase is a protein-enzyme which when it
is activated, contributes a high-energy ATP molecule to
another protein, which is then said to be "phosphorylated."
References available upon request.

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Delaware County Medical Society Summer/Fall 2020

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