Mitochondrial Oxidation and Insulin Resistance in Burn Patients Treated With Fenofibrate
| Status: | Archived |
|---|---|
| Conditions: | Hospital, Endocrine |
| Therapuetic Areas: | Endocrinology, Other |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 7/1/2011 |
| Start Date: | August 2008 |
| End Date: | August 2013 |
The Role of Mitochondrial Oxidation on Insulin Resistance in Burn Patients Treated With Fenofibrate
Major burn injury causes significant insulin resistance on glucose and protein metabolism
that persists for up to 6 months after the acute injury
This project proposes to answer the following questions:
1. Will fenofibrate given to burn patients with insulin resistance restore their insulin
sensitivity?
2. What is the relationship between mitochondrial dysfunction in muscle tissue as the
causative mechanism of burn related insulin resistance?
3. To what extent will the restored insulin sensitivity affect glucose and protein
metabolism in muscle, regenerating wounds and the liver, i.e. ameliorate burn related
hyperglycemia and protein catabolism?
The following specific hypotheses will be investigated:
1. Following severe burn injury in human patients the mitochondrial fat oxidation capacity
is decreased in muscle. This is associated with a corresponding progression in the
severity of the resistance to the action of insulin on glucose disposal and protein
synthesis and breakdown in muscle, regenerating wound and liver.
2. Fatty acids, or their active intracellular products (e.g., DAG, acyl-CoA, or
acylcarnitine), are the direct inhibitors of insulin action, rather than tissue TG
itself. In other words, impaired mitochondrial fatty acid oxidation is the mechanism
that causes altered lipid metabolism that ultimately contributes to insulin resistance.
3. Accumulation of active fatty acid products, such as DAG, acyl-CoA, or acylcarnitine
esters in muscle cells is due to the rate of uptake of plasma FFA exceeding the rate of
oxidation within muscle due principally to a reduced capacity of mitochondria to
oxidize fatty acids.
4. Decreased insulin sensitivity in muscle is related to impaired insulin signaling. This
will be reflected by increased activity of protein kinase C (PKC). Because PKC is
thought to exert its regulatory effect primarily on either tyrosine kinase activity on
the insulin receptor or downstream kinase insulin receptor substrate (IRS)
phosphorylation, these elements of the insulin signaling cascade will be decreased. In
turn, elements of insulin signaling related to the response of muscle glucose (PI3
kinase) and protein (P70S6k) metabolism will be reduced. We propose that increased
tissue PKC activity will be associated with increased tissue concentration of DAG,
acyl-CoA, or acylcarnitine.
5. Treatment of patients with the peroxisome proliferator-activated receptor (PPAR) alpha
agonist fenofibrate will improve mitochondrial capacity to oxidize fatty acids.
6. Insulin sensitivity in muscle, skin and liver in terms of both glucose and protein
metabolism will be improved by fenofibrate treatment.
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