Page 184 - 73_04

MARGARITA LORENZO Y COLS. ANAL. REAL ACAD. NAC. FARM.

ikkb?? reversed obesity and diet-induced insulin resistance (15). Our
group has explored in deep the mechanism by which TNF-a produces
insulin resistance on glucose uptake in two physiological models:
murine neonatal myocytes and fetal brown adipocytes.

INSULIN RESISTANCE BY TNF-a IN MYOCYTES:
AMELIORATION BY TREATMENT WITH SALICYLATE

Skeletal muscle is responsible for 80% of the glucose disposal of
the body and is the organ where insulin resistance is first detectable.
Acute insulin treatment stimulates glucose transport in myocytes
largely by mediating translocation of GLUT4 to the plasma
membrane, being accomplished by activation of PI3K, AKT and
several PKC isoforms including ?, ?, a and d (16, 17). Moreover,
skeletal muscle has an insulin-independent mechanism to increase
glucose transport that involves the activation of AMP-activated
protein kinase (AMPK) by stimuli such as exercise, hypoxia or
ischemia (18). The AKT substrate of 160 kDa (AS160) has recently
emerged as a point of convergence for both effectors of glucose
transport and seems to modulate GLUT4 trafficking (18). While
GLUT4 protein content is normal in muscle from subjects with type
2 diabetes, the capacity of insulin to stimulate translocation of
GLUT4 to plasma membrane is impaired. In contrast to the effect of
insulin, contraction-stimulated glucose uptake and GLUT4
translocation in diabetic patients is normal, providing evidence that
exercise might be able to bypass defects in insulin signaling.

Both genetic and environmental factors have been identified to
contribute to insulin resistance in skeletal muscle. The genetic
approach shows that targeted disruption of the igf-1 and ir, or of
glut4, selectively, in murine skeletal muscle causes insulin resistance
and insulin intolerance (19-21). Furthermore, IRS-1 is the key
mediator of insulin action in muscle since IRS-1-deficient mice show
insulin resistance in muscle. In this regard, IRS-1 silencing using
small interfering RNA caused a marked reduction in insulin-inducing
acting remodeling and GLUT4 translocation, but silencing IRS-2 was
without effect (22). Among the environmental factors, adipokines
secreted by adipocytes and/or macrophages in the obese state are

994