In this study, we extend previous work on iron deficiency and dopamine (DA) transporters to include an examination of central serotonin (5-HT) and noradrenergic (NE) transporters. Rats were fed either iron deficient (ID) or iron adequate (CN) diets from weaning until adulthood. In males, an additional group of iron deficient animals (IR) were given iron supplementation. DA, 5-HT, and NE transporter binding was done in situ on thin sections. ID males, but not females, decreased DA transporter binding in the nucleus accumbens, caudate putamen and substantia nigra by 20-40%. ID males also had a 20-30% reduction in 5-HT transporter binding in several areas (nucleus accumbens, olfactory tubercle, colliculus) while in ID females there was 15-25% increased serotonin transporter binding in the olfactory tubercle, zona incerta, anteroventral thalamic nucleus and vestibular nucleus. Iron deficiency reduced 3H-nisoxetine binding to the NE transporter in locus ceruleus and anteroventral thalamic nucleus in males but not females. Only some of the changes observed in DA, serotonin and NE transporter binding were reversible by iron supplementation. These findings show that iron deficiency affects monoamine systems related to homeostasis and in most cases males appear to be more vulnerable than females.

Insulin binding activates the receptor tyrosine kinase toward the insulin receptor substrate-1 (IRS-1). Phosphorylated IRS-1 then interacts with the p85 alpha subunit of phosphatidylinositol 3-kinase (PI3K), Nck, growth factor receptor-bound protein 2 (GRB2), and Syp, thus branching insulin's signal for both mitogenic and metabolic responses. To determine whether the expression of these proteins is altered in insulin resistance, the levels of these proteins were compared in adipose and liver tissues of nondiabetic mice and obese insulin-resistant diabetic KKAy mice. IR and PI3K p85 alpha protein levels were significantly lower in KKAy mice than in control nondiabetic mice, whereas IRS-1 protein levels were not altered. In contrast, the protein levels of GRB2, Nck, Syp, and GLUT-1 were dramatically elevated in KKAy fat, with less striking changes in liver. Treatment of diabetic animals with pioglitazone, an insulin-sensitizing antihyperglycemic agent, partially corrected the expression of some of these proteins. Taken together, these findings suggest that the insulin-resistant diabetic condition is characterized by changes in expression of insulin signal transduction components that may be associated with altered glucose metabolism.

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