Hyperinsulinemia and Hyperglycemia Contribute to Diabetic Complications Through Cytokine Resistance and Altered Macrophage Function
Hartman, Matthew Edward
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https://hdl.handle.net/2142/83572
Description
Title
Hyperinsulinemia and Hyperglycemia Contribute to Diabetic Complications Through Cytokine Resistance and Altered Macrophage Function
Author(s)
Hartman, Matthew Edward
Issue Date
2004
Doctoral Committee Chair(s)
Freund, Gregory G.
Department of Study
Animal Sciences
Discipline
Animal Sciences
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Cell
Language
eng
Abstract
Disruption of the cytokine signaling systems responsible for regulating the inflammatory activity of macrophages and direct alterations in macrophage function due to exposure to the conditions of diabetes may play an integral role in the generation of diabetes-associated accelerated atherosclerosis. This literature review focuses on information related to the association between two hallmarks of type 2 DM, hyperinsulinemia and hyperglycemia, and the conditions pertinent to the development of diabetes-accelerated atherosclerosis. Chapters 2 through 4 establish that (1) the rapamycin pathway plays an integral role in serine phosphorylation dependent impaired JAK tyrosine of IRS proteins; more specifically, only mTOR, one of the two known serine kinases in this pathway, is able to generate serine phosphorylation that has a negative effect on the ability of JAK1 to tyrosine phosphorylate IRS-1, (2) with conditions mimicking hyperinsulinemia and hyperglycemia, as well as in an animal model of type 2 DM, the ability of IL-4 to stimulate PI3-kinase activity is reduced through a mTOR-dependent mechanism, and (3) hyperinsulinemia and hyperglycemia have a negative impact on normal macrophage cholesterol metabolism such that under these conditions macrophages are more prone to take up cholesteryl esters. Taken together these findings indicate that the hyperinsulinemic and hyperglycemic conditions associated with type 2 DM produce cytokine resistance in IRS-dependent signaling systems potentially resulting in a proinflammatory state and alter macrophage function giving rise to an increased propensity for foam cell development. Importantly, both chronic inflammation and the generation of foam cells are correlated with the pathogenesis of atherosclerosis and therefore may play an important role in diabetes-accelerated atherosclerosis.
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