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Title:Cellular Mechanisms Involved in Reactive Carbonyl and Hyperinsulinemia Enhancement of Diabetic Complications
Author(s):Godbout, Jonathan Philip
Doctoral Committee Chair(s):Freund, Gregory G.
Department / Program:Animal Sciences
Discipline:Animal Sciences
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Chemistry, Biochemistry
Abstract:The findings in this thesis demonstrate that (1) hyperinsulinemia negatively impacts B-cell survival (2) and impairs the anti-inflammatory actions of IL-4 in macrophages and finally (3) the reactive carbonyl methylglyoxal enhances chemotherapeutic drug-dependent cytotoxicity. We report that hyperinsulinemia decreases survival of serum deprived B-cells through a PI 3-kinase and JNK pathway. We describe a mechanism where rapamycin sensitive serine/threonine-proline phosphorylation of IRS-2 reduces IL-4/IRS-2/PI 3-kinase dependent reduction of TNF-alpha receptor (TNF-R1). Finally, we show that the circulating glucose metabolite, methylglyoxal (MGO), enhances cisplatin-induced apoptosis by activating protein kinase Cdelta (PKCdelta). Taken together, these data indicate that exposure to chronic insulin disrupts cell survival and impairs IRS-dependent cytokine signaling which may alter the immune response and contribute to the accelerated proinflammatory conditions of diabetes mellitus. Furthermore, these findings suggest that elevated blood MGO levels may increase the cytotoxic effects of anti-neoplastic agents in the patient with DM.
Issue Date:2001
Description:151 p.
Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2001.
Other Identifier(s):(MiAaPQ)AAI3017082
Date Available in IDEALS:2015-09-25
Date Deposited:2001

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