Cellular Mechanisms Involved in Reactive Carbonyl and Hyperinsulinemia Enhancement of Diabetic Complications
Godbout, Jonathan Philip
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https://hdl.handle.net/2142/83531
Description
Title
Cellular Mechanisms Involved in Reactive Carbonyl and Hyperinsulinemia Enhancement of Diabetic Complications
Author(s)
Godbout, Jonathan Philip
Issue Date
2001
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)
Chemistry, Biochemistry
Language
eng
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.
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