Cellular Mechanisms Involved in Reactive Carbonyl and Hyperinsulinemia Enhancement of Diabetic Complications

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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Animal Sciences

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Godbout, Jonathan Philip

Contributors dc:contributor

• Freund, Gregory G.

• Chemistry, Biochemistry

Language dc:language

eng

Identifier

(MiAaPQ)AAI3017082

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/83531