| Diabetes mellitus is a chronic metabolic disorder characterized by a loss of insulin secretion or insulin bioactivity. Importantly, diabetes mellitus results in serious macrovascular and microvascular complications including retinopathy, neuropathy, nephropathy, circulation abnormalities and increased risk for coronary artery disease and stroke. Moreover, diabetics have impaired immunity, increased risk for cancer, and problematic chemotherapeutic treatment. Significantly, these diabetic complications increase patient morbidity and mortality, accounting for the 7th leading cause of death in the United States. This literature review focuses on the defects in both insulin signal transduction and glucose metabolism that lead to the development of these complications. A framework of a molecular model is proposed by which hyperinsulinemia-induced serine phosphorylation of IRS-2 reduces the ability of IRS-2 to serve as a substrate for Janus kinase impairing survival and cytokine signaling in immune cells. Furthermore, we provide a model for increased diabetic toxicity to platinum-derived chemotherapeutic drugs through a PKCδ dependent mechanism.; 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-α receptor (TNF-R1). Finally, we show that the circulating glucose metabolite, methylglyoxal (MGO), enhances cisplatin-induced apoptosis by activating protein kinase Cδ (PKCδ). 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. |
