Mechanistic insights into diabetes mellitus and oxidative stress

Abstract

Diabetes mellitus (DM) is a significant healthcare concern worldwide that affects more than 165 million individuals leading to cardiovascular disease, nephropathy, retinopathy, and widespread disease of both the peripheral and central nervous systems. The incidence of undiagnosed diabetes, impaired glucose tolerance, and impaired fasting glucose levels raises future concerns in regards to the financial and patient care resources that will be necessary to care for patients with DM. Interestingly, disease of the nervous system can become one of the most debilitating complications and affect sensitive cognitive regions of the brain, such as the hippocampus that modulates memory function, resulting in significant functional impairment and dementia. Oxidative stress forms the foundation for the induction of multiple cellular pathways that can ultimately lead to both the onset and subsequent complications of DM. In particular, novel pathways that involve metabotropic receptor signaling, protein-tyrosine phosphatases, Wnt proteins, Akt, GSK-3beta, and forkhead transcription factors may be responsible for the onset and progression of complications form DM. Further knowledge acquired in understanding the complexity of DM and its ability to impair cellular systems throughout the body will foster new strategies for the treatment of DM and its complications.

Fig. 1. Elevated glucose leads to injury in primary hippocampal neurons

Primary hippocampal neurons were obtained from E-19 Sprague-Dawley rat pups and maintained in growth medium (Leibovitz’s L-15 medium, containing 6% sterile rat serum, 150 mM NaHCO₃, 2.25 mg/ml of transferrin, 2.5 μg/ml of insulin, 10 nM progesterone, 90 μM putrescine, 15 nM selenium, 35 mM glucose, 1 mM L-glutamine, 50 μg/ml penicillin and streptomycin, and vitamins) in 35 mm polylysine/laminin-coated plates at 37 °C in a humidified atmosphere of 5% CO₂ and 95% room air for 10~14days. For the induction of elevated glucose, neurons were incubated in L-15 growth medium with free serum containing D-glucose at the concentration of 50 mM for 24 h at 37°C and cell survival was determined by trypan blue exclusion method. Representative images reveal trypan blue uptake in cells with elevated glucose that reflects neuronal injury.

Fig. 2. Diabetes mellitus integrates with a host of cellular pathways controlled by oxidative stress

Cellular injury during diabetes mellitus employs a series of pathways of oxidative stress that involve mitochondrial dysfunction, G-protein signaling, PTPs, Wnt, the serine-threonine kinase Akt, and its downstream substrates of GSK-3β and FOXO3a that can impact upon glucose tolerance, insulin sensitivity, and insulin secretion.