Novel avenues of drug discovery and biomarkers for diabetes mellitus

Abstract

Globally, developed nations spend a significant amount of their resources on health care initiatives that poorly translate into increased population life expectancy. As an example, the United States devotes 16% of its gross domestic product to health care, the highest level in the world, but falls behind other nations that enjoy greater individual life expectancy. These observations point to the need for pioneering avenues of drug discovery to increase life span with controlled costs. In particular, innovative drug development for metabolic disorders such as diabetes mellitus becomes increasingly critical given that the number of diabetic people will increase exponentially over the next 20 years. This article discusses the elucidation and targeting of novel cellular pathways that are intimately tied to oxidative stress in diabetes mellitus for new treatment strategies. Pathways that involve wingless, β-nicotinamide adenine dinucleotide (NAD(+)) precursors, and cytokines govern complex biological pathways that determine both cell survival and longevity during diabetes mellitus and its complications. Furthermore, the role of these entities as biomarkers for disease can further enhance their utility irrespective of their treatment potential. Greater understanding of the intricacies of these unique cellular mechanisms will shape future drug discovery for diabetes mellitus to provide focused clinical care with limited or absent long-term complications.

Figure 1. Transfection of FoxO3a siRNA in endothelial cells prevents apoptotic phosphatidylserine (PS) exposure during elevated D-glucose

Representative images illustrate that gene knockdown of FoxO3a with FoxO3a siRNA (siRNA) significantly blocks endothelial cell membrane PS externalization assessed by annexin V phycoerythrin (green fluorescence). FoxO3a siRNA alone was not toxic and non-specific scrambled siRNA did not reduce PS exposure during elevated D-glucose.

Figure 2. Erythropoietin (EPO) blocks mitochondrial depolarization during elevated D-glucose

Elevated D-glucose (20 mM) resulted in a significant decrease in the red/green fluorescence intensity ratio of mitochondria using a cationic membrane potential indicator JC-1 within 48 hours when compared with untreated endothelial cells, illustrating that elevated D-glucose leads to mitochondrial membrane depolarization. In contrast, pre-treatment with EPO (10 ng/ml) during elevated D-glucose significantly increased the red/green fluorescence intensity of mitochondria in endothelial cells, indicating that mitochondrial membrane potential was restored by EPO.