Currently, cancer and diabetes are two of the more devastating diseases worldwide, both in the number of people affected as well as the financial cost it takes to treat those with said conditions. While these two diseases are significantly different in their pathologies and physiological impacts, they both have characteristics of altered mechanisms by which they metabolize glucose when compared to healthy individuals. In fact, there is an increased risk that has been identified for people with diabetes to develop certain types of cancer. Motivated by the finding observed 90 years ago by Otto Warburg regarding the `aerobic glycolytic' conditions exhibited by cancer cells and a study indicating a risk of developing cancer in non-obese persons with elevated fasting glucose levels, the presented work examines how the glucose metabolism of healthy cells is altered following exposure to biomolecules that are elevated in diabetes, drugs for the treatment of diabetes, and elevated glucose levels. The altered metabolism can then be compared to that of cancerous cells.First, certain metabolic alterations in cultured bovine pulmonary artery endothelial cells following treatment with metal-activated C-peptide were monitored using liquid scintillation, platereader, and microfluidic techniques. As recent reports from the Spence group have identified C-peptide as a stimulator of glucose uptake and adenosine triphosphate (ATP) release from the red blood cell (RBC), similar in vitro experiments were performed on the endothelial cells lining the inner walls of the vasculature. Results indicate that C-peptide not only has a similar influence on the glucose uptake in endothelial cells as it does on the RBCs, but also stimulates the production of a significant vasodilator in endothelial nitric oxide (NO) by a RBC mediated mechanism.C-peptide is then administered to the RBCs and endothelial cells in the presence of the type 2 diabetes drug, metformin. The metabolism of the two cell types is monitored by measuring the glucose uptake and lactate release. The studies provide a hypothesis behind metformin's action by increasing the interaction of C-peptide with the RBCs while also increasing glucose uptake. In the endothelial cells, metformin alone causes a similar increase in glucose uptake. However, this uptake increase in both cell types results in the production of elevated levels of lactate, especially in hyperglycemic conditions, which can potentially lead to lactic acidosis. This increased lactate production from the endothelial cells following metformin administration led to an overall decrease in the intracellular pH hypothesized to be caused from the release of lactate from the cell through the monocarboxylate transporter (MCT1).Lastly, the metabolic changes that occur in healthy endothelial cells in normal and elevated glucose environments are compared to those same changes in cancerous HeLa cells. The endothelial cells had an increased lactate release when they were incubated in the hyperglycemic buffers while the HeLa cells' metabolism remained relatively constant. This suggests a change in the healthy cells' metabolism depending on the sources of energy, namely glucose and pyruvate, available to it while the cancer cells' metabolism remains the same in any condition.This research demonstrates some of the factors that alter the metabolism of normal, healthy cells. While the findings do not show that high glucose causes cancer directly, it does show that the metabolism can be altered by changes brought about by hyperglycemia, sometimes resembling many metabolic characteristics observed in cancer cells.
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