Master of Science
Meredith Protas, PhD
Pankaj Kapahi, PhD
Ian Barr, PhD
Reactive a-dicarbonyls (a-DC’s), such as methylglyoxal (MGO), are unavoidable metabolites generated during glycolysis that accumulate with age and have been linked with chronic age-related metabolic diseases such as Diabetes Mellitus. Diabetes Mellitus is generally characterized by peripheral neuropathy and sustained hyperglycemia. Chronic hyperglycemia leads to an increase in glycolysis and a downstream increase in reactive a-DC’s. The human body has a natural method of detoxifying these a-DC’s. Glycolytic cells have enzymes which can detoxify a-DC’s, but if overwhelmed, a-DC’s can accumulate and react non-enzymatically with proteins, lipids and DNA to yield a group of molecules called advanced glycation end-products (AGEs). A Caeonorhabditis elegans model, used to study the effects of a-DC accumulation, has paved the way for a study which has aimed to mitigate a-DC stress in a vertebrate model. Here we propose that the accumulation of AGEs in vivo enhances the likelihood of physiological phenotypes associated with age-related metabolic diseases such as diabetes. We propose that we are able to reduce metabolic disorder phenotypes, partly through activation of the conserved TRPA-1 ion channel, and the metabolic NAD+ salvage pathway, and rescue their pathological effects in a type II diabetic mouse model through drug interventions. Reconstituting the idea that AGEs are sufficient to cause adverse behavioral and physiological metabolic complications is necessary in establishing a novel target for drug treatment. Instituting a successful mouse model of drug-induced a-dicarbonyl detoxification could lead to human clinical trials for alternative diabetic treatments, and a reduction in secondary diabetic complications.
Wimer, Lauren, "Determining the link between advanced glycation endproducts (AGEs), feeding, and metabolism" (2020). Natural Sciences and Mathematics | Biological Sciences Master's Theses. 7.
Available for download on Tuesday, June 01, 2021