Using human-derived pancreatic beta cells, the Wang lab examines the effects of metabolic stress on insulin secretion. Pancreatic beta cells sense glucose in the blood and secrete insulin proportional to blood glucose levels.
Too much glucose and lipid over time creates cellular mayhem – more scientifically called glucotoxicity – which induces metabolic stress.
Under metabolic stress, beta cells shift into overdrive to compensate for reduced insulin secretion. They begin to work harder, physically growing larger in size and number to produce more insulin. The increased workload ultimately leads to cellular exhaustion and eventual cell death.
“ Beta cells are somewhat like a balloon under pressure. They can stretch and adapt as demand increases, but if the pressure keeps rising, they eventually reach a breaking point,” Wang said.
“ Beta cells try to adjust and adapt, but with continuous exposure to high glucose and high lipid levels, they switch from adaptive to maladaptive. And they actually carry memory, too.”
Beta cell“ memory” allows the cells to adapt and remain functional during temporary glucose spikes. However, consistently high blood glucose and high lipid levels overwork these cells, as they remain in the adaptive state. Over time, beta cells can no longer keep up with demand, and they shift into a maladaptive, or dysfunctional, state.
The overnutrition cell culture model the Wang lab uses mimics what pancreatic beta cells in our bodies might experience when exposed to chronic high fat, high sugar intake.
With funding from NIDDK, the Wang lab will use genome editing and bioinformatic technologies to determine how beta cell stress contributes to Type 2 diabetes progression.
“ We think the key memory marker is actually epigenetics,” Wang said.“ We found a specific epigenetic modification that seems to really follow along the switch from beta cell adaptation to maladaptation.”
Epigenetics is the study of how your behaviors and environment can cause chemical modifications that change how your genes work. Unlike genetic mutations, epigenetic changes do not alter your underlying DNA sequence; instead, they act as switches, turning genes“ on” or“ off” to determine which proteins are produced.
Epigenetic modifications change how DNA is packaged, causing DNA to condense, making the cell’ s instruction manual inaccessible to promote cell survival. In Type 2 diabetes, though, the instructions needed to sense glucose and secrete insulin aren’ t readable, and beta cells overwork until they lose their function.
Wang’ s lab has already identified several regulatory epigenetic processes involved in the switch from adaptive to maladaptive states, and Wang aims to use her recent grant award to fund molecular and genetic approaches to unravel these epigenetic modifications.
“ This grant is taking advantage of all the technology development for the past decade,” she said.“ With gene-editing technology, we can open and close one regulatory region and basically make this region more active or make this region more repressive to see if it is really involved in the process.”
Wang hopes these findings can be used to diagnose and even treat Type 2 diabetes.
“ Dr. Wang’ s R01 award is a remarkable achievement that reflects both the exceptional quality of her science and her dedication to addressing one of our nation’ s most pressing health challenges,” said Jin Xie, Senior Associate Dean for Research and Graduate Programs at the College of Medicine.
“ Securing NIH R01 funding is a defining milestone for biomedical investigators, and this award positions Dr. Wang and her team to make discoveries that could fundamentally advance our understanding of Type 2 diabetes. It also underscores the growing strength of the FSU College of Medicine’ s research enterprise and our commitment to supporting innovative, high-impact science that improves human health.”
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