“We were stuck in the mindset that glucose is an energy source and nothing else,” Stanford Medicine chairman of dermatology Dr. Paul Khavari said. His are the words that define the paradigm shift brought by a pioneering study that has confirmed glucose to be much, much more than energy fuel. Actually, glucose is the master controller of tissue differentiation a discovery that negates cell biology dogma of recent decades and perhaps creates new windows of medical exploration. Glucose has been the holy grail of decades as the intermediate and driving force in energy metabolism and biochemical processes of life.
But the Stanford Medicine study discovers that glucose is also an active signaling molecule, a protein bound one that affects gene expression and directs stem cells into differentiated cells. This two way life redefines our picture of glucose as a passive energy provider into the active role of assisting cells to become developed. “Glucose interacts with hundreds of proteins throughout the cell and modulates their function to promote differentiation,” Khavari said, highlighting the molecule’s new versatility. Researchers started by trying to characterize biomolecules that play a role in cellular differentiation.
With mass spectrometry and high throughput screening, they followed thousands of biomolecules in human skin stem cells as they differentiated into keratinocytes, those ubiquitous skin cells. Out of the 193 suspect molecules, glucose was the sole odd one out molecule for all the surprises. “We had expected glucose levels to decrease during differentiation because the cells begin to divide less rapidly, and their energy requirements are less,” Khavari said. While decreasing, the level of glucose actually increased, confirmed by fluorescent and radioactive glucose analogues labeling up cells’ increasing activity in glucose metabolism upon differentiation. This initial glucose increase was not preceded by increased metabolic degradation.
Instead, glucose import pathways and reduced export led to its accumulation. Additional experimentation with engineered skin organoids a tissue model most similar to endogenous tissue skin indicated impaired differentiation when glucose concentration was artificially decreased. To everyone’s surprise, differentiation worked once more when an unmetabolizable glucose analogue was added, and this again indicated that the regulatory role of glucose is distinguishable from its energizing role. “That was really the biggest shock,” Khavari admitted. The implications are deep. In diabetes, where tissue regeneration is inhibited by hyperglycemia, deranged tissue regeneration occurs due to interruption of glucose signal transduction. In cancer, in which neoplastic cells are usually dominant, glucose’s capacity to induce differentiation is a therapeutic paradox. Some glucose analogs, intended to starve the cancer cells, instead attack not cancer cells but undifferentiated cancer cells and induce differentiation, a novel therapy.
Heads in the world position of glucose had already preceded.
Embryonic stem cells are unable to be differentiated at high glucose levels, and this indicates glucose as a cell state stabilizing signal needed. There’s Stanford evidence to demonstrate one pathway, though glucose binds to proteins such as IRF6, a differentiation consequence regulating gene expression, with the binding changing the IRF6 shape, enhancing its capacity to drive the cell’s differentiation to differentiated states. “We’re seeing glucose acting like a broadcast signal in the cell,” Khavari said. “When glucose levels rise in a cell, they rise everywhere, all at once. It’s like a fire alarm going off in a firehouse. Everyone in the firehouse activates in response.” The study’s findings extrapolate to one particular disease to lay the groundwork for future research in glucose dysregulation.
“This is an entirely new and growing field,” Khavari said. “People have thought that small biomolecules like glucose were quite passive in the cell. This is another piece of evidence to pay close attention to other roles these molecules might play.” And that is another great reason for being extremely interested in other roles which such molecules might play. With conservatively estimated hundreds of millions of individuals suffering from glucose disease, possible medical developments are astronomical. In remaking our understanding of glucose, this research leaves us to ask questions about other small biomolecules that may be playing similarly unforeseen roles in cells.
The discovery is a testament to the sensitivity of cell biology, where molecules as small as these can be giants at what they accomplish. And just as with every new thing they are learning about the work glucose does, what they are learning potentially can help change diabetes and cancer treatments and all the rest. Meanwhile, however, glucose is the classic case of where cell signaling meets up with metabolism a molecule whose value increases with each new discovery. Stanford Medicine researchers put this two fold function to the test and shed light on the function of glucose in the case of a cell. Scientists have brought one home for biomedical science in a Cell Stem Cell report. Disease curing prospects and regenerative medicine opportunities are yet to come in the distant future, because it is only when the fate of glucose as glucose in health or disease that this potential exists.
To health biologists, doctors, and scientists, this is an appeal to step back and think about what slog long molecules have been creating. Their change from energy substrate to master controller has only commenced, and the size of the process is as world enveloping as are the cell worlds that it has come to subdue.
