In rodents with type 2 diabetes, a single surgical injection of a protein called fibroblast growth factor 1 can bring blood sugar levels back to normal over weeks or months. Little is known about how this growth factor works in the brain to achieve this lasting benefit.
Clarifying how this happens could lead to more effective diabetes treatments that harness the brain’s inherent potential to improve the condition.
“Until recently, the brain’s ability to normalize high blood sugar levels in diabetic animals was not recognized,” said Dr. Michael Schwartz, Professor of Medicine at the University of Washington Medical School and Co-Director of the UW Medicine Diabetes Institute. “By interrogating cellular and molecular responses induced in the hypothalamus by a brain peptide called fibroblast growth factor 1, the latest findings from our international teams show a way to gain a more complete understanding of how this effect is achieved.
“These findings,” he said, “could one day influence therapeutic strategies for inducing sustained diabetes remission rather than simply lowering blood sugar levels on a daily basis, as is currently the case.”
Type 2 diabetes affects 10% of the US population. It’s closely linked to obesity and causes serious health problems such as heart disease, vision loss, kidney failure, dementia, hard-to-heal infections, and nerve damage. It also increases the risk of needing amputations. Controlling blood sugar levels can prevent these problems, but it is often difficult to achieve and becomes an ongoing battle for many patients.
In two accompanying papers in the September 7 issues of Nature Communications and Nature Metabolism, international teams of researchers describe the complex biology of the brain’s response to fibroblast growth factor 1. The first team describes robust cellular responses that appear to be critical in protecting the brain’s signaling pathways, to keep blood sugar in check.
A second team, including some of the same researchers, made discoveries about extracellular matrix arrangements called “perineuronal networks” that interlock groups of neurons involved in blood sugar control. The researchers learned that fibroblast growth factor 1 repairs perineuronal networks damaged by diabetes. This response is necessary for diabetes remission to be sustained.
Dr. Tunes Pers from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen in Denmark and the diabetes and obesity researcher Dr. Michael Schwartz of UW Medicine in Seattle were lead authors on the Nature Communications report. The main authors from their laboratories were Dr. Marie Bentsen and Dr. Dylan Rush.
The international team of scientists they assembled began detailing changes in gene expression induced by treatment with fibroblast growth factor 1 across different types of brain cells in the hypothalamus. This small region of the brain regulates many body functions, including blood sugar levels, hunger, food intake, and energy use and storage.
The scientists found that glial cells, which not only provide structural support but also help to organize and regulate the activity of neurocirculation, reacted more intensely than neurons, brain cells known for the electrical transmission of information.
The researchers also observed increased interactions between astrocytes and a subset of neurons that make agouti-related protein (called agrp neurons). Astrocytes are abundant, star-shaped glial cells that nourish neurons and aid in their electrical transmission. Agrp neurons are essential parts of the melanocortin signaling system, a brain circuit that is critical to controlling diet, body weight, and blood sugar.
It is known that excessive activation of Agrp neurons attenuates melanocortin signal transmission. This effect has been linked to the development of diabetes in humans and rodents. The researchers found that banning melancortin signaling after fibroblast growth factor 1 was injected into the brain prevented sustained diabetes remission.
Among other cell types that responded robustly to fibroblast growth factor 1 are tanycytes, elongated, nutrient-sensitive glial cells found only in the hypothalamus. Their contributions to the normalization of glucose levels require additional research.
The paper, published in Nature Metabolism, looked at what the scientists called “the previously unrecognized participants” in the mechanism behind the ability of fibroblast growth factor 1 to induce diabetes remission.
These are the perineuronal networks that interlock blood sugar regulating neurons in the hypothalamus, including Agrp neurons. The lead author of this paper is Kim Alonge, an acting teacher in medicine at the UW School of Medicine. The lead author is Michael Schwartz.
Perineuronal networks promote the stability of neurocircuits by interlocking neurons and girdling the connections between them. The researchers wanted to know whether obesity-related diabetes is linked to structural changes in these perineuronal networks and whether these could be treated.
The research team found that these nets are rare in the sugar-diabetes-fatty rat model of type 2 diabetes in the hypothalamus compared to rats with normal blood sugar levels. In other parts of the brain, however, the networks are normal.
This loss of perineuronal networks was quickly reversed after a single injection of fibroblast growth factor 1 into the brain. The ability of fibroblast growth factor 1 to alleviate diabetes was compromised by removal of the nets by enzymatic digestion. In contrast, intact perineuronal networks are not required for fibroblast growth factor 1 to affect food intake.
These results identify perineuronal networks as the main targets for sustained diabetes remission induced by the action of fibroblast growth factor 1. The researchers speculate that these networks may help limit the activity of Agrp neurons, thereby increasing melanocortin signaling.
The researchers plan to continue trying to bridge the gap between cellular (and extracellular) responses to fibroblast growth factor 1 and normalizing blood sugar levels. Ultimately, they hope this may uncover new strategies for achieving sustained diabetes remission in patients.