The brain can cause remission of diabetes in rodents, but how?

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 for weeks or months. However, how this growth factor works in the brain to produce this lasting benefit is not well understood.

Clarifying how this happens may lead to more effective diabetes treatments that take advantage of the brain’s inherent potential to improve conditions.

“Until recently, the brain’s ability to normalize elevated blood sugar levels in diabetic animals was unrecognized,” said Dr Michael Schwartz, a professor of medicine and co-director at the University of Washington School of Medicine. .. UW Medical Institute of Diabetes.. “By examining the cellular and molecular responses evoked in the hypothalamus by a brain peptide called fibroblast growth factor 1, our latest findings from our international team show how this effect is achieved. Shows the path to a more complete understanding of.

“These insights may at some point inform treatment strategies to induce sustained remission of diabetes, rather than simply lowering blood sugar levels on a daily basis as current treatments do,” he said. Said.

Type 2 diabetes affects 10% of the US population. Closely associated with obesity, it causes serious health problems such as heart disease, blindness, renal failure, dementia, incurable infections, and neuropathy. It also increases the risk of having to disconnect. Controlling blood sugar can prevent these problems, but it is often difficult to achieve and an ongoing struggle for many patients.

Two related papers in the September 7 issue Natural communication And Natural metabolism, A team of international researchers, describes the complex biology of the brain’s response to fibroblast growth factor 1. The first team describes a robust cellular response that appears to protect the brain signaling pathways that are important for maintaining blood glucose levels.

A second team, including some of the same researchers, discovered an extracellular matrix assembly called the “perineural net,” which meshes the groups of neurons involved in glycemic control. Researchers have learned that fibroblast growth factor 1 repairs perineural nets damaged by diabetes. This reaction is necessary to sustain the remission of diabetes.

Dr. Tunes Pers, Novo Nordisk Foundation Center for Basic Metabolic Studies, Michael Schwartz, a diabetes and obesity researcher at the University of Copenhagen, Denmark, and UW Medicine in Seattle, was a senior author of the Nature Communications Report. The first authors in their lab were Dr. Marie Bentsen and Dr. Dylan Rausch.

An international team of scientists they assembled began by elaborating on the changes in gene expression caused by treatment of fibroblast growth factor 1 across different types of brain cells in the hypothalamus. This small area of ​​the brain regulates many physical functions such as blood sugar, hunger, food intake, energy use and storage.

Scientists say that glial cells, which not only provide structural support, but also organize and regulate the activity of neural circuits, are more likely than neurons, which are brain cells known for the electrical transmission of information. I found it to respond strongly.

Researchers have also observed enhanced interactions between astrocytes and a subset of neurons that make agouti-related proteins, called Agrp neurons. Astrocytes are abundant star-shaped glial cells that nourish neurons and support their electrical transmission. Agrp neurons are essential components of the melanocortin signaling system, a brain circuit important in controlling food intake, body weight, and blood glucose.

Excessive activation of Agrp neurons is known to weaken melanocortin signaling. This effect is associated with the development of diabetes in humans and rodents. The researchers pointed out that inhibiting melancortin signaling after injection of fibroblast growth factor 1 into the brain would prevent sustained remission of diabetes.

Another cell type that responded strongly to fibroblast growth factor 1 is tanisite, an elongated nutrient-sensing glial cell found only in the hypothalamus. Their contribution to the normalization of glucose levels requires additional research.

A paper published in Nature Metabolism explores the structure scientists termed “previously unrecognized participants” for the mechanism behind the ability of fibroblast growth factor 1 to induce remission in diabetes. It was

These are perineural nets that surround the hypothalamic blood glucose-regulating neurons, including the Agrp neurons. The lead author of this paper is Kim Alonge, a lecturer in medicine at the UW School of Medicine. The first author is Michael Schwartz.

Perineural nets promote the stability of neural circuits by intertwining neurons and connecting the connections between them. Researchers wanted to know if obesity-related diabetes was associated with structural changes in these perineural nets and if they could be treated.

The team found that in the Zucker Diabetes Fatty rat model of type 2 diabetes, these nets are deficient in the hypothalamus, but normal in other parts of the brain, compared to rats with normal blood glucose levels. I pointed out that.

This loss of perineural network rapidly recovered after a single injection of fibroblast growth factor 1 into the brain. The ability of fibroblast growth factor 1 to improve diabetes was impeded by removal of the net by enzymatic digestion. In contrast, the intact perineural net is not required because fibroblast growth factor 1 affects food intake.

These findings identify the perineural net as a major target for persistent diabetic remission caused by the action of fibroblast growth factor 1.

Researchers plan to continue efforts to bridge the gap between the cellular (and extracellular) response to fibroblast growth factor 1 and the normalization of blood glucose levels. They hope this may ultimately reveal new strategies for achieving sustained diabetic remission in patients.