Brain can induce diabetes excretion in rodents, but how?

Glucogregulatory neurons within the brain’s hypothalamic arcuate nucleus – median immunity are enameled by extracellular matrices known as perinoronal nets that may profoundly affect neuronal function. The latest findings add these constructs as potential targets for brain control of glucose homeostasis and the treatment of diabetes. Sincerely: KImberly Alonge / Schwartz Lab / UW Medicine Diabetes Research Institute

In rodents with type 2 diabetes, a single surgical injection of a protein called fibroblast growth factor 1 can restore blood sugar levels to normal for weeks or months. Yet how this growth factor functions in the brain to produce this lasting benefit has been poorly understood.

To illustrate how this occurs there may be more effective diabetes treatments that tap into the brain’s inherent ability to improve the condition.

“Until recently, the brain’s ability to normalize elevated blood sugar levels in diabetic animals was not recognized,” Professor of Medicine at the University of Washington School of Medicine and co-director of the UW Medicine Diabetes Institute Dr. “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 create a chart for a more complete understanding of how this effect is achieved.

“These insights,” he said, “may one day inform therapeutic strategies to maintain diabetes treatment, rather than lowering blood sugar levels on a day-to-day basis as current treatments Instead.”

Type 2 diabetes affects 10% of the US population. It is intimately associated with obesity and causes serious health problems including heart disease, vision loss, kidney failure, dementia, difficult-to-treat infections and nerve damage. It also increases the risk of needing amputation. Controlling blood sugar levels can prevent these problems, but is often difficult to achieve and becomes a constant struggle for many patients.

In two companion papers in 7 volumes of Nature communication And Nature metabolism, International teams of researchers have described the complex biology of the brain’s response to the fibroblast growth factor. The first team describes strong cellular responses that secure the important brain-signaling pathway to contain blood sugar.

The same team, consisting of just a few researchers, discovered about an extracellular matrix assembly called the “perineuronal net” that incorporates groups of neurons involved in blood sugar control. Investigators found that fibroblast growth factor 1 repair perinuronal net that has been damaged by diabetes. Prevention of diabetes requires this response.

Dr. Tunes Purse, a diabetes and obesity researcher at the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen in Denmark and UW Medicine in Seattle, Drs. Michael Schwartz was the senior author of the Nature Communications report. The lead author of his labs, Drs. Mary Bentsen and Drs. Dylan Rausch was.

The international team of scientists that he assembled began the transformation of gene expression induced by fibroblast growth factor 1 treatment into different brain cell types located in the hypothalamus. This small area of ​​the brain controls many functions of the body, including blood sugar levels, hunger, food intake and energy use and storage.

Scientists found that glial cells, which not only provide structural support, but also help to organize and regulate neurocyclic activity, responded more acutely than neurons, for the electrical transmission of information to brain cells Is known.

Researchers also observed enhanced interactions between astrocytes and a subset of neurons that make up Aguti-related proteins (called Agrip neurons). Astrocytes are abundant, star-shaped glial cells that nourish neurons and support their electrical transmission. Agrip neurons are essential components of the melanocortin signaling system, a brain circuit that is important for the control of feeding, body weight, and blood sugar.

Hyperactivity of Agrp neurons is known to dampen melanocortin signaling. This effect is associated with the development of diabetes in people and rodents. Researchers have noted that restricting melanocortin signal in the brain of fibroblast growth factor 1 injection leads to continued diabetes prevention.

Other cell types that respond strongly to fibroblast growth factor 1 are tannacitus, elongated, nutrient-sensitive glial cells found only in the hypothalamus. Additional studies are required for their contribution to normalizing glucose levels.

Paper published in Nature metabolism The mechanisms behind the ability to induce diabetes infection in fibroblast growth factor 1 have scientists observed structures called “previously unfamiliar participants”.

These are perinuronal nets that enmesh blood sugar-regulating neurons in the hypothalamus, including Agape neurons. The lead author of this paper is Kim Eljon, an acting instructor in medicine at the UW School of Medicine. The senior writer is Michael Schwartz.

Perinuronal nets promote neurocyclic stability by enamaging neurons and connecting connections between them. Researchers wanted to find out whether obesity-related diabetes is associated with structural changes in these perinuronal nets, and whether they can be treated.

The research team noted that in the Zucker Diabetic fatty rat model of type 2 diabetes, these traps are rarer than mice with normal blood sugar levels in the hypothalamus, yet traps are common in other parts of the brain.

This loss of the perinuronal net was rapidly reversed after one injection of fibroblast growth factor 1 into the brain. Removing the trap through enzyme digestion hindered the ability of amoelorate diabetes from fibroblast growth factor 1. In contrast, intact perinoronal plexus is not required for fibroblast growth factor 1 to affect food intake.

These discoveries identify perinuronal NETs as key targets for the continuation of diabetes induced by the action of fibroblast growth factor 1. Researchers speculate that perhaps these nets help inhibit the activity of AgRip neurons and thereby pump out melanocyanin signaling.

Researchers plan to continue to bridge the gap between cellular (and extracellular) responses to fibroblast growth factor 1 and normalization of blood sugar levels. This, they hope, may eventually uncover novel strategies for achieving sustained diabetes remission in patients.

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more information:
Hypothalamic perinuronal net assembly is required for treatment of sustained diabetes induced by fibroblast growth factor 1 in mice. Nature metabolism (2020). DOI: 10.1038 / s42255-020-00275-6,

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