Brain and diabetes: new data
In rodents with type 2 diabetes, a single injection of fibroblast growth factor 1 (FGF1) into the ventricles of the brain can restore normal blood sugar levels for several weeks or months. However, the mechanism of its action has been poorly understood.
Figuring out how FGF1 leads to a reduction in elevated blood sugar levels may lead to a more effective strategy for achieving sustained remission of diabetes, rather than just lowering blood sugar levels daily, as modern treatments do.
Until recently, the brain's ability to normalize elevated blood sugar levels in animals with diabetes was not recognized. By analyzing the cellular and molecular responses induced in the hypothalamus by the FGF1 peptide, recent studies have come to a more complete understanding of how this effect is achieved.
Type 2 diabetes affects 10% of US residents. It is closely associated with obesity and causes serious health problems, including cardiovascular diseases, vision loss, kidney failure, dementia, severe infections and nerve damage. It also increases the risk of amputation of the so-called diabetic foot and higher parts of the lower extremities. Blood sugar control can prevent these problems, but it can be difficult for patients to achieve normal indicators.
In two articles published in the journals Nature Communications and Nature Metabolism, an international team of researchers described the complex biology of the brain's response to FGF1. The first article describes sustained cellular responses that appear to protect brain signaling systems important for controlling blood sugar levels. The second article by the same scientists studied the structure of the extracellular matrix of nervous tissue – the perineuronal network that surrounds neurons involved in controlling blood sugar levels. Researchers have shown that FGF1 restores perineuronal networks damaged by diabetes, thus causing persistent remission of diabetes.
The senior authors of the article in Nature Communications are Dr. Thunes Perse from the University of Copenhagen and Dr. Michael Schwartz from the University of Washington. The international team of scientists they assembled began with a detailed study of changes in gene expression caused by FGF1 administration in various types of cells located in the hypothalamus. This area of the brain regulates many body functions, including blood sugar, hunger, and energy use and storage.
Scientists have found that glial cells, which provide structural support and regulate the activity of neuronal circuits, respond to FGF1 more intensively than neurons.
The researchers also observed an increased interaction between astrocytes and a subset of neurons that produce agouti-bound protein (AgRP). Astrocytes are stellate glial cells that feed neurons and support their ability to transmit electrical impulses. AgRP neurons are important components of the melanocortin signaling system, a brain circuit that is of great importance for controlling nutrition, body weight and blood sugar levels.
Excessive activation of AgRP neurons is known to inhibit the transmission of melanocortin signals, which is associated with the development of diabetes in humans and rodents. The researchers noted that after intraventricular injection of FGF1, complete blocking of the transmission of melanocortin signals does not allow diabetes to go into persistent remission.
Other cell types that responded to FGF1 included tanycytes, elongated, nutrient–sensitive glial cells found only in the hypothalamus. Their role in normalizing glucose levels requires additional research.
In an article published in Nature Metabolism, previously unknown participants in the development of persistent remission of diabetes under the action of FGF1 were considered. These are perineuronal networks that surround blood sugar-regulating neurons in the hypothalamus, including AgRP neurons. The authors of this article are Kim Alonj from the University of Washington, Michael Schwartz and others.
Perineuronal networks ensure the stability of neuronal circuits, covering neurons and connections between them. The researchers wanted to find out whether obesity-associated diabetes is associated with structural changes in perineuronal networks and whether they can be treated.
Perineuronal networks around glucose-regulating neurons in the arcuate nucleus of the hypothalamus. Source: Kim Alonge/Schwartz lab.
The research team noted that rat models of type 2 diabetes and obesity have fewer perineuronal networks in the hypothalamus than in rats with normal blood sugar levels, but in other parts of the brain the number of networks is comparable.
This deficiency of perineuronal networks was quickly eliminated after a single intraventricular injection of FGF1. The ability of FGF1 to facilitate the course of diabetes was impaired by the removal of nets by enzymatic digestion. In contrast, intact perineuronal networks are not required for FGF1 to influence food intake.
These data indicate that perineuronal networks are a key target of FGF1 to achieve sustained remission of diabetes. The researchers suggest that perhaps these networks help to limit the activity of AgRP neurons and thereby increase the transmission of melanocortin signals.
The researchers plan to continue trying to decipher cellular (and extracellular) responses to FGF1 and the mechanism of normalization of blood sugar levels. They hope this will help create new strategies to achieve sustained remission of diabetes in patients.
Article by M.A.Bentsen et al. Transcriptomic analysis links diverse hypothalamic cell types to fibroblast growth factor 1-induced sustained diabetes remission published in the journal Nature Communications; article by K.M.Alonge et al. Hypothalamic perineuronal net assembly is required for sustained diabetes remission induced by fibroblast growth factor 1 in rats – in the journal Nature Metabolism.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on UW Medicine: Brain can induce diabetes remission in rodents, but how?