Insulin and diabetes
Insulin is a peptide hormone produced by beta cells of the pancreas. It regulates the metabolism by promoting the absorption of glucose from the blood into liver, fat and skeletal muscle cells. When the blood glucose level is high, the beta cells secrete insulin into the blood, and when glucose levels are low, the secretion of insulin is inhibited. If the pancreas produces little or no insulin, it results in type 1 diabetes, while insulin resistance – a condition in which cells fail to respond normally to the insulin – is characteristic for type 2 diabetes.

Insulin signaling in the brain
The brain was traditionally considered to be an insulin‐insensitive organ. While insulin and insulin receptors in the brain were discovered in 19781,2, this discovery was not appreciated until recently, when the role of insulin signaling was shown in disorders of the central nervous system. There are two types of insulin receptor, differing in functionality and distribution: 1) peripheral tissues express predominantly IR‑B, which targets metabolic effects of insulin, and 2) neurons express exclusively the IR‐A. The insulin receptor belongs to the family of tyrosine kinase receptors and is structurally similar to the receptors of neurotrophins, which play an important role in survival, development and the functioning of neurons. Impaired insulin signaling in the brain, which is commonly termed as ‘central insulin resistance’ is now viewed as a pathogenetic mechanism of neurodevelopmental, neurodegenerative and neuropsychiatric disorders

Insulin and excitotoxicity
A recent study showed that insulin can protect against glutamate excitotoxicity4. Excitotoxicity is a pathological process, by which excessive activation of glutamate receptors allows high levels of calcium ions to enter the cell and activate enzymes that damage the cell. This process is implicated in neurodegenerative disorders such as Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, and Huntington’s disease, affective disorders, traumatic brain injury, stroke.

In this study, effects of short-term insulin exposure on several parameters of excitotoxicity were investigated in cultured rat neurons. Insulin prevented the onset of so-called delayed calcium deregulation, the postulated point-of-no-return in the mechanisms of excitotoxicity. Additionally, insulin improved depletion of the brain-derived neurotrophic factor, which is a critical neuroprotector in excitotoxicity. Also, insulin improved the viability of cells exposed to glutamate. Thus, this study showed that short-term insulin exposure is protective against excitotoxicity, one of the key mechanisms of neurodegeneration, which opens new therapeutic possibilities.

Insulin and Therapeutic Possibilities
Thus, insulin supplementation or enhancement of insulin receptor functioning can be considered as a potential therapy for neurodegenerative and neuropsychiatric disorders. Extensive experimental work is ongoing in order to further uncover the underlying mechanisms of this new function of insulin in the brain and develop effective therapies of neurodegeneration.

[1] J. Havrankova, D. Schmechel, J. Roth, M. Brownstein, Identification of insulin in rat brain, Proc. Natl. Acad. Sci. 75 (1978) 5737–5741. doi:10.1073/pnas.75.11.5737.
[2] J. Havrankova, J. Roth, M. Brownstein, Insulin receptors are widely distributed in the central nervous system of the rat, Nature. 272 (1978) 827–829. doi:10.1038/272827a0.
[3] I. Pomytkin, J.P. Costa-Nunes, V. Kasatkin, E. Veniaminova, A. Demchenko, A. Lyundup, K.-P. Lesch, E.D. Ponomarev, T. Strekalova, Insulin receptor in the brain: Mechanisms of activation and the role in the CNS pathology and treatment, CNS Neurosci. Ther. (2018). doi:10.1111/cns.12866.
[4] I. Krasil’nikova, A. Surin, E. Sorokina, A. Fisenko, D. Boyarkin, M. Balyasin, A. Demchenko, I. Pomytkin, V. Pinelis, Insulin protects cortical neurons against glutamate excitotoxicity, Front. Neurosci. 13 (2019). doi:10.3389/fnins.2019.01027.

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Real time measurements of intestinal gases: a novel method to study how food is being digested

Researchers in Wageningen (The Netherlands), have been able to identify for the first time, how gut microorganisms process different types of carbohydrates by measuring in real time the intestinal gases of mice. This is not only a novel method to understand how food is digested but could also tell us more about the role of gut microorganisms in gut health.

Intestinal gases

The intestinal microbiota is a diverse and dynamic community of microorganisms which regulate our health status. The advancement of biomolecular techniques and bioinformatics nowadays allows researchers to explore the residents of our intestines, revealing what type of microorganisms are there. However, studying only the microbial composition of an individual provides limited insights on the mechanisms by which microorganisms can interact with the rest of our body. For example, far less is understood about the contribution of the gut microorganisms in the production of intestinal gases such as hydrogen, methane and carbon dioxide through the breakdown of food and how these gases affect the biochemical pathways of our bodies.

Intestinal gases consist mostly of nitrogen, and carbon dioxide, which originate primarily from inhaled air. Hydrogen and methane though, are produced as by-products of carbohydrate fermentation (break down), by intestinal microorganisms. However, not all carbohydrates are digested in the same way. For instance, food with simple sugars can be rapidly absorbed in the small intestine unlike complex carbohydrates such as fibers, which reach the colon where they are digested by the colonic microbiota.


Measuring hydrogen in mouse intestines

To study these interactions and gain knowledge on how microorganisms process carbohydrates, the research team led by Evert van Schothorst from the Human and Animal Physiology Group of Wageningen University (WU) in collaboration with the WU-Laboratory of Microbiology fed mice two different diets with the same nutritional values but with different types of carbohydrates (1). The first diet contained amylopectin, a carbohydrate which can be digested readily in the small intestine while the second diet contained amylose, a slowly digestible carbohydrate that is digested by intestinal microorganisms in the colon.

Animals fed the easily digestible carbohydrates showed minimal production of hydrogen whereas the group fed with the complex carbohydrates presented high levels of hydrogen. Moreover, the two groups were characterized not only by distinct microbial composition (different types of bacteria present) but also distinct metabolic profiles (short chain fatty acids), suggesting that the type of carbohydrate strongly affects microbial composition and function.

The importance of hydrogen

Hydrogen consumption is essential in any anoxic (without oxygen) microbial environment to maintain fermentative processes. In the intestine it can be utilised through three major pathways for the production of acetate, methane and hydrogen sulphide. These molecules are critical mediators of gut homeostasis, as acetate is the most predominant short chain fatty acid produced in mammals with evidence suggesting a role in inflammation and obesity (2). Methane, which is produced by a specific type of microorganisms, called archaea, has been associated with constipation related diseases, such as irritable bowel syndrome(3) and also recently with athletes’ performance (4)! Finally hydrogen sulphide is considered to be a toxic gas, although recent findings support the notion that it also has neuroprotective effects in neurodegenerative disorders such as Parkinson and Alzheimer diseases (5).

To the best of our knowledge, this is the first time that food-microbiota interactions have been studied continuously, non-invasively and in real time in a mouse model. Hydrogen is a critical molecule for intestinal health and understanding its dynamics can provide valuable information about intestinal function, and deviations in conditions such as Crohn’s disease or irritable bowel syndrome (IBS).

Further reading

1. Fernández-Calleja, J.M., et al., Non-invasive continuous real-time in vivo analysis of microbial hydrogen production shows adaptation to fermentable carbohydrates in mice. Scientific reports, 2018. 8(1): p. 15351.

2. Perry, R.J., et al., Acetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome. Nature, 2016. 534(7606): p. 213

3. Triantafyllou, K., C. Chang, and M. Pimentel, Methanogens, methane and gastrointestinal motility. Journal of neurogastroenterology and motility, 2014. 20(1): p. 31.

4. Petersen, L.M., et al., Community characteristics of the gut microbiomes of competitive cyclists. Microbiome, 2017. 5(1): p. 98.

5. Cakmak, Y.O., Provotella‐derived hydrogen sulfide, constipation, and neuroprotection in Parkinson’s disease. Movement Disorders, 2015. 30(8): p. 1151-1151.

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