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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The bacteria in your gut affect blood insulin levels and may influence your chances of developing type 2 diabetes

Developing type 2 diabetes is for a large part influenced by your diet but also genes. However, a recent study has now shown that your gut microorganisms might also play an important role in the risk of developing type 2 diabetes (T2D). The article published in Nature Genetics entitled “Causal relationships among the gut microbiome, short-chain fatty acids (SCFA’s) and metabolic diseases”, claims evidence that bacterial metabolites such as SCFA’s are able to influence insulin levels and increase the risk of getting T2D.

Various studies have suggested that increased SCFA production benefits the host by exerting anti-obesity and antidiabetic effects, however, results of different studies are not always in agreement. Moreover, there is also evidence that increased production of SCFAs in the gut might be related to obesity, due to energy accumulation. Resolving these conflicting findings requires a detailed understanding of the causal relationships between the gut-microbiome and host energy metabolism, and the present study contributes to this.

The authors analyzed data from a large population study based in Groningen (The Netherlands), comprising 952 individuals with known genetic data, as well as information on parameters associated with metabolic traits such as BMI and insulin sensitivity. In addition, data were acquired for the type and the function of the bacteria which were present in the gut of the study participants. Combining this data, the authors tried to answer the question of whether changes in microbiome features causally affect metabolic traits or vice versa?

A technique called Mendelian randomization (MR) which is increasingly accepted to establish cause-effect relationships in the onset of diseases was applied. The primary outcome of the analysis was that host genes influence the production of the SCFA butyrate in the gut, which is associated with improved insulin response in the blood after an oral glucose tolerance test. In addition, abnormalities in the production or absorption of propionate, another SCFA, were causally related to an increased risk of T2D.

So far available data suggest that overweight humans or those with type 2 diabetes may have different microorganisms in their gut compared to healthy people. These microorganisms which are commonly found in healthy people are absent from the T2D patients. Whether the differences in the microbiota between healthy and T2D patients are an effect of the disease development or account for causality is challenging to be answered. With the data from the present study, authors are able to go one step further and demonstrate potential routes by which microorganisms are able to regulate our metabolic status underlying their importance for our wellbeing.

Collectively the present article suggests that production of bacterial SCFA’s play a pivotal role in the regulation of metabolic traits such as blood insulin levels and are associated with the onset of T2D.

Since the study was observational and did not include any T2D patients, confirmation of the results is essential. Follow up studies including T2D patients would be highly informative. With the rising prevalence of obesity in adults, which is reaching epidemic levels, the prevalence of T2D will also continue to rise. In the past years, scientists have mainly focused on the role of human gene data, but this has not led to major breakthroughs. Perhaps knowledge of the microbiome will elucidate molecular mechanisms which can be translated to novel effective treatments for metabolic disorders such as T2D.

Sanna, S., van Zuydam, N. R., Mahajan, A., Kurilshikov, A., Vila, A. V., Võsa, U., . . . Oosting, M. (2019). Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases. Nature genetics, 1.

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