In an article in the journal Nature Communications, researchers at the Sahlgrenska Academy present a novel mechanism underlying the reduced production of insulin in type 2 diabetes (T2D). They describe how insulin-producing cells regress in their development, become immature and do not work properly. A discovery that opens the door to new clinical treatments. It has long been known that insulin producing cells are malfunctioning in T2D. The body does not receive enough insulin and increases blood sugar. One theory holds that insulin-producing cells become less numerous, while another claims that their function is impaired. The new explanation, which combines theories discussed, states that insulin-producing beta-cells regress in their development and become immature. This reduces the number of functional cells. With the help of 124 tissue samples, of which 41 from people with type 2 diabetes, the researchers were able to determine which genetic changes in the cells affected the disease course most. Dr. Anders Rosengren describes the analysis by comparing it to the world of air transport.
“All airports are connected in a large network, but an interruption in a hub like the Frankfurt airport is much more serious than an interruption in Göteborg.” We examined the hubs, which are the key genes and the main links. changed in diabetes, 168 could be described as Frankfurt genes, and it is on these that we have focused, “he says. Continuing the analysis, it was found that the SOX5 gene, previously unknown in a diabetes context, influences the disease. Scientists have experimentally suppressed and deactivated SOX5: as a result, the function of the 168 genes deteriorates and the cells decrease in maturity. When, on the contrary, the levels of SOX5 increased, the 168 genes also increase and insulin administration can be normalized. The expression pattern of these genes in the human pancreatic islets of T2D donors is very similar to that of de-differentiated beta cells. In addition to SOX5, scientists also observed a consistent reduction of LPAR1, PTCH1, SMARCA1, TCF3, TMEM196 and TMEM63C, in response to high levels of both palmitate and glucose in the blood.
Human T2D develops through a vicious circle, characterized by progressive changes in a plethora of genes that lead to metabolic perturbations, including beta-cell dysfunction. Chronically increased nutrient intake increases the secretory demands of the beta-cell, which produces a compensatory response that initially maintains a good blood sugar but also evokes the stress of beta cells. In this context, the pancreatic islets show similar gene expression perturbations to those of the human T2D islands. These gene expression changes have been reversed by treatment with florizine, which is assumed to alleviate the demands of beta cells. There was no induction of NGN3, NANOG or other progenitor markers of development in T2D islets, and the T2D signature can therefore also be described as “immaturity” or “loss of beta cell identity”. The results suggest that changes in SOX5 and gene form represent early events in the vicious circle leading to a failure of beta cells that precipitated from chronic and elevated nutrient intake. An interesting thing is that the expression of SOX5 in pancreatic cells has been possible to restore it with valproic acid. This drug has been used for decades as an anti-epileptic, but it has been known for twenty years to be able to reshape the genetic material through nuclear enzymes (HDACs).
Valproic acid has not been clinically tested for diabetes, but hyper-insulinemia has been reported in epileptic patients being treated. Furthermore, it stimulates insulin secretion in vitro. According to the team, it will not take long before we see drugs that restore the maturity of insulin-producing cells. They may already exist in the form of medicines used for other diseases. At the same time, they emphasize the importance that healthy lifestyle habits play in type 2 diabetes. Current research shows that SOX5 decreases with unhealthy diet or does too little exercise. Anders Rosengren, an associate professor who is active at the Department of Neuroscience and Physiology, as well as the Wallenberg Center for Molecular and Translational Medicine at the University of Gothenburg, comments: “If you can influence things at the cellular level and restore body regulation, It is possible to more accurately regulate blood sugar than what is possible with insulin injections. However, it is important to remember that everyone is different – some manage long despite unhealthy life habits. For others, the critical point is very first, but apart from the genetic conditions, you can always do something about your illness”.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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