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Depression, diabetes and everything in between

A study by the Weizmann Institute shows that the use of antidepressants requires caution, especially when it comes to diabetics or people with a tendency to develop diabetes

From the right: Sharina Shetrim, Prof. Rivka Polak, Itai Afudi, Prof. Sanford Sampson, Dr. Yaron Winik, Roi Yitzchak, Prof. Yehiel Zik, Dr. Eitan Elkhanani, Hadas Shatz-Azolai, Dr. Siglit Bora-Chalpon . resistance
From the right: Sharina Shetrim, Prof. Rivka Polak, Itai Afudi, Prof. Sanford Sampson, Dr. Yaron Winik, Roi Yitzchak, Prof. Yehiel Zik, Dr. Eitan Elkhanani, Hadas Shatz-Azolai, Dr. Siglit Bora-Chalpon . resistance

One of the known side effects of a certain type of anti-depressant and anxiety medication, which includes, among others, Prozac and Cipralax, is obesity. A study by Weizmann Institute of Science scientists, led by Prof. Yehiel Zik, shows that drugs of this type may contribute to the development of diabetes. The findings of the study imply that the use of this type of medication requires extra caution, especially when it comes to diabetics or people with a tendency to develop the disease.

The interrelationship between antidepressants of the type that inhibits the absorption of serotonin (known as SSRIs) and obesity is well known: the inhibition of the absorption of the neurotransmitter serotonin (found, for example, in chocolate), which is responsible for a good feeling and also for increasing appetite, in the nerve cells of the brain, causes that its level in the mind rises. As a result, increased eating is caused leading to obesity. This is the great plague of the last decades, and its damages include, among other things, an increased risk of developing cancer, heart disease, and especially diabetes, meaning the body's inability to regulate sugar levels.

In addition to their effect on the sense of appetite in the brain, recently accumulated findings indicate a more direct link between antidepressants and diabetes, because they cause insulin resistance: a condition in which the beta cells in the pancreas - which are the insulin factory - fail to fulfill their role. Normally, the increase in blood sugar level leads to the release of insulin from the beta cells, which takes care of getting the sugar into the body's cells. In a state of insulin resistance, a larger than normal amount of insulin is required to get the sugar into the cells (this is the origin of the name "insulin resistance"). This resistance may deteriorate into the development of diabetes - that is, into the body's inability to regulate sugar levels. So how exactly do SSRI drugs cause insulin resistance?

The team of scientists from the Weizmann Institute of Science wanted to test the possibility that these drugs directly affect the beta cells in the pancreas. To this end, they closely examined the chain of events that occurs after insulin binds to its receptor on the beta cells. The receptor, which is actually a phosphorylating enzyme, as Prof. Zick discovered in his post-doctoral research, in the 80s of the last century, causes the phosphorylation of tyrosine type amino acids in a certain protein (called IRS-2). It was later discovered that this phosphorylation is the first in a sequence of biochemical events that accelerates the production of insulin and its secretion from the beta cells, and is also responsible for maintaining a high vitality of the cells. On the other hand, in a state of insulin resistance, caused by states of stress or an excess of fatty acids in the blood, it was found that other amino acids, of the serine type, are phosphorylated on the IRS-2 protein, thus causing a disconnection between the first two links in the chain, that is, between the receptor and IRS- 2, and the chain of biochemical events is inhibited. As a result, extremely large amounts of insulin are required for the system to function. When the resistance reaches an extreme degree, where the pancreatic cells are unable to withstand the load of the large amounts of insulin they are required to produce, and at some point they are even destroyed and die, diabetes is caused.

In the current study, which was done in the beta cells of humans and mice, the scientists discovered that, similar to what happens in anxiety states, SSRI antidepressants also interfere with the sequence of events that accelerates the secretion of insulin, by inhibiting the first link in the chain (that is, the phosphorylation of amino acids of the tyrosine type, found on IRS-2, by the insulin receptor). Later, the scientists discovered the exact mechanism by which the drugs inhibit IRS-2. It turns out that they cause the phosphorylation of the sites that inhibit protein activity - the same mechanism activated by stress and excess fatty acids in the blood. The "agent" through which the drugs affect IRS-2 is an enzyme called GSK3β.

Besides the fatal damage to the beta cell function, it was discovered that the antidepressants lead to the destruction of the cells, and ultimately to their death, through the activation of a cellular "suicide" pathway (apoptosis). They do this by activating a series of enzymes that cause constriction in the endoplasmic reticulum - the cell organelle where the proteins are formed. As a result of the strain, large amounts of abnormal proteins accumulate in the endoplasmic reticulum. In the end, when the cell "realizes" that it cannot solve the problem, it prefers to commit suicide - and sacrifice itself for the integrity of the entire organism. The beta cells in the pancreas are destroyed, which considerably reduces the insulin levels in the body and its ability to regulate sugar levels. The research findings were recently published in the scientific journal Journal of Biological Chemistry.

Prof. Zick: "SSRI drugs promote obesity, and also, as we showed in this study, promote insulin resistance and cause a reduction in insulin secretion. Therefore, they may accelerate the deterioration from insulin resistance to diabetes. It is possible that following these findings it will be necessary to examine the use of these drugs, and perhaps develop ways to prevent their harmful effect."

The research was carried out by Roi Yitzchak, Dr. Siglit Bora-Chalpon and Diana Gurvitz, from Prof. Zik's group, in the Department of Molecular Biology of the Cell, together with those from the Biological Services Unit and Prof. Yehiel Lebkovitz from the Shlavta Mental Health Center.

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