Side Effects


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(l-r) Dr. Sigalit Boura-Halfon, Hadas Shatz-Azoulay, Dr. Eytan Elhanan, Prof. Yehial Zick, Roi Isaac, Dr. Yaron Vinik, Prof. Sanford Simpson, Itai Efodi, Prof. Rivka Pollak and Sarina Striem

One of the known side effects of certain antidepressants and antianxiety drugs, including the popular drug Prozac, is weight gain. Research at the Weizmann Institute led by Prof. Yehiel Zick has now shown that this class of drugs can also contribute to the development of diabetes. The study’s findings hint that caution might need to be exercised in the use of these medications, especially in people with diabetes or those at risk for the disease.

The connection between these drugs, known as selective serotonin reuptake inhibitors (SSRIs), and weight gain is well known: They hinder the absorption of the neurotransmitter serotonin, so that its levels in the brain rise. Serotonin (which is also found in such foods as chocolate) is a natural “feel good” neurotransmitter, but it also increases appetite. If people using SSRIs overeat as a result, they can end up with that plague of recent decades – obesity – and they will be at risk for cancer, heart disease and diabetes.

In short

•    Antidepressants known as SSRIs have been known to cause weight gain.
    New Weizmann Institute research shows that SSRIs may also promote obesity and diabetes in much the same way as fatty acids do – by hindering insulin production.
    They can also initiate cell death in the insulin-producing cells.

But various scientific findings in recent years have suggested that the links between antidepressant use and diabetes go beyond hunger pangs. These drugs can cause insulin resistance, a condition in which the beta cells in the pancreas – the body’s insulin factories – cannot function properly. Normally, the beta cells produce insulin, the hormone responsible for getting sugar into the body’s cells, in response to a rise in blood sugar levels. But when the cells develop insulin resistance, more insulin is needed to overcome the resistance. Insulin resistance can eventually turn into diabetes – a breakdown in the body’s ability to regulate sugar levels. How, exactly, do SSRIs cause insulin resistance in beta cells?

To understand what happens, Zick and his team closely observed the chain of events that begins with the binding of insulin to a receptor on the beta cells. This receptor, whose action Zick had discovered in his postdoctoral research in the 1980s, activates another protein called IRS-2 by attaching a phosphorous-based chemical group to one of its amino acids. This phosphorylation then sets off a chain of biochemical events that facilitates insulin production and secretion, as well as maintaining the viability of the beta cells. Normally it is an amino acid called tyrosine that is phosphorylated; but following a rise in agents in the blood that induce insulin resistance, for instance, fatty acids, another amino acid in the IRS-2 protein – serine – is phosphorylated. This hinders the first step –  tyrosine phosphorylation by the insulin receptor. By breaking the connection between the first two links in the chain – between the receptor and IRS-2 – further activity is held up. When this happens, extra insulin is needed to get things moving again. At some point, if resistance builds up to very high levels, the pancreatic cells buckle under the non-stop demand for insulin and they begin to die.
Image: Thinkstock- fat guy pops a pill
In the new study, conducted on mouse and human pancreatic beta cells, the scientists discovered that SSRIs disrupt the chain of events that lead to insulin secretion in much the same way as the agents that induce insulin resistance – by hindering the insulin-induced tyrosine phosphorylation of IRS-2. In further experiments, the team discovered the exact mechanism by which antidepressants interfere with IRS-2, showing it is the same mechanism that is activated by fatty acids and other similar molecules.

If this were not enough to deal a fatal blow to the functioning of the beta cells, the researchers discovered that SSRIs can also kill them off more directly, by initiating a cellular suicide pathway (apoptosis). They do this by activating a series of enzymes in the cells’ endoplasmic reticulum – the cellular organelle in which proteins are processed before use. This leads to a buildup of defective proteins within the endoplasmic reticulum. When the buildup threatens to cause serious problems, the cell will sacrifice itself for the greater good of the organism. But if too many beta cells go the suicide route, the body’s capacity to produce insulin is impaired and it loses the ability to regulate sugar. The findings of this study appeared in the Journal of Biological Chemistry.

Says Zick: “SSRI medications not only promote obesity but, as we have shown, they directly contribute to insulin resistance and a drop in insulin secretion. Thus they can hasten the progression of insulin resistance into diabetes. This suggests that we may need to reevaluate the use of these drugs and possibly search for ways of preventing their negative side effects.”

The research was conducted by Roi Isaac, Dr. Sigalit Boura-Halfon and Diana Gurevitch in Zick’s group in the Molecular Cell Biology Department, together with Alla Shainskaya, of the Biological Services Unit and Prof. Yechiel Levkovitz of the Shalvata Mental Health Center and Tel Aviv University.
Prof. Yehiel Zick’s research is supported by the Adelis Foundation. Prof. Zick is the incumbent of the Marte R. Gomez Professorial Chair.