More On Glitazone – And a Possible Alternative | Levin Papantonio Rafferty - Personal Injury Law Firm

More On Glitazone – And a Possible Alternative


K.J. McElrath

Last week, I posted a lay person's explanation of diabetic glitazone drugs. You may want to review that one in order to understand the information I'm presenting here this week.


What most of us know and understand about glitazones such as Avandia and Actos is that they have potentially fatal side effects. The former is known to lead to cardiac arrest in some patients, while the latter has been connected to increased incidences of bladder cancer. If you read the previous post (A Glitazone Primer), you now have an understanding of how these drugs work to address the problem of "insulin resistance."


In medical terms, glitazone is what is known as an agonist, which is a compound that binds to a specific, targeted molecule, or cell receptor. As you know from the last post, receptors are what "receive" biochemical signals from hormones, containing instructions for the cell to carry out a specific function. Agonists "awaken" or "open up" these receptors, allowing them to better receive biochemical signals. (In contrast, some neuroleptic medications used in the treatment of mental illness are antagonists – which are designed to block such signals.)


Here is the problem: when glitazones activate the PPARG receptor, it has a "cascade" effect on other genes and proteins down the line (in other words, once the receptor is activated and the cell goes into action, it has an effect on other cells and systems, which in turn affect other cells and systems, and so on), triggering an entire sequence of events. Current research suggests that a number of unintended consequences result; in fact, the drug makers themselves do not fully understand everything that happens "downstream."


However, researchers at the Dana-Farber Cancer Institute in Boston have pinpointed one of the problems. It has to do with a cellular process known as phosphorylation. If you think the first part of that term looks like "phosphorus," you are correct: in simplest terms, the word describes a biochemical process by which a form of phosphorus oxide (PO4) is added to the mix, acting as an "on-off" switch for a number of  the protein enzymes that enable biochemical reactions to occur at a rate sufficient to sustain life. In some cases,  phophorylation is necessary; in other cases, it can be harmful. It's a delicate balancing act, and when this balance is upset, any number of complications can occur.


The molecule responsible for phophorylation in this case is CDK5. Evidence indicates that when this molecule is improperly regulated, the result can be invasive cancer.


The researchers at Dana-Farber have recently developed "synthetic small molecules" they report accomplish the same thing as the glitazone drugs, but without interfering with the normal phophorylation.  The most promising of these is identified as SR1664, which when tested in mice, had the same anti-diabetic effect as Avandia – but without the dangerous side effects.


These studies are in their preliminary stages; it could be several years before a "safer" anti-diabetic drug is developed. In the meantime, the best treatment for Type-II diabetes is proper diet and exercise; the condition is usually due to excess weight and a sedentary lifestyle and can often be reserved without the use of potentially harmful drugs – regardless of what Big Pharma often says in their fear-based advertising about how it "may not be enough."





N/A. "New Twist In Diabetes Drugs Could Reduce Life-Threatening Side Effects. ( ). Updated 07 September 2011. Retrieved 15 September 2011.


Quintavalle, Manuela, et. al. "A Cell-Based High-Content Screening Assay Reveals Activators and Inhibitors of Cancer Cell Invasion." Science Signal, 26 July 2011.


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