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A novel class of chemicals may provide the advantages of gastric bypass surgery without the need for surgery. These prospective medicines significantly reduce body weight and blood sugar in laboratory mice. The side effects of nausea and vomiting, which are frequent with modern diabetic and weight-loss medications, are also avoided by injectable chemicals. Scientists now claim that the new therapy increases calorie expenditure while also reducing eating.
Today at the American Chemical Society’s spring meeting, the researchers will report their findings. (ACS). The hybrid ACS Spring 2023 conference will take place from March 26 to 30.
“Obesity and diabetes were the pandemics before the COVID-19 pandemic,” says Robert Doyle, Ph.D., one of the two principal investigators on the project, along with Christian Roth, M.D. “They are a massive problem, and they are projected to only get worse.”
One option is bariatric surgery, which includes gastric bypass and related procedures. It frequently leads to long-lasting weight loss and even the remission of diabetes. But many of the hundreds of millions of obese or diabetic people around the world cannot access these procedures because they are risky, not fit for everyone, and contain risks. Doyle suggests that as an alternative, patients may treat their metabolic issues with a medication that mimics the long-term advantages of surgery.
These advantages are connected to changes in the levels of a few hormones, such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), secreted by the gut after bypass surgery. These hormones communicate fullness, control appetite, and normalize blood sugar. The pancreas and brain contain GLP-1 receptors that are predominantly activated by the current medications designed to mimic this action. Celebrities have been posting frequently on social media recently about this method, which has had excellent success in treating type 2 diabetes and helping people lose weight. However, Doyle claims that many patients cannot withstand the negative effects of the medications. “Within a year, 80 to 90% of people who start on these drugs are no longer taking them.” Doyle is at Syracuse University and SUNY Upstate Medical University, and Roth is at Seattle Children’s Research Institute. Other medicines have been developed by various researchers that interact with multiple types of gut hormone receptors in order to overcome that limitation. For instance, Doyle’s team developed a peptide that stimulates two PYY receptors as well as the GLP-1 receptor. This substance, known as GEP44, made obese rats consume up to 80% less food than they normally would. They lost an average of 12% of their body weight during the course of one 16-day research. That was more than three times the amount of weight loss in rats given liraglutide, an injectable medication that solely activates the GLP-1 receptor and is authorized by the United States Food and Drug Administration. In contrast to liraglutide, studies using GEP44 in rats and shrews (a species capable of vomiting, unlike rats) showed no signs of nausea or vomiting. Doyle theorizes that this may be because activating multiple receptors may cancel out the intracellular signaling pathway that causes such symptoms.
In its most recent findings, his team is now revealing that the weight loss brought on by GEP44 can be linked to increased energy expenditure, which can manifest as increased exercise, heart rate, or body temperature, in addition to decreased eating.
GEP44 only has a half-life of around an hour in the body, but Doyle’s team has just created a peptide with a substantially longer half-life. It might thus be injected just once or twice a week as opposed to several times every day. In contrast to commonly the situation with currently licensed medications, Doyle notes that the researchers are now finding that rats treated with this novel substance maintain their new, smaller physique long after therapy is finished.
However, peptide therapies have other advantages besides weight loss. Additionally, they lower blood sugar levels by transporting glucose into muscle tissue, where it may be used as fuel, and by transforming specific pancreatic cells into insulin-producing cells, thereby assisting in the replacement of those that have been harmed by diabetes. There is even another advantage: According to a recent study by Doyle and Heath Schmidt, Ph.D. of the University of Pennsylvania, GEP44 lessens rats’ cravings for opioids like fentanyl. Doyle claims that if it is successful in humans, it may be able to aid drug addicts in quitting their addiction or prevent relapse.
The scientists intend to test their peptides in monkeys and have applied for patents on their substances. They will also investigate how the medications alter gene expression and reorganize the brain, and what implications that may have for these substances and other kinds of drugs.
“For a long time, we didn’t think you could separate weight reduction from nausea and vomiting because they’re linked to the exact same part of the brain,” Doyle says. But the researchers have now uncoupled those two pathways—and that has implications for chemotherapy, which causes similar side effects. “What if we could maintain the benefit of chemotherapy drugs but tell the part of the brain that causes vomiting and nausea to knock it off? Then we could dose patients at a higher level, so they would have a better prognosis, and they would also have a better quality of life while undergoing chemotherapy,” he says.
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