Clever gene construct combats metabolic syndrome

17 06 2013

Researchers under ETH-Zurich professor Mar- tin Fussenegger have created a new genetic network that could cure the various symptoms of so-called metabolic syndrome in one fell swoop. It already works in mice.

 

Too much of the wrong food and not enough exercise: sooner or later, an increasing number of people in industrial nations pay the price for their lifestyle. High blood pressure, changed blood fat values, insulin resistance as a precursor to diabetes, and abdominal fat are characteristic of metabolic syndrome, the ‘killer of the twenty-first century’. After all, it is the major risk factor for the development of coronary heart diseases. Today, many more people die of cardiovascular diseases worldwide than from cancer.

Until now, however, there has not been a holistic therapy for metabolic syndrome. Medicine diagnoses and treats every single symptom of metabolic syndrome separately. “However, all these diseases are linked,” says ETH-Zurich professor Martin Fussenegger from the Department of Biosystems in Basel. His research group has now found an approach that could treat all the symptoms of metabolic syndrome at once.

 

Antihypertensive drug triggers cascade

The biotechnologists have constructed a synthetic signaling cascade from different biological molecules that can be triggered with the antihypertensive drug guanabenz and controlled based on the dosage. After the start signal, a chain reaction is set in motion in the cell and culminates with the production of a “super hormone” in the cell nucleus. This includes GLP1, which is connected to leptin via a molecular bridge. GLP1 reduces the blood sugar level; leptin inhibits the feeling of hunger and thus plays a key role in regulating the lipid metabolism.

The combination of the drug guanabenz, which has already been approved for clinical use, and the ‘super hormone’ produced by the synthetic signal cures all three key diseases associated with metabolic syndrome at the same time. The researchers tested their network in a model experiment using diabetic, obese mice suffering from high blood pressure. The animals lack the satiety hormone leptin so are always hungry and eat more than is good for them. The ETH- Zurich biotechnologists inserted an implant with ten million cells, each of which contained the synthetic signalling pathway, into the mice.

 

Construct successful in mice

The animals responded very well to the dose of guanabenz: the GLP1 and leptin concentration rose dramatically and twenty-four hours after the drug was dispensed insulin secretion also increased on account of the GLP1 content. After only three days, the level of cholesterol and other free fatty acids in the blood dropped – a good sign that the animals were beginning to recover from metabolic syndrome. Free guanabenz even lowered the blood pressure, too.

“This application is also realistic for the treatment of metabolic syndrome in humans,” Fussenegger predicts. GLP1 is already administered as an alternative to insulin in the battle against diabetes. Leptin, on the other hand, would have to be substituted with another hormone that has a similar effect. “Leptin has failed to live up to its hopes as a therapeutic agent against obesity, as obese patients have sufficient leptin but have grown resistant to it,” stresses the ETH-Zurich professor. However, he is confident that they can incorporate an alternative satiety hormone into their network. They merely used leptin to demonstrate the principle. It works perfectly well in mice.

In planning and constructing this network, the researchers were able to fall back on the Fussenegger group’s existing expertise. The ingenious scientists had already assembled gene networks for diabetes or gout with similar biological components, the properties of which are renowned. “But we only discovered that the antihypertensive drug guanabenz can be used as a start button by chance,” says the ETH-Zurich professor from Basel.

Even though he is convinced that a gene construct designed in this way could treat metabolic syndrome with its array of symptoms, for the time being Fussenegger is reluctant to make any promises as to when a corresponding product might hit the market.

Original: Ye H, Charpin-El Hamri G, Zwicky K, Christen M, Folcher M, Fussenegger M. Pharmaceutically controlled designer circuit for the treatment of the metabolic syndrome. PNAS online, doi: 10.1073/pnas.1216801110.

 

 

Ethz.ch [en línea] Zurich (SUI): ethz.ch, 17 de junio de 2013 [ref. 17 de diciembre de 2012] Disponible en Internet: http://www.ethz.ch/media/detail_EN?pr_id=1134



Weight Loss Surgery May Not Combat Diabetes Long-Term

17 12 2012

Weight loss surgery, which in recent years has been seen as an increasingly attractive option for treating Type 2 diabetes, may not be as effective against the disease as it was initially thought to be, according to a new report. The study found that many obese Type 2 diabetics who undergo gastric bypass surgery do not experience a remission of their disease, and of those that do, about a third redevelop diabetes within five years of their operation.

Stuart Bradford

Stuart Bradford

The findings contrast with the growing perception that surgery is essentially a cure for Type II diabetes. Earlier this year, two widely publicized studies reported that surgery worked better than drugs, diet and exercise in causing a remission of Type 2 diabetes in overweight people whose blood sugar was out of control, leading some experts to call for greater use of surgery in treating the disease. But the studies were small and relatively short, lasting under two years.

The latest study, published in the journal Obesity Surgery, tracked thousands of diabetics who had gastric bypass surgery for more than a decade. It found that many people whose diabetes at first went away were likely to have it return. While weight regain is a common problem among those who undergo bariatric surgery, regaining lost weight did not appear to be the cause of diabetes relapse. Instead, the study found that people whose diabetes was most severe or in its later stages when they had surgery were more likely to have a relapse, regardless of whether they regained weight.

“Some people are under the impression that you have surgery and you’re cured,” said Dr. Vivian Fonseca, the president for medicine and science for the American Diabetes Association, who was not involved in the study. “There have been a lot of claims about how wonderful surgery is for diabetes, and I think this offers a more realistic picture.”

The findings suggest that weight loss surgery may be most effective for treating diabetes in those whose disease is not very advanced. “What we’re learning is that not all diabetic patients do as well as others,” said Dr. David E. Arterburn, the lead author of the study and an associate investigator at the Group Health Research Institute in Seattle. “Those who are early in diabetes seem to do the best, which makes a case for potentially earlier intervention.”

One of the strengths of the new study was that it involved thousands of patients enrolled in three large health plans in California and Minnesota, allowing detailed tracking over many years. All told, 4,434 adult diabetics were followed between 1995 and 2008. All were obese, and all underwent Roux-en-Y operations, the most popular type of gastric bypass procedure.

After surgery, about 68 percent of patients experienced a complete remission of their diabetes. But within five years, 35 percent of those patients had it return. Taken together, that means that most of the subjects in the study, about 56 percent — a figure that includes those whose disease never remitted — had no long-lasting remission of diabetes after surgery.

The researchers found that three factors were particularly good predictors of who was likely to have a relapse of diabetes. If patients, before surgery, had a relatively long duration of diabetes, had poor control of their blood sugar, or were taking insulin, then they were least likely to benefit from gastric bypass. A patient’s weight, either before or after surgery, was not correlated with their likelihood of remission or relapse.

In Type 2 diabetes, the beta cells that produce insulin in the pancreas tend to wear out as the disease progresses, which may explain why some people benefit less from surgery. “If someone is too far advanced in their diabetes, where their pancreas is frankly toward the latter stages of being able to produce insulin, then even after losing a bunch of weight their body may not be able to produce enough insulin to control their blood sugar,” Dr. Arterburn said.

Nonetheless, he said it might be the case that obese diabetics, even those whose disease is advanced, can still benefit from gastric surgery, at least as far as their quality of life and their risk factors for heart disease and other complications are concerned.

“It’s not a surefire cure for everyone,” he said. “But almost universally, patients lose weight after weight loss surgery, and that in and of itself may have so many health benefits.”

 

Well.blogs.nytimes.com [en línea] New York (USA): well.blogs.nytimes.com, 17 de diciembre de 2012 [ref. 28 de noviembre de 2012] Disponible en Internet: http://well.blogs.nytimes.com/2012/11/28/weight-loss-surgery-may-not-combat-diabetes-long-term/?ref=health