The hormones GIP and GLP-1 are important in combating obesity and type 2 diabetes. Researchers from Germany, Switzerland and the US have now conducted mouse experiments that raise hopes for a drug.
To understand the new findings, one has to take in a bit of basic research. The focus here is on two messenger substances that researchers at Helmholtz Zentrum München, the German Center for Diabetes Research (DZD), ETH Zurich and Indiana University feel show particular promise. These substances are gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1).
GIP and GLP-1 are produced in the digestive tract and play vital roles in regulating body weight and food intake. A study on their effects now published in the journal Cell Metabolism provides pointers for developing drugs to treat obesity and type 2 diabetes.
GIP acts on receptors of the central nervous system located in the brain, stimulating the release of insulin and lowering blood glucose levels. But how exactly this works has not been clear until now.
First author Qian Zhang and her team had two different types of mice at their disposal for their experiment: normal wild-type mice and specially bred mice that lacked the GIP receptors in the brain. The researchers injected both types with GIP.
Mice naturally have GIP receptors, but for the trial, scientists used specially bred mice without them
It was found that body weight and food intake decreased in the wild-type mice, indicating that the hormone has an effect on appetite regulation. In contrast, food intake remained the same in the special laboratory mice lacking the GIP receptor. Their body weight decreased only minimally.
The researchers also looked at the mice's brain activity. "After administration of GIP, increased neuronal activity was evident in the area of the hypothalamus associated with the control of appetite ," says Christian Wolfrum of ETH Zurich.
As far as the treatment of type 2 diabetes goes, it is GLP-1 that plays an important role. It enhances the glucose-dependent release of insulin from the cells of the pancreas. Diabetics do not produce enough insulin themselves and have to inject it regularly.The problem is that GLP-1 is broken down again very quickly in the body and has to be constantly produced again. A solution to this problem has been available since 2005: a drug called Exenatide from AstraZeneca.
This contains an active ingredient derived from the saliva of the North American Gila monster, a venomous lizard. It acts in a similar way to GLP-1 but is not broken down as quickly by the body.
The active ingredient is therefore an "agonist." This means that it mimics the action of a hormone at a receptor and stimulates the receptor in the same way.
A similar approach using GLP-1 and GIP agonists had already been taken by researchers at Helmholtz Zentrum München together with colleagues from Indiana University. They had combined two hormones in a single molecule that acts on and stimulates both GIP and GLP-1 receptors.
This dual agonist simultaneously lowers weight and improves blood glucose levels. The researchers published their research in Science Translational Medicine in 2013.
The compound has now already entered a phase III clinical trial. It has been shown that the combination drug reduces body weight more than just one molecule does when acting at the GLP-1 receptor.
In the more recent mouse trial, it became clear, however, that the drug had no effect in mice lacking the GIP receptor in the brain. "Our work shows for the first time that the GLP-1/GIP dual agonist requires the GIP receptor in the brain to reduce body weight and food intake," said Timo Müller, last author of the new study and head of the Institute for Diabetes and Obesity (IDO) at Helmholtz Zentrum München.
His next goal is now to find further active substances to improve GIP receptor signaling because these appear to be the central mechanism for treating both conditions.