Anti-diabetic drugs are common to control blood glucose levels in diabetes. However, these treatment options leave room for improvement. The need for more effective drugs and increase of the population with diabetes makes that many new therapies are being developed. Most of the time, when testing these new drugs, the effect on blood glucose levels is evaluated. Although this is the ultimate goal of the drugs, it only measures the final outcome measure, and you don’t investigate the mechanism of action. With molecular imaging you can investigate the mode of action of (new) anti-diabetic drugs. This will help to improve existing medication and create more effective new drugs by better understanding the interaction of the therapies with the complex disease processes of diabetes.
Glucose metabolism.
After you eat a meal, the food is digested in your intestines. During digestion your body absorbs the nutrients from food. One of these nutrients is glucose. This leads to higher levels of glucose in the blood. In healthy people the glucose level is normalized by the secretion of insulin by the beta cells in the pancreas. Insulin converts glucose intro glycogen that is stored in the liver and muscles. In this way glucose is stored for times when glucose demands increases. When you need more glucose, for example when you exercise, glucagon is secreted in the blood and glycogen is converted in glucose.
Current treatments and the need for (new) anti-diabetic drug development.
Diabetes mellitus is characterised by repeated high levels of glucose in the blood. When you have type 1 diabetes, your body doesn’t produce enough insulin to control the blood glucose levels. This is caused by the destruction of the insulin producing beta cells.
When you have type 2 diabetes, your body does produce enough insulin, but the cells of your body don’t respond properly to insulin. As a result, glucose is not stored in the muscles and the liver but remains in the blood. In later stages of type 2 diabetes insulin production is also lost.
Diabetes is treated by controlling blood glucose. When you suffer from type 1 diabetes, you need to inject insulin several times per day. You must go on a specific diet and exercise when you have type 2 diabetes. Also, you might need to take anti-diabetic drugs to control your blood glucose levels.
Anti-diabetic drug development
Since anti-diabetic drugs are still not optimal, new drugs are being developed. Often the effect on blood glucose levels is used as the main success factor for anti-diabetic drugs. Even though this is the aim of the drugs, it only measures the final outcome. With molecular imaging you can also investigate the mode of action of new anti-diabetic drugs.
Molecular imaging of the Glucagon-like peptide 1 receptor.
When you want to know how your new anti-diabetic drug works, you can label your compound and visualize the distribution and find out the mode of action. An example of labeling an anti-diabetic drug are compounds that target the glucagon-like peptide 1 receptor (GLP-1R). One drug that binds to the GLP-1R is the peptide exenatide. You can use this drug to treat type 2 diabetes. It improves the blood glucose levels and induces weight loss. However, the mode of action is not completely known, and it does not work in all patients with type 2 diabetes.
When you label exenatide with a radionuclide or fluorescent dye you can visualize the distribution of the drug in vivo and ex vivo. Various studies showed binding of the labeled drug in the pancreas and intestines. These organs are known to express the GLP-1R. Other studies showed that you can measure the amount of beta cells with this technique. This is important data when developing new drugs for for type 1 diabetes, where you try to replace lost beta cells are lost. In other words, with radiolabeled exenatide imaging you can measure the efficacy of these replacement therapies. Whereas without molecular imaging you can only measure the changes in blood glucose. Although this is an indication of efficacy, it does not tell you the success of the replacement therapy.
Molecular imaging of glucose metabolism in anti-diabetic drug development.
When you develop a new drug for diabetes, you want to know if this new therapy has a positive effect on the glucose metabolism. You want to know if your drug can improve blood glucose levels by storage of glucose in the liver and muscles. One way would be to measure blood glucose levels, but this does not give you information on the glucose metabolism.
The radioactive analog of glucose, fluorine-18 fluorodeoxyglucose ([18F]-FDG), can give you real-time information on the changes in glucose metabolism with PET imaging. For example, the effect on glucose metabolism of the commonly used drug for type 2 diabetes, metformin, was studied by [18F]-FDG PET imaging. With the use of molecular imaging, you get more information on the mode of action of metformin. Even before you can measure differences in blood glucose levels.
Molecular imaging in anti-diabetic drug trials
Molecular imaging can help you to study the mode of action of new anti-diabetic drugs. You can gather this data by labeling the drug of interest and consecutive molecular imaging. This method visualizes the distribution of your drug. At the same time, you can also use molecular imaging to study the mode of action of your new drug by imaging an outcome measure. This gives you a more in depth understanding of the interaction of your (new) drug with the complex disease processes of diabetes. In the end, allowing you to develop more effective anti-diabetic drugs for patients.