SS antagonists as a potential treatment for type 2 diabetes
In her postdoctoral project, Sara Lind Jepsen aims to provide ‘important and necessary information for the development of SS antagonists as a potential new treatment for T2D’, as she writes in her project funding application to the Danish Diabetes Academy.
Describing the background to her work, she points out that the prevalence of obesity and type 2 diabetes (T2D) worldwide has been growing steeply in recent decades, and also that there is a need to develop new treatment methods capable of improving the prognosis for patients.
‘By relying on the body’s own hormone production rather than administering hormones systemically, we hope to be able to make treatment more effective and reduce the incidence of side effects such as nausea and vomiting’, she says.
Sara Lind Jepsen notes that one characteristic of T2D is insufficient production of insulin in relation to the tissues’ reduced sensitivity to insulin after eating. ‘It turns out that insulin secretion is greatly influenced by gut hormones that are normally very important in blood sugar and appetite regulation.
Two of these hormones come under the designation ‘incretins’; they are called glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The incretins are released from the gut during food intake and are then transported to the pancreas, where they stimulate insulin secretion. Studies have shown that T2D patients have a reduced GLP-1 response and a severely impaired incretin effect, which contributes to the reduced insulin secretion’, she says.
Today, thanks to this knowledge, GLP-1-based drugs are used to treat T2D patients. These drugs are given in doses that are limited by side effects such as nausea and vomiting.
At the same time, it is believed that the hormones normally work locally in the intestines by influencing nerves that send signals to the central nervous system. Therefore, if local secretion of the hormones could be increased, they might possibly work better and cause fewer side effects (as is observed following obesity surgery). It looks as though it may be possible to do this by blocking the normal secretion-inhibiting effect of SS.
Can glucose control be improved by manipulating the SS receptors?
The aim of this project is therefore to find out whether better glucose control can be achieved by manipulating the SS receptors. The hypothesis is that only a few SS receptor subtypes are important for incretin secretion and the brain’s regulation of glucose control and food intake, and that a specific inhibition of one particular SS receptor will enable improved, targeted glucose control and reduced food intake to be achieved by increasing the body’s own production of incretins.
‘In this study, we aim to find out which SS receptors are expressed on the GIP cell and whether specific inhibition of the most-expressed SS receptor can stimulate GIP secretion, something that has not previously been studied’, says Sara Lind Jepsen.
‘The study also aims to find out whether the increased incretin secretion achieved by removing the braking effect of SS on the secretion of both GLP-1 and GIP will have a stronger effect on the volume of glucose in the blood, and/or whether one system is more effective than the other. We will also investigate whether these SS antagonists can improve blood sugar regulation in type 2 diabetic mouse models. Finally, we will look into whether the antagonists have a direct effect on glucose control in the brain and whether they can affect food intake, because a study has shown that some SS receptor antagonists are able to enter the brain when injected into the body.’
The use of GIP as a potential treatment remains a matter of debate, because GIP administered by itself does not improve glucose control in T2D patients. A recently published study showed that a combination of GIP and GLP-1 had a positive, additive effect on patients’ glucose control. Something the two incretin hormones have in common is that the hormone somatostatin (SS) inhibits their secretion. Most SS is produced in the gut, but SS is also formed in areas of the brain involved in food intake and glucose control. Studies have shown that activation of SS-producing cells in the brain increases food intake in rodents. SS exerts this effect by binding to one of five SS receptors known as SSTr1-5, which are found on the surface of the cells influenced by SS. These five SS receptors are expressed to varying degrees on different cell types. In this project, we want to study the effect of antagonists against each of these receptors.
Sara Lind Jepsen MSc, PhD,
Department of Biomedical Sciences, University of Copenhagen
+45 2099 2050