The ability to undertake repeated, quantitative, non-invasive monitoring of pancreatic beta cell mass (BCM) in subjects with T1D would be of immense importance for our understanding of the pathophysiology of diabetes. Positron Emission Tomography (PET) is a molecular imaging technique, which is non-invasive, has high sensitivity and resolution. In addition it is fully quantifiable, a requirement for accurate determination of BCM in vivo.
Several neurotransmitter systems, such as the dopaminergic and serotonergic systems, are expressed in the islets of Langerhans. Of importance is the fact that the exocrine pancreas is devoid of these systems. 5-hydroxy-L-[11C]tryptophane ([11C]5-HTP) was originally developed to assess the rate of serotonin biosynthesis. Recent studies have established the serotonergic system in human beta cells, and intravenous administration of [3H]5-HTP in mice show a preferential accumulation in the granules of the beta cell. Based on these promising preclinical data a prospective clinical study comparing the pancreatic uptake of [11C]5-HTP in T1D and healthy controls was conducted. Obtained results demonstrate that [11C]5-HTP can be used for non-invasive quantification of islet mass in health and disease.
Glucagon-like peptide 1 receptor (GLP-1R) is present on the beta cells within the islets of Langerhans and is absent or limited in the exocrine parenchyma. Since native GLP-1 is degraded rapidly by dipeptidyl peptidase-IV, a more stable agonist of GLP-1 such as Exendin4 is a preferred imaging agent. Uptake of [68Ga]Exendin4 in tissues is correlated to the expression of GLP-1R, and uptake in the pancreas is markedly decreased in STZ induced diabetes. Notably, the levels of endogenous GLP-1 compete with [68Ga]Exendin4 for GLP-1R occupancy which may cause a substantial underestimation of BCM. Likewise, imaging tracers applied must have a high specific labeling to properly reflect BCM.
In conclusion, preclinical, including non-human primate studies, and clinical evidence show that both [11C]5-HTP and [68Ga]DO3A-Exendin4 can serve as quantitative imaging biomarkers for the BCM making possible prompt and distinct evaluation of intervention and replacement strategies to delay or prevent T1D.