Introduction: Most phaeochromocytomas produce insulin, and some produce glucagon-like peptide 1 receptor (GLP-1R). In pancreatic β-cells, stimulation of GLP-1R causes insulin release. A few phaeochromocytoma patients experience hypoglycaemic attacks. Therefore, we studied the distribution of GLP-1R-containing and insulin-containing phaeochromocytoma cells and their relation.
Methods: In 20 phaeochromocytomas, we performed sequential double staining with anti-insulin and anti-GLP-1R antibodies and, in selected cases, staining with anti-insulin alone. We quantified tumour cells with positive staining and compared their distribution to that of randomly distributed cells using simulations. We obtained GLP-1R transcript data from 182 such tumours from The Cancer Genome Atlas (TCGA) Research Network.
Results: GLP-1R-containing cells were found in six of the 20 tumours, and insulin-containing cells were found in fifteen. Moreover, in the TCGA cohort, almost half of the tumours produce GLP-1R transcripts, and patients with the highest number of transcripts show longer disease-free survival. In the tumours, we found that cells expressing insulin were present in the cytoplasm and GLP-1R in the membrane, with a frequency of 2.59 and 1.34%, respectively. These cells showed clustering, and one tumour showed a large clonal expansion. Interestingly, we found deposits of insulin, which we suggest naming insulin bodies in two tumours. Very few cells contained both proteins.
Conclusion: Most phaeochromocytomas contain tumour cells producing insulin. About half produce GLP-1R. The producing cells show clustering, and clonal expansion occurs. Insulin release might cause hypoglycaemia. Increased GLP-1R levels might induce less aggressive tumours.
Keywords: glucagon-like peptide 1 receptor; insulin; phaeochromocytoma; tumour-induced hypoglycaemia.