Glucagon Like Peptide 1 Receptor (GLP1R) Expression and Beta-cell Mass in Patients With Type 2 Diabetes (GLP1R-T2D)

Glucagon Like Peptide 1 Receptor (GLP1R) Expression and Beta-cell Mass in Patients With Type 2 Diabetes

Glucagon Like Peptide 1 Receptor (GLP1R) Expression and Beta-cell Mass in Patients With Type 2 Diabetes - the Role of Glucose Homeostasis on Uptake of Beta-cell Tracer Exendin-4

Rationale: Reliable imaging biomarkers for non-invasive characterisation of beta-cell mass (BCM) are needed to aid understanding regarding the relationship between beta-cell mass and function during the course of type 2 diabetes (T2D). This study will provide critical information necessary to validate the applicability of exendin-based imaging techniques in patients with T2D. The characterization of beta-cells is currently limited to pancreatic specimens available at autopsy, as in vivo pancreatic biopsy is associated with complications unacceptable in clinical studies. To date, only measurements of circulating C-peptide and insulin levels can be obtained, but these measures do not reflect beta-cell mass, only total beta-cell function. Reliable imaging biomarkers for non-invasive characterisation of beta cell mass are therefore needed. These biomarkers could also be used to validate novel therapeutic strategies aimed to increase or preserve BCM or identify whether patients are eligible for a certain therapeutic strategy (e.g. when certain amount of beta-cells is required). One can also think of identifying early responders to therapies, to avoid unnecessary drug use and the accompanying costs. The objective of this study is to determine the specificity of Exendin-4 during the course of T2D and to examine the role of glycemic control on the correlation between pancreatic Exendin-4 uptake, BCM and GLP-1R expression in patients with T2D undergoing (partial) pancreatectomy. This will allow examination of the role of glycemic control on exendin uptake in humans, but also implementation of clinical guidelines for the interpretation of clinical exendin-based scans in patients with T2D to avoid false interpretation of the scans.

Injection of 111In-exendin-DTPA for subsequent localization of the tracer in excised tissue using autoradiography

Injection of exendin-4-IRDye800CW for subsequent localization of the tracer in excised tissue using fluorescence microscopy

Injection of 111In-DTPA-exendin-4 and localization of the tracer in excised pancreatic tissue using autoradiography

Injection of IRDye800CW-exendin-4 and localization of the tracer in excised pancreatic tissue using fluorescence microscopy

111In-DTPA-exendin-4 injection will be performed a day before planned surgery, and uptake will be determined using ex vivo SPECTof the resected tissue one day after surgery

111In-DTPA-exendin-4 injection will be performed a day before planned surgery, and uptake will be determined with tissue autoradiography immediately after resection

IRDye800CW-exendin-4 injection will be performed a day before planned surgery, and uptake will be determined using microscopy in the excised tissue

Inclusion Criteria: Scheduled for partial or complete pancreatectomy at Radboudumc Exclusion Criteria: Previous treatment with synthetic exendin or dipeptidyl-peptidase IV inhibitors within the past 3 months Breast feeding Pregnancy or the wist to become pregnant within 6 months Creatinine clearance below 40ml/min Liver disease defined as aspartate aminotransferase of alanine aminotransferase level of more than three times the upper limit of normal range