Detection of pancreatic beta cell mass in vivo in humans: studies in individuals with long-standing type 1 diabetes and in individuals with obesity

Detection of pancreatic beta cell mass in vivo in humans: studies in individuals with long-standing type 1 diabetes and in individuals with obesity | medRxiv Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Detection of pancreatic beta cell mass in vivo in humans: studies in individuals with long-standing type 1 diabetes and in individuals with obesity View ORCID Profile Alessandra Dei Cas , View ORCID Profile Valentina Spigoni , View ORCID Profile Raffaella Aldigeri , View ORCID Profile Federica Fantuzzi , View ORCID Profile Gloria Cinquegrani , View ORCID Profile Elisabetta Giordano , View ORCID Profile Roberta Eufrasia Ledda , Valentina Casale , View ORCID Profile Silvia Migliari , View ORCID Profile Maura Scarlattei , View ORCID Profile Livia Ruffini , View ORCID Profile Riccardo C. Bonadonna doi: https://doi.org/10.64898/2026.03.12.26348138 Alessandra Dei Cas 1 Department of Medicine and Surgery, University of Parma , Italy 2 Division of Endocrinology and Metabolic Diseases , Azienda Ospedaliera Universitaria Parma, Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Alessandra Dei Cas Valentina Spigoni 1 Department of Medicine and Surgery, University of Parma , Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Valentina Spigoni Raffaella Aldigeri 1 Department of Medicine and Surgery, University of Parma , Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Raffaella Aldigeri Federica Fantuzzi 1 Department of Medicine and Surgery, University of Parma , Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Federica Fantuzzi Gloria Cinquegrani 1 Department of Medicine and Surgery, University of Parma , Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Gloria Cinquegrani Elisabetta Giordano 1 Department of Medicine and Surgery, University of Parma , Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Elisabetta Giordano Roberta Eufrasia Ledda 1 Department of Medicine and Surgery, University of Parma , Italy 3 Division of Radiological Sciences , Azienda Ospedaliera Universitaria Parma, Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Roberta Eufrasia Ledda Valentina Casale 3 Division of Radiological Sciences , Azienda Ospedaliera Universitaria Parma, Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Silvia Migliari 4 Division of Nuclear Medicine , Azienda Ospedaliera Universitaria Parma, Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Silvia Migliari Maura Scarlattei 4 Division of Nuclear Medicine , Azienda Ospedaliera Universitaria Parma, Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Maura Scarlattei Livia Ruffini 4 Division of Nuclear Medicine , Azienda Ospedaliera Universitaria Parma, Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Livia Ruffini Riccardo C. Bonadonna 1 Department of Medicine and Surgery, University of Parma , Italy 5 Department of Medicine, University of Verona , Italy 6 Division of Endocrinology , Diabetology and Metabolic Diseases, Azienda Ospedaliera Universitaria Integrata Verona, Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Riccardo C. Bonadonna For correspondence: riccardo.bonadonna{at}univr.it Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Background PET-CT scans of radioactive exendin-4, a ligand of the GLP-1 receptor, are claimed to provide a biomarker of pancreatic beta cell mass (BCM), although the GLP-1 receptor is expressed also in the exocrine pancreas (PX). Parotid glands may be a reference tissue for GLP-1 receptor expression in exocrine cells of the GI system. Our aims were 1. To assess biomarker(s) of BCM derived from 68 Ga-NODAGA-exendin-4 PET-CT scans in participants with long-standing type 1 diabetes (T1DM) or in subjects with obesity (OBESE); 2. To investigate the relationship between biomarker(s) of BCM and a biomarker of beta cell functional mass (BCFxM) in OBESE. Methods T1DM (n=8, Age: 50.4±3.8 yrs; T1DM duration: 34.2±3.0 yrs; BMI: 26.6±1.1 kg/m 2 ; HbA1c: 7.5±0.36%) and OBESE (n=9; Age:48.2±2.2 yrs; BMI: 37.4±1.1 kg/m 2 ; HbA1c: 5.4±0.17%) underwent two studies: 1) 68 Ga-NODAGA-exendin-4 PET-CT scan of both PX and parotid glands 45’-60’ after i.v. injection and with CT-assessment of PX volume to compute biomarkers of BCM based on SUV (BCM SUV ) or clearance (CLEAR; BCM CLEAR ); 2) Mixed meal test (MMT), with measurement of plasma glucose, C-peptide, GLP-1 and GIP curves to assess BCFxM with state-of-art mathematical modeling. Results The C-peptide response to the MMT in T1DM participants was absent or negligible, whereas the OBESE displayed a robust BCFxM. The PX volume was smaller in T1DM than in OBESE (51.7±6.6 vs 92.9±10.9 cc; p=0.007). The biomarkers of BCM, as assessed by 68 Ga-NODAGA-exendin-4 SUV or CLEAR, were 6.6-fold (p=0.003) and 5.0-fold (p=0.002) lower, respectively, in T1DM than in OBESE. BCFxM was correlated in OBESE to both biomarkers of BCM (r=0.91 p<0.001, and r=0.82 p=0.006, respectively). Conclusion/interpretation 68 Ga-NODAGA-exendin-4 derived biomarkers of BCM can discriminate T1DM from OBESE. In OBESE 68 Ga-NODAGA-exendin-4 derived BCM appears to be a pivotal determinant of the beta cell response to MMT and may be valuable to compare and monitor BCM both in research and in clinical settings. What is already known about this subject? Changes in pancreatic beta cell functional mass are at the heart of alterations in glucose regulation, including diabetes mellitus. Beta cell functional mass can be assessed by mathematical modeling of the in vivo beta cell response to intravenous or oral challenges. Beta cell functional mass is the product of beta cell mass times beta cell function per mass unit, i.e. the result of two distinct entities, mass and function. No in vivo methods can dissect out beta cell mass and function. Pancreatic 68 Ga-exendin-4 uptake, as measured by PET-CT, has been proposed as a non-invasive biomarker of beta cell mass. However, the ratio of 3.6:1 between endocrine and exocrine pancreas 68 Ga-exendin 4 uptake suggests that there is room for improvement. What are the key questions? Does an improved 68 Ga-exendin4 method provide a better separation between participants with type 1 diabetes and expected zero/nil beta cell mass vs people with nondiabetic obesity? What is the role of beta cell mass in determining beta cell functional mass in people living with obesity? What are the new findings? The improvement in the quantitation of beta cell 68 Ga-exendin-4 binding to beta cells resulted in a clearcut separation of participants with type 1 diabetes and expected zero/nil beta cell mass from people living with obesity In people living with obesity, beta cell mass, as assessed by 68 Ga-exendin-4 PET-CT scan, is a pivotal determinant of beta cell functional mass, as assessed by mathematical modeling of a frequently sampled mixed meal test How might this impact on clinical practice in the foreseeable future? This method has the potential to track changes in beta cell mass both between-subjects and within-subjects over time Natural history of glucose (in)tolerance and the impact of disease modifier candidates in diabetes mellitus can be assessed with the present method Competing Interest Statement The authors have declared no competing interest. Funding Statement University of Parma -Bando FIL - Quota incentivante 2019; Italian Ministry of University and Research (MUR) under the PRIN 2022 PNRR program (Grant No. P2022445ES, CUP D53D23020950001), Mission 4 'Education and Research', Component 2 'From Research to Business', Investment 1.1 Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was reviewed and approved by the Area Vasta Emilia Nord Ethical Committee (approval prot. n. 41494 of 14th October 2021). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Back to top Previous Next Posted March 18, 2026. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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Bonadonna medRxiv 2026.03.12.26348138; doi: https://doi.org/10.64898/2026.03.12.26348138 Share This Article: Copy Citation Tools Detection of pancreatic beta cell mass in vivo in humans: studies in individuals with long-standing type 1 diabetes and in individuals with obesity Alessandra Dei Cas , Valentina Spigoni , Raffaella Aldigeri , Federica Fantuzzi , Gloria Cinquegrani , Elisabetta Giordano , Roberta Eufrasia Ledda , Valentina Casale , Silvia Migliari , Maura Scarlattei , Livia Ruffini , Riccardo C. 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