Human subjects with impaired beta-cell function and glucose tolerance have higher levels of intra-islet intact GLP-1

Teresa Mezza, Nicolai J. Wewer Albrechtsen, Gianfranco Di Giuseppe, Pietro Manuel Ferraro, Laura Soldovieri, Gea Ciccarelli, Michela Brunetti, Giuseppe Quero, Sergio Alfieri, Enrico Celestino Nista, Antonio Gasbarrini, Vincenzo Tondolo, Andrea Mari, Alfredo Pontecorvi, Andrea Giaccari*, Jens J. Holst

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

2 Downloads (Pure)

Abstract

Aims: A number of studies have suggested that pancreatic α cells produce intact GLP-1, thereby constituting a gut-independent paracrine incretin system. However, the debate on whether human α cells contain intact GLP-1 and whether this relates to the presence of diabetes is still ongoing. This study aimed to determine the presence of proglucagon-derived peptides, including GLP-1 isoforms, in pancreas biopsies obtained during partial pancreatectomy from metabolically profiled human donors, stratified according to pre-surgery glucose tolerance. Methods: We enrolled 61 individuals with no known history of type 2 diabetes (31F/30M, age 64.6 ± 10.6 yrs., BMI 24.2 ± 3.68 kg/m2) scheduled for partial pancreatectomy for periampullary neoplasm. Differences in glucose tolerance and insulin secretion/sensitivity were assessed using preoperative 2 h OGTT, 4 h-Mixed Meal Test and Hyperinsulinemic Euglycemic Clamp. Subjects were subsequently classified as normal glucose tolerant (NGT, n = 19), impaired glucose tolerant (IGT, n = 20) or newly diagnosed diabetes (DM) (n = 22). We measured total GLP-1, intact GLP-1, glucagon, insulin, and C-peptide in pancreas biopsies and plasma from these subjects and correlated the results with their secretory and metabolic parameters. Results: Extractable levels of total GLP-1 were 23.9 ± 2.66 pmol/g, while intact GLP-1 levels were 1.15 ± 0.18 pmol/g. When we examined proglucagon derived peptides (adjusted for glucagon levels), in subjects classified according to glucose tolerance, we observed similar levels of total GLP-1, however, intact GLP-1 was significantly increased in IGT and DM groups and inversely associated with beta cell glucose sensitivity and insulin secretion in vivo. Conclusions: Our data show that development of glucose intolerance and beta cell dysfunction are significantly associated with increased levels of intra-islet intact GLP-1, a potentially beneficial adaptation of the paracrine regulation of insulin secretion in type 2 diabetes.

Original languageEnglish
Article number156087
JournalMetabolism: Clinical and Experimental
Volume163
Number of pages8
ISSN0026-0495
DOIs
Publication statusPublished - 2025

Bibliographical note

Publisher Copyright:
© 2024 The Authors

Keywords

  • Alpha-cells
  • Glucagon-like peptide 1
  • Islets biology
  • Type 2 diabetes

Cite this