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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 156087 |
| Tidsskrift | Metabolism: Clinical and Experimental |
| Vol/bind | 163 |
| Antal sider | 8 |
| ISSN | 0026-0495 |
| DOI | |
| Status | Udgivet - 2025 |
Bibliografisk note
Funding Information:This study was supported by grants from the Universit\u00E0 Cattolica del Sacro Cuore (Fondi Ateneo Linea D.3.2, Fondi Ateneo Linea D.1, anno 2020 and Fondi Ateneo Linea D.1, anno 2021) to T.M. and (Fondi Ateneo Linea D.1 2019 and Linea D.1 2021) to A.G.; the Italian Ministry of Health (The study of human islet cell plasticity to predict diabetes onset, progression and personalize therapy. CUP C54I19002210001 com. 5900039 COD. GR-2018-12365577) (to T.M.); by a European Foundation for the Study of Astra Zeneca Awards (to T.M.). NJWA is supported by NNF Excellence Emerging Investigator Grant \u2013 Endocrinology and Metabolism (Application No. NNF19OC0055001 ), EFSD Future Leader Award ( NNF21SA0072746 ) and DFF Sapere Aude ( 1052-00003B ). Authors have no conflicts to declare. JJH was supported by a grant from the NovoNordisk Foundation (NNF 18 CC0034900 ). The authors would like to thank Christine Rasmussen (Department of Clinical Biochemistry, Bispebjerg Hospital) for technical assistance with measurement of hormones and Serena Rotunno and Giulia Gliozzo (Universit\u00E0 Cattolica del Sacro Cuore) for assistance with the editing.
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