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; Bolette Hartmann; Jens Frederik Rehfeld

doi:10.1016/j.metabol.2024.156087

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^*, Bolette Hartmann, Jens Frederik Rehfeld

^*Corresponding author for this work

4 Citations (Scopus)

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 language	English
Article number	156087
Journal	Metabolism: Clinical and Experimental
Volume	163
ISSN	0026-0495
DOIs	https://doi.org/10.1016/j.metabol.2024.156087
Publication status	Published - Feb 2025

Keywords

Humans
Glucagon-Like Peptide 1/blood
Middle Aged
Male
Female
Aged
Glucose Intolerance/metabolism
Insulin-Secreting Cells/metabolism
Glucose Tolerance Test
Diabetes Mellitus, Type 2/metabolism
Islets of Langerhans/metabolism
Glucose Clamp Technique
Pancreatectomy
Insulin/metabolism
Blood Glucose/metabolism
Type 2 diabetes
Alpha-cells
Islets biology
Glucagon-like peptide 1

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10.1016/j.metabol.2024.156087Licence: CC BY

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Mezza, T., Wewer Albrechtsen, N. J., Di Giuseppe, G., Ferraro, P. M., Soldovieri, L., Ciccarelli, G., Brunetti, M., Quero, G., Alfieri, S., Nista, E. C., Gasbarrini, A., Tondolo, V., Mari, A., Pontecorvi, A., Giaccari, A., Holst, J. J., Hartmann, B., & Rehfeld, J. F. (2025). Human subjects with impaired beta-cell function and glucose tolerance have higher levels of intra-islet intact GLP-1. Metabolism: Clinical and Experimental, 163, Article 156087. https://doi.org/10.1016/j.metabol.2024.156087

Mezza, T, Wewer Albrechtsen, NJ, Di Giuseppe, G, Ferraro, PM, Soldovieri, L, Ciccarelli, G, Brunetti, M, Quero, G, Alfieri, S, Nista, EC, Gasbarrini, A, Tondolo, V, Mari, A, Pontecorvi, A, Giaccari, A, Holst, JJ, Hartmann, B & Rehfeld, JF 2025, 'Human subjects with impaired beta-cell function and glucose tolerance have higher levels of intra-islet intact GLP-1', Metabolism: Clinical and Experimental, vol. 163, 156087. https://doi.org/10.1016/j.metabol.2024.156087

@article{d4dc56bd350540bcadbf50768de52113,

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

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.",

keywords = "Humans, Glucagon-Like Peptide 1/blood, Middle Aged, Male, Female, Aged, Glucose Intolerance/metabolism, Insulin-Secreting Cells/metabolism, Glucose Tolerance Test, Diabetes Mellitus, Type 2/metabolism, Islets of Langerhans/metabolism, Glucose Clamp Technique, Pancreatectomy, Insulin/metabolism, Blood Glucose/metabolism, Type 2 diabetes, Alpha-cells, Islets biology, Glucagon-like peptide 1",

author = "Teresa Mezza and \{Wewer Albrechtsen\}, \{Nicolai J\} and \{Di Giuseppe\}, Gianfranco and Ferraro, \{Pietro Manuel\} and Laura Soldovieri and Gea Ciccarelli and Michela Brunetti and Giuseppe Quero and Sergio Alfieri and Nista, \{Enrico Celestino\} and Antonio Gasbarrini and Vincenzo Tondolo and Andrea Mari and Alfredo Pontecorvi and Andrea Giaccari and Holst, \{Jens J\} and Bolette Hartmann and Rehfeld, \{Jens Frederik\}",

year = "2025",

month = feb,

doi = "10.1016/j.metabol.2024.156087",

language = "English",

volume = "163",

journal = "Metabolism: Clinical and Experimental",

issn = "0026-0495",

publisher = "W.B. Saunders",

}

TY - JOUR

T1 - Human subjects with impaired beta-cell function and glucose tolerance have higher levels of intra-islet intact GLP-1

AU - Mezza, Teresa

AU - Wewer Albrechtsen, Nicolai J

AU - Di Giuseppe, Gianfranco

AU - Ferraro, Pietro Manuel

AU - Soldovieri, Laura

AU - Ciccarelli, Gea

AU - Brunetti, Michela

AU - Quero, Giuseppe

AU - Alfieri, Sergio

AU - Nista, Enrico Celestino

AU - Gasbarrini, Antonio

AU - Tondolo, Vincenzo

AU - Mari, Andrea

AU - Pontecorvi, Alfredo

AU - Giaccari, Andrea

AU - Holst, Jens J

AU - Hartmann, Bolette

AU - Rehfeld, Jens Frederik

PY - 2025/2

Y1 - 2025/2

N2 - 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.

AB - 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.

KW - Humans

KW - Glucagon-Like Peptide 1/blood

KW - Middle Aged

KW - Male

KW - Female

KW - Aged

KW - Glucose Intolerance/metabolism

KW - Insulin-Secreting Cells/metabolism

KW - Glucose Tolerance Test

KW - Diabetes Mellitus, Type 2/metabolism

KW - Islets of Langerhans/metabolism

KW - Glucose Clamp Technique

KW - Pancreatectomy

KW - Insulin/metabolism

KW - Blood Glucose/metabolism

KW - Type 2 diabetes

KW - Alpha-cells

KW - Islets biology

KW - Glucagon-like peptide 1

UR - https://www.scopus.com/pages/publications/85211066381

UR - https://www.metabolismjournal.com/article/S0026-0495(25)00241-0/pdf

U2 - 10.1016/j.metabol.2024.156087

DO - 10.1016/j.metabol.2024.156087

M3 - Journal article

C2 - 39626843

SN - 0026-0495

VL - 163

JO - Metabolism: Clinical and Experimental

JF - Metabolism: Clinical and Experimental

M1 - 156087

ER -

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

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