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The Human and Mouse Islet Peptidome: Effects of Obesity and Type 2 Diabetes, and Assessment of Intraislet Production of Glucagon-like Peptide-1.

Accepted version
Peer-reviewed

Change log

Authors

Galvin, Sam G 
Kay, Richard G 
Foreman, Rachel 
Larraufie, Pierre 
Meek, Claire L 

Abstract

To characterize the impact of metabolic disease on the peptidome of human and mouse pancreatic islets, LC-MS was used to analyze extracts of human and mouse islets, purified mouse alpha, beta, and delta cells, supernatants from mouse islet incubations, and plasma from patients with type 2 diabetes. Islets were obtained from healthy and type 2 diabetic human donors, and mice on chow or high fat diet. All major islet hormones were detected in lysed islets as well as numerous peptides from vesicular proteins including granins and processing enzymes. Glucose-dependent insulinotropic peptide (GIP) was not detectable. High fat diet modestly increased islet content of proinsulin-derived peptides in mice. Human diabetic islets contained increased content of proglucagon-derived peptides at the expense of insulin, but no evident prohormone processing defects. Diabetic plasma, however, contained increased ratios of proinsulin and des-31,32-proinsulin to insulin. Active GLP-1 was detectable in human and mouse islets but 100-1000-fold less abundant than glucagon. LC-MS offers advantages over antibody-based approaches for identifying exact peptide sequences, and revealed a shift toward islet insulin production in high fat fed mice, and toward proglucagon production in type 2 diabetes, with no evidence of systematic defective prohormone processing.

Description

Keywords

glucagon, insulin, mass spectrometry, pancreatic islets, peptidomics, type 2 diabetes, Animals, Diabetes Mellitus, Type 2, Glucagon, Glucagon-Like Peptide 1, Humans, Insulin, Islets of Langerhans, Mice, Obesity

Journal Title

J Proteome Res

Conference Name

Journal ISSN

1535-3893
1535-3907

Volume Title

20

Publisher

American Chemical Society (ACS)

Rights

All rights reserved
Sponsorship
Biotechnology and Biological Sciences Research Council (1799260)
Wellcome Trust (220271/Z/20/Z)
BBSRC (2124411)
MRC (MC_UU_00014/3)
Wellcome Trust (100574/Z/12/Z)
Medical Research Council (MC_UU_12012/3)
Medical Research Council (MC_UU_12012/5)
Medical Research Council (MR/M009041/1)
MRC (MC_UU_00014/5)
Medical Research Council (MC_PC_12012)
AstraZeneca LGC EFSD Diabetes UK NIHR