Dataset Information

Strategic Reduction of Hybrid Insulin Peptide Formation Significantly Delays Diabetes Onset in NOD Mice

ABSTRACT: Hybrid insulin peptides (HIPs) form in pancreatic beta cells through the covalent cross-linking of proinsulin peptides with various beta cell peptides, creating unique amino acid sequences not encoded in the genome. HIPs have been confidently identified in both human and mouse islets by mass spectrometry and are targeted by autoreactive T cells in type 1 diabetes (T1D) patients and disease-triggering CD4 T cells in non-obese diabetic (NOD) mice. Previous work identified cathepsin D (CatD) as an enzyme involved in HIP formation through transpeptidation reactions targeting a conserved leucine residue (L26) in the C-peptide region of proinsulin. In this study, we generated NOD mice with a leucine-to-isoleucine substitution at this position in the insulin 2 gene (NOD INS2I/I) to prevent CatD-mediated HIP formation. Mass spectrometry analysis of islet peptidomes revealed that the L26I modification effectively blocked CatD-mediated cleavage at this site and significantly reduced the levels of disease-relevant HIPs, including HIP11 and 6.9HIP. These findings were validated through T cell assays showing reduced antigenicity of islets from modified mice when exposed to HIP-reactive T cell clones. The functional consequences of reduced HIP formation were demonstrated in a year-long monitoring study, where NOD INS2I/I mice exhibited significantly delayed disease onset compared to wild-type NOD mice, with 43% versus 10% remaining disease-free after one year. In vitro experiments with human C-peptide further confirmed that the L26I substitution prevents CatD-mediated HIP formation in human samples as well. Our results establish CatD as the primary enzymatic driver of disease-relevant HIP formation and demonstrate that preventing CatD-mediated processing of proinsulin 2 C-peptide in NOD mice significantly reduces HIP formation and delays autoimmune diabetes progression, identifying a potential therapeutic target for T1D prevention.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Pancreatic Islet

DISEASE(S): Type 1 Diabetes Mellitus

SUBMITTER: Jason Groegler

LAB HEAD: Thomas Delong

PROVIDER: PXD063329 | Pride | 2025-12-22

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	Hu_Cpep_A01_LI_0nM_catD_AspN.mgf	Mgf
	Hu_Cpep_A01_LI_0nM_catD_AspN.mzdata.xml	Xml
	Hu_Cpep_A02_LI_112nM_catD_AspN.mgf	Mgf
	Hu_Cpep_A02_LI_112nM_catD_AspN.mzdata.xml	Xml
	Hu_Cpep_A03_WT_0nM_catD_AspN.mgf	Mgf

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Strategic Reduction of Hybrid Insulin Peptide Formation Significantly Delays Diabetes Onset in NOD Mice.

Groegler Jason J Mangold Kaitlin K Nicholson Kelli K Dang Mylinh M Wenzlau Janet J Beard K Scott KS Hohenstein Anita A Powell Roger R Baker Rocky R Haskins Kathryn K Matsuda Jennifer J Delong Thomas T

Diabetes 20260101 1

Type 1 diabetes (T1D) is characterized by autoimmune destruction of insulin-producing β-cells. Recent evidence has implicated hybrid insulin peptides (HIPs) as targets of autoreactive CD4 T cells in human T1D patients and as critical autoantigens recognized by diabetogenic T cells in nonobese diabetic (NOD) mice. HIPs form within pancreatic islets through cross-linking reactions between proinsulin fragments and various β-cell peptides. In the NOD mouse model, highly pathogenic CD4 T cells specif ...[more]

PMID: 41118637

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Project description:This a model from the article: Modelling the onset of Type 1 diabetes: can impaired macrophage phagocytosis make the difference between health and disease? Maree AF, Kublik R, Finegood DT, Edelstein-Keshet L.Philos Transact A Math Phys Eng Sci.2006 May 15;364(1842):1267-82. 16608707, Abstract: A wave of apoptosis (programmed cell death) occurs normally in pancreatic beta-cells of newborn mice. We previously showed that macrophages from non-obese diabetic (NOD) mice become activated more slowly and engulf apoptotic cells at a lower rate than macrophages from control (Balb/c) mice. It has been hypothesized that this low clearance could result in secondary necrosis, escalating inflammation and self-antigen presentation that later triggers autoimmune, Type 1 diabetes (T1D). We here investigate whether this hypothesis could offer a reasonable and parsimonious explanation for onset of T1D in NOD mice. We quantify variants of the Copenhagen model (Freiesleben De Blasio et al. 1999 Diabetes 48, 1677), based on parameters from NOD and Balb/c experimental data. We show that the original Copenhagen model fails to explain observed phenomena within a reasonable range of parameter values, predicting an unrealistic all-or-none disease occurrence for both strains. However, if we take into account that, in general, activated macrophages produce harmful cytokines only when engulfing necrotic (but not apoptotic) cells, then the revised model becomes qualitatively and quantitatively reasonable. Further, we show that known differences between NOD and Balb/c mouse macrophage kinetics are large enough to account for the fact that an apoptotic wave can trigger escalating inflammatory response in NOD, but not Balb/c mice. In Balb/c mice, macrophages clear the apoptotic wave so efficiently, that chronic inflammation is prevented. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. For more information see the terms of use. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.