Dataset Information

INGAP-Peptide Variants as a Novel Therapy for Type 1 Diabetes: Effect on Human Islet Insulin Secretion and Gene Expression.

ABSTRACT: Islet transplantation offers a long-term cure for Type 1 Diabetes (T1D), freeing patients from daily insulin injections. Therapeutic peptides have shown potential to increase the insulin output of pancreatic islets, maximizing the impact of grafted cells. The islet neogenesis-associated protein (INGAP), and its bioactive core (INGAP-P), stimulate beta-cell function and viability, offering the possibility for islet treatment prior to implant. However, dosing efficacy is limited by low circulation time and enzyme degradation. This proof-of-concept study presents the investigation of novel molecular variants of INGAP-P to find a more bioactive form. Custom-designed peptide variants of INGAP-P were synthesized and tested for their effect on the insulin secretion and gene expression of live human islets. We exposed the live islets of five donors to varying glucose concentrations with INGAP-P variants in solution. We identified four peptide variants (I9, I15Tyr, I19 and I15Cys) which displayed statistically significant enhancements over negative controls (representing a 1.6-2.8-fold increase in stimulation index). This is the first study that has assessed these INGAP-P variants in human islets. It highlights the potential for customized peptides for type 1 diabetes therapy and provides a foundation for future peptide-screening experiments.

SUBMITTER: Porter JM

PROVIDER: S-EPMC9502412 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

INGAP-Peptide Variants as a Novel Therapy for Type 1 Diabetes: Effect on Human Islet Insulin Secretion and Gene Expression.

Porter James M JM Guerassimoff Léa L Guerassimoff Léa L Castiello Francisco Rafael FR Charette André A Tabrizian Maryam M

Pharmaceutics 20220831 9

Islet transplantation offers a long-term cure for Type 1 Diabetes (T1D), freeing patients from daily insulin injections. Therapeutic peptides have shown potential to increase the insulin output of pancreatic islets, maximizing the impact of grafted cells. The islet neogenesis-associated protein (INGAP), and its bioactive core (INGAP-P), stimulate beta-cell function and viability, offering the possibility for islet treatment prior to implant. However, dosing efficacy is limited by low circulation ...[more]

PMID: 36145580

Similar Datasets

Project description:AIMS/HYPOTHESIS:Genetic studies show coupling of genes affecting beta cell function to type 1 diabetes, but hitherto no studies on whether beta cell dysfunction could precede insulitis and clinical onset of type 1 diabetes are available. METHODS:We used 40-day-old BioBreeding (BB) DRLyp/Lyp rats (a model of spontaneous autoimmune type 1 diabetes) and diabetes-resistant DRLyp/+ and DR+/+ littermates (controls) to investigate beta cell function in vivo, and insulin and glucagon secretion in vitro. Beta cell mass was assessed by optical projection tomography (OPT) and morphometry. Additionally, measurements of intra-islet blood flow were performed using microsphere injections. We also assessed immune cell infiltration, cytokine expression in islets (by immunohistochemistry and qPCR), as well as islet Glut2 expression and ATP/ADP ratio to determine effects on glucose uptake and metabolism in beta cells. RESULTS:DRLyp/Lyp rats were normoglycaemic and without traces of immune cell infiltrates. However, IVGTTs revealed a significant decrease in the acute insulin response to glucose compared with control rats (1685.3 ± 121.3 vs 633.3 ± 148.7; p < 0.0001). In agreement, insulin secretion was severely perturbed in isolated islets, and both first- and second-phase insulin release were lowered compared with control rats, while glucagon secretion was similar in both groups. Interestingly, after 5-7 days of culture of islets from DRLyp/Lyp rats in normal media, glucose-stimulated insulin secretion (GSIS) was improved; although, a significant decrease in GSIS was still evident compared with islets from control rats at this time (7393.9 ± 1593.7 vs 4416.8 ± 1230.5 pg islet-1 h-1; p < 0.0001). Compared with controls, OPT of whole pancreas from DRLyp/Lyp rats revealed significant reductions in medium (4.1 × 109 ± 9.5 × 107 vs 3.8 × 109 ± 5.8 × 107 μm3; p = 0.044) and small sized islets (1.6 × 109 ± 5.1 × 107 vs 1.4 × 109 ± 4.5 × 107 μm3; p = 0.035). Finally, we found lower intra-islet blood perfusion in vivo (113.1 ± 16.8 vs 76.9 ± 11.8 μl min-1 [g pancreas]-1; p = 0.023) and alterations in the beta cell ATP/ADP ratio in DRLyp/Lyp rats vs control rats. CONCLUSIONS/INTERPRETATION:The present study identifies a deterioration of beta cell function and mass, and intra-islet blood flow that precedes insulitis and diabetes development in animals prone to autoimmune type 1 diabetes. These underlying changes in islet function may be previously unrecognised factors of importance in type 1 diabetes development.

Dataset Information

INGAP-Peptide Variants as a Novel Therapy for Type 1 Diabetes: Effect on Human Islet Insulin Secretion and Gene Expression.

Publications

INGAP-Peptide Variants as a Novel Therapy for Type 1 Diabetes: Effect on Human Islet Insulin Secretion and Gene Expression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets