Destruction Of Insulin-secreting Β-cells Research Articles

Advances in Stem Cell and Regenerative Therapies in Autoimmune and Metabolic Diseases: Implications for Healthy Longevity

Type 1 diabetes (T1D) is an important autoimmune disease characterized by the destruction of insulin-secreting β-cells in pancreatic islets of Langerhans resulting in hyperglycemia. More than 1.3 people in United States are suffering from T1D, and current treatments have failed to offer a lasting cure. T1D management requires lifelong daily injections of exogenous insulin to control blood sugar levels and secondary complications of this progressive disease, unless receiving pancreas or islet transplant with its associated risks from immunosuppression. Peptide therapy aims to alter the response of cells by inducing or reducing cellular responses appropriate to the type of peptides used. The aim of this study was to investigate the protective effect on autoimmunity of Mito Organelle (MO) Peptides on the function and survival of peptides on pancreatic β-cells in non-obese diabetes (NOD) mice model. MO peptide product (Biopep Inc) is a mixture of organ-specific cellular extracts that were extracted from organ specific cells, homogenized, filtered, and sterilized. MO Peptides administered twice-weekly (IM) over 17-week period in NOD mice model were able to prevent the progression of autoimmune-mediated β–cell destruction and the onset of hyperglycemia (blood glucose >300 mg dL) as compared to the saline treated control mice. These studies will help understand the mechanisms of immunological protection in T1D and may serve as a model for other autoimmune disorders with peptides.

Dietary ingestion of 2-aminoanthracene (2AA) and the risk for type-1 diabetes (T1D)

Type 1 diabetes (T1D) is an autoimmune disorder caused by the destruction of insulin-secreting β-cells.T1D is on the rise around the world. Exposure to polycyclic aromatic hydrocarbons (PAHs) including 2-aminoanthracene (2AA) is considered a contributor to TID increase. The contribution of the ingestion of 2AA toward T1D vulnerability is examined. 2AA is found in a variety of household products. Juvenile male Sprague Dawley rats ingested various amounts of 2AA contaminated diet for 12 weeks. Results showed marginal reduction in body weight gain for the 100 mg/kg treated animals. Glucose tolerance test (GTT) indicated no changes at six weeks. However, at week 12, both treated groups had higher levels of blood glucose than the control group. Serum insulin concentration was elevated in the 50 mg/kg group while reduced in the 100 mg/kg animals. Serum lactate dehydrogenase activity was elevated in treated groups. Evaluation of pancreatic inflammatory cytokines revealed overexpression of IL-1B, IL-6, and IL-7. Apoptotic genes in the pancreas of exposed rats were overly expressed. Histopathology and insulin immunohistochemistry data showed the presence of mesenteric vessels surrounded by lymphocyte and enlarged size of islet cells respectively in the high dose group. These results suggest 2AA ingestion may enhance T1D development.

1696-P: PBMC of Recent-Onset Patients with Type 1 Diabetes Present a Differential Gene Expression Profile

Introduction: Type 1 diabetes is characterized by the autoimmune destruction of insulin-secreting β-cells, mediated by T auto reactive infiltrating cells, inflammatory cytokines and immunological mechanisms. However, little is known about the expression of genes and pathways dysregulated in peripheral blood mononuclear cells of patients with T1D. Objective: to investigate the gene expression profiles of circulating PBMC in recent-onset T1D patients (up to 6 months of diagnosis) in comparison with controls in the context of putative disease-related pathobiological processes and pathways. Methods: expression of mRNA from PBMC of 20 T1D patients, 15.8±8.6 years and age-matched 20 healthy controls, 14.7±6.7 years, (p>0.05) was evaluated with the Whole Human Genome Microarray Agilent and analyzed by GeneSpring with a fold change cutoff of 1.5 and adjusted P value <0.05; pathways analysis was performed with the software IPA. Results: 326 genes were differentially expressed between T1D patients and controls, being 204 (63%) upregulated, and 122 (37%) downregulated in T1D. Interactions between the differentially expressed genes evidenced expression patterns of 24 networks. The most significantly enriched canonical pathways were namely ErbB (erythroblastic leukemia viral oncogene) signaling, micropinocytosis signaling, savage pathways of pyrimidine ribonucleotides and hepathocyte growth factor in descending order of significance. The up-regulated protein targets within these signaling pathways were NEK2, PLK1, ATM, PRKCD, CCND1, NRG2 and those down regulated were AREG, CDC42 and CDADC1. Conclusion: The majority of upregulated genes of patients with T1D was related to cell cycle control, mitotic progression, proliferation and DNA repair, probably related to changes in PBMC metabolism and function due to DNA damage associated with hyperglycemia. The lower expression of AREG and CDC42 can be related to reduce immunosuppressive activity of regulatory T cells and B cell functions. Disclosure A. Santos: None. C. Chevillard: None. N. Gonfinetti: None. F. Bertonha: None. C. Moreira-Filho: None. J. Kalil: None. E. Cunha-Neto: None. M. Silva: None. Funding European Foundation for the Study of Diabetes; São Paulo Research Foundation

Reprogramming Cells to Make Insulin.

Type 1 diabetes is a disease characterized by the destruction of insulin-secreting β-cells in the pancreas. Individuals are treated for this disease with lifelong insulin replacement. However, one attractive treatment possibility is to reprogram an individual’s endogenous cells to acquire the ability to secrete insulin, essentially replacing destroyed β-cells. Herein, we review the literature on the topic of reprogramming endodermal cells to produce insulin.

SAT-LB036 Late Weaning Leads to Enrichment of Treg Cells Which Consequently Regulates Effector T Cell Responses in Peri-Pancreatic Lymph Nodes and Pancreas of Humanized Model T1D

The hallmark of type 1 diabetes (T1D) is immune-mediated destruction of insulin secreting β-cells in pancreatic islets. Children who progress to clinical T1D have detectable levels of islet-specific autoantibodies before age three. Early development of gut microbiota also has limited resilience and is vulnerable to perturbation. We recently developed humanized mice that spontaneously develop T1D. This mouse model mimics clinical human T1D, allowing us to carry out controlled studies where we investigated diabetes development and gut microbiota after normal weaning (NW) and late weaning (LW) stages. Our data revealed that the gut microbiota changes as weaning is delayed and that disease progression correlates with these changes. We hypothesized that a delay in T1D onset in our model might have been due to an enrichment of regulatory T (Treg) cells secondary to increased diversity of gut microbiome. We tested this hypothesis by setting up experiments where the breeder’s cages with larger litter sizes (8 pups) were separated into two groups. We allowed the breeder mice for a second-time pregnancy, and after birth, the second litters were sacrificed, and first litter (late weaning group) were allowed to stay with their mothers until day 45 as normal weaning group was separated at day 21. Late weaning was then separated from mothers and allowed to settle into new cages. At day 60 and 150, mice from both groups (n=10-12) were sacrificed. Organs (Peyer’s patches, peri-pancreatic lymph nodes (PLN), pancreas (PN) and spleen) were harvested and lymphocytes isolated. Flow cytometry of Peyer’s patches, a site of first immune cell interaction/activation with gut antigens, revealed that Tregs were significantly increased in late weaning group. In PLN, a site for islet antigen-specific T cell activation and recruitment in case of pancreas autoimmunity, flow cytometry data revealed that late weaning leads to enrichment of Tregs and consequently regulation of cytotoxic CD8 T lymphocytes (CTLs). Most interestingly, late weaning enriched the Treg population at the spleen level too. The enrichment of Tregs may have been due to a more diverse microbiome, which is known to increase immune tolerance, which might have regulated the diabetogenic Th1, Th17, and CTLs at PLN, PN, and spleen. Our data is the first to provide a scientific explanation for observed prolong nursing as affecting T1D outcomes in humans. We also investigated the possibility that induction of immune tolerance would protect pancreatic islet architecture. Newborn mice littermates were divided into late weaning and normal weaning groups. Pancreatic sections were stained with hematoxylin/eosin (H&E) for histological identification and localization of islets and lymphocytic infiltrates. Late weaning group, preserved the pancreatic islet architecture with fewer lymphocytic infiltrates and a significantly higher number of islet per H&E section. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Impact of Mig6 on ß-Cell Regeneration and Repair

Following autoimmune-mediated destruction of insulin secreting β-cells in type 1 diabetes (T1D), regenerative and repair pathways aim to restore β-cell mass and maintain euglycemia. However, these pathways are often unable to compensate for the loss of β-cell mass, resulting in insufficient insulin secretion and chronic hyperglycemia. Our lab previously demonstrated that this inability to compensate for the loss of β-cell mass may be at least in part due to mitogen inducible gene 6 (Mig6), an anti-proliferative negative feedback inhibitor of epithelial growth factor receptor signaling, which is induced by proinflammatory cytokines central to macrophage-mediated β-cell destruction in T1D. Both Mig6 haploinsufficient mice (Mig6+/-) and mice with pancreas-specific Mig6 knockout (PKO) have increased β-cell mass and improved glucose tolerance when compared to littermate controls in a β-cell ablation model. We sought to determine the extent to which β-cell specific loss of Mig6 confers resistance to depletion of β-cell mass by streptozotocin (STZ, 35 mg/kg). We hypothesized that mice with β-cell specific loss of Mig6 (βKO) would have increased β-cell mass and improved glucose tolerance following STZ treatment when compared to control mice. We treated βKO and littermate controls with multiple low doses of STZ and measured both glucose tolerance and β-cell mass for up to 20 days following STZ treatment. At baseline, Mig6 expression was reduced by 63 ± 3% in βKO mice, and βKO mice had normal glucose homeostasis, insulin sensitivity, and islet architecture compared to littermate control. Unlike Mig6+/- and PKO mice, βKO mice had no improvements in β-cell mass or glucose tolerance compared to STZ-treated control littermates. Therefore, whereas both Mig6+/- and Mig6 PKO mice are able to preserve or restore β-cells with STZ treatment, loss of Mig6 in β-cells alone does not confer the same level of protection, suggesting a potential role for Mig6 in beta β-cell transdifferentiation or neogenesis. Disclosure B.M. Bauer: None. K. El: None. P.T. Fueger: None.