Gene expression profiles for the human pancreas and purified islets in Type 1 diabetes: new findings at clinical onset and in long-standing diabetes

Planas, Raquel; Carrillo, Jorge; Sánchez-Pla, Álex; Villa, M. C. Ruiz de; Núñez, Fernando Rueda; Verdaguer, Joan; James, R. F. L.; Pujol-Borrell, Ricardo; Vives-Pi, Marta

doi:10.1111/j.1365-2249.2009.04053.x

Cited by 91 publications

(84 citation statements)

References 51 publications

(54 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This finding is in accordance with available whole-genome profiling data that show TMEM27 as one of the 370 genes differentially expressed between diabetic and control human islets [26]. In the same line, a recent report shows that TMEM27 expression is tenfold lower in islets from recent diagnosed type 1 diabetic pancreatic donors as compared with healthy controls [27]. Taken together, these data point to TMEM27 as a potentially important protein for consideration in beta cell physiology and diabetes in humans.…”

Section: Tmem27 Rolesupporting

confidence: 79%

The role of transmembrane protein 27 (TMEM27) in islet physiology and its potential use as a beta cell mass biomarker

et al. 2010

View full text Add to dashboard Cite

Aims/hypothesis Transmembrane protein 27 (TMEM27) is a membrane protein cleaved and shed by pancreatic beta cells that has been proposed as a beta cell mass biomarker. Despite reports of its possible role in insulin exocytosis and cell proliferation, its function in beta cells remains controversial. We aimed to characterise the function of TMEM27 in islets and its potential use as a beta cell mass biomarker. Methods To determine TMEM27 function, we studied TMEM27 gene expression and localisation in human healthy and diabetic islets, the correlation of its expression with cell cycle and insulin secretion genes in human islets, its expression in tungstate-treated rats, and the effects of its overproduction on insulin secretion and proliferation in a beta cell line and islets. To elucidate its utility as a beta cell mass biomarker, we studied TMEM27 cleavage in a beta cell line, islets and primary proximal tubular cells. Results TMEM27 mRNA levels in islets are lower in diabetic donors than in controls. Its gene expression correlates with that of insulin and SNAPIN in human islets. TMEM27 expression is downregulated in islets of tungstate-treated rats, which exhibit decreased insulin secretion and increased proliferation. TMEM27 overproduction in a beta cell line and islets significantly enhanced glucose-induced insulin secretion, with modest or no effects on proliferation. Finally, TMEM27 is cleaved and shed by renal proximal tubular cells and pancreatic islets.A. Barbera and R. Gomis contributed equally to this study. Electronic supplementary material The online version of this article

show abstract

Section: Tmem27 Rolesupporting

confidence: 79%

The role of transmembrane protein 27 (TMEM27) in islet physiology and its potential use as a beta cell mass biomarker

et al. 2010

View full text Add to dashboard Cite

show abstract

“…7C), characteristic for viral infection, and is similarly detected in pancreata and islets from patients at clinical onset and long-standing diabetes (12). Furthermore, the gene-expression program induced by enteroviral infection of human islets (14,15) is also prominently mimicked by the IKK2-CA Pdx-1 model, suggesting that IKK/NF-kB is a critical downstream effector in this context.…”

Section: Discussionmentioning

confidence: 79%

“…3I). This inflammatory profile is reminiscent of those found in islets from patients, in animals with type 1 diabetes (11,12), and in normal human islets subjected to cytokines or enteroviruses (13)(14)(15).…”

Section: Ikk2-ca-induced Diabetes Is Associated With Inflammation Andmentioning

confidence: 84%

Long-Term IKK2/NF-κB Signaling in Pancreatic β-Cells Induces Immune-Mediated Diabetes

et al. 2014

View full text Add to dashboard Cite

Type 1 diabetes is a multifactorial inflammatory disease in genetically susceptible individuals characterized by progressive autoimmune destruction of pancreatic b-cells initiated by yet unknown factors. Although animal models of type 1 diabetes have substantially increased our understanding of disease pathogenesis, heterogeneity seen in human patients cannot be reflected by a single model and calls for additional models covering different aspects of human pathophysiology. Inhibitor of kB kinase (IKK)/nuclear factor-kB (NF-kB) signaling is a master regulator of inflammation; however, its role in diabetes pathogenesis is controversially discussed by studies using different inhibition approaches. To investigate the potential diabetogenic effects of NF-kB in b-cells, we generated a gain-of-function model allowing conditional IKK2/NF-kB activation in b-cells. A transgenic mouse model that expresses a constitutively active mutant of human IKK2 dependent on Pdx-1 promoter activity (IKK2-CA Pdx-1 ) spontaneously develops full-blown immunemediated diabetes with insulitis, hyperglycemia, and hypoinsulinemia. Disease development involves a gene expression program mimicking virus-induced diabetes and allergic inflammatory responses as well as increased major histocompatibility complex class I/II expression by b-cells that could collectively promote diabetes development. Potential novel diabetes candidate genes were also identified. Interestingly, animals successfully recovered from diabetes upon transgene inactivation. Our data give the first direct evidence that b-cell-specific IKK2/NF-kB activation is a potential trigger of immune-mediated diabetes. Moreover, IKK2-CA Pdx-1 mice provide a novel tool for studying critical checkpoints in diabetes pathogenesis and mechanisms governing b-cell degeneration/ regeneration. Diabetes 2014;63:960-975 | DOI: 10.233763:960-975 | DOI: 10. /db13-1037 Type 1 diabetes is an autoimmune disease in genetically predisposed individuals and presumably triggered and/or accelerated by environmental factors (1). Analyses of animal models of type 1 diabetes have greatly improved our knowledge about disease pathophysiology and genetic contribution. However, there is still an unmet need to understand islet cell pathology and ongoing inflammatory processes within the islets of Langerhans.

show abstract

“…Autoreactive T cells were identified in vitro by expansion against insulin, GAD, I-A2, IGRP (7)(8)(9)(10), and ex vivo by positive staining with self-peptide-MHC tetramers (11,12). Although there are no data on the specificity of intrapancreatic T cells in human T1D, phenotypic analysis of infiltrating lymphocytes have shown that the human pancreas is infiltrated with both CD8 + and CD4 + T cells (13)(14)(15)(16)(17)(18). In addition, several analyses of the TCR repertoire of pancreatic T cells demonstrate the dominance of some Vb families, despite the lack of consensus imposed by the interindividual variability of MHC (15,16,19,20).…”

Section: T Ype 1 Diabetes (T1d) Is An Autoimmune Disease Defined By Tmentioning

confidence: 99%

TCR Bias of In Vivo Expanded T Cells in Pancreatic Islets and Spleen at the Onset in Human Type 1 Diabetes

Codina-Busqueta

Scholz

Torres

et al. 2011

The Journal of Immunology

View full text Add to dashboard Cite

Autoreactive T cells, responsible for the destruction of pancreatic β cells in type 1 diabetes, are known to have a skewed TCR repertoire in the NOD mouse. To define the autoreactive T cell repertoire in human diabetes, we searched for intraislet monoclonal expansions from a recent onset in human pancreas to then trace them down to the patient’s peripheral blood and spleen. Islet infiltration was diverse, but five monoclonal TCR β-chain variable expansions were detected for Vβ1, Vβ7, Vβ11, Vβ17, and Vβ22 families. To identify any sequence bias in the TCRs from intrapancreatic T cells, we analyzed 139 different CDR3 sequences. We observed amino acid preferences in the NDN region that suggested a skewed TCR repertoire within infiltrating T cells. The monoclonal expanded TCR sequences contained amino acid combinations that fit the observed bias. Using these CDR3 sequences as a marker, we traced some of these expansions in the spleen. There, we identified a Vβ22 monoclonal expansion with identical CDR3 sequence to that found in the islets within a polyclonal TCR β-chain variable repertoire. The same Vβ22 TCR was detected in the patient’s PBMCs, making a cross talk between the pancreas and spleen that was reflected in peripheral blood evident. No other pancreatic monoclonal expansions were found in peripheral blood or the spleen, suggesting that the Vβ22 clone may have expanded or accumulated in situ by an autoantigen present in both the spleen and pancreas. Thus, the patient’s spleen might be contributing to disease perpetuation by expanding or retaining some autoreactive T cells.

show abstract

Gene expression profiles for the human pancreas and purified islets in Type 1 diabetes: new findings at clinical onset and in long-standing diabetes

Cited by 91 publications

References 51 publications

The role of transmembrane protein 27 (TMEM27) in islet physiology and its potential use as a beta cell mass biomarker

The role of transmembrane protein 27 (TMEM27) in islet physiology and its potential use as a beta cell mass biomarker

Long-Term IKK2/NF-κB Signaling in Pancreatic β-Cells Induces Immune-Mediated Diabetes

TCR Bias of In Vivo Expanded T Cells in Pancreatic Islets and Spleen at the Onset in Human Type 1 Diabetes

Contact Info

Product

Resources

About