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Valérie Bergeron, Julien Ghislain, Vincent Poitout
Free fatty acid receptor 1 (FFA1/GPR40) plays a key role in the potentiation of glucose-stimulated insulin secretion by fatty acids in pancreatic beta cells. We previously demonstrated that GPR40 signaling leads to cortical actin remodeling and potentiates the second phase of insulin secretion. In this study, we examined the role of p21 activated kinase 4 (PAK4), a known regulator of cytoskeletal dynamics, in GPR40-dependent potentiation of insulin secretion. The fatty acid oleate induced PAK4 phosphorylation in human islets, in isolated mouse islets and in the insulin secreting cell line INS832/13...
October 4, 2016: Islets
Hye Seung Jung, Yu Mi Kang, Ho Seon Park, Byung Yong Ahn, Hakmo Lee, Min Joo Kim, Jin Young Jang, Sun-Whe Kim
Post-translational modification by bonding of small ubiquitin-like modifier (SUMO) peptides influences various cellular functions, and is regulated by SUMO-specific proteases (SENPs). Several proteins have been suggested to have diverse impact on insulin synthesis and secretion through SUMO modification in beta cells. However, the role of SUMO modification in beta cell mass has not been established. Here, we examined the changes in expression of Senp in INS1 cells and pancreatic islets under diabetes-relevant stress conditions and associated changes in beta cell mass...
September 20, 2016: Islets
Kenjiro Kumano, Hitomi Nishinakamura, Toshiyuki Mera, Takeshi Itoh, Hiroyuki Takahashi, Toshiyoshi Fujiwara, Shohta Kodama
Although current immunosuppression protocols improve the efficacy of clinical allogenic islet transplantation, T cell-mediated allorejection remains unresolved, and major histocompatibility complexes (MHCs) play a crucial role in this process. Papain, a cysteine protease, has the unique ability to cleave the extracellular domain of the MHC class I structure. We hypothesized that pretreatment of donor islets with papain would diminish the expression of MHC class I on islets, reducing allograft immunogenicity and contributing to prolongation of islet allograft survival...
September 2, 2016: Islets
Kazuma Tago, Ken-Ichi Inoue, Motoshi Ouchi, Yoshikazu Miura, Keiichi Kubota
The receptor for advanced glycation endproducts (RAGE) is a pattern recognition receptor that plays an important role in natural immunity. It is suggested that mesenchymal cells are the major players during inflammation. Previously, we reported that advanced glycation end products (AGE), known to be one of the ligands of RAGE, inhibited glucose-induced insulin secretion from ex vivo pancreatic islets, although the mechanism responsible remains largely unknown. In the present study, we examined the cascades operating downstream from RAGE using the insulinoma cell line INS1E and primary-cultured pancreatic fibroblasts as in vitro models for parenchymal (β) cells and mesenchymal cells, respectively...
September 2, 2016: Islets
Joshua A Levine, Kelly A Kaihara, Brian T Layden, Barton Wicksteed
Type 2 diabetes is associated with obesity, insulin resistance and β-cell failure. Therapeutic aims are to reduce adiposity, improve insulin sensitivity and enhance β-cell function. However, it has been proposed that chronically increasing insulin release leads to β-cell exhaustion and failure. We previously developed mice to have increased activity of the cAMP-dependent protein kinase (PKA), specifically in β-cells (β-caPKA mice). β-caPKA mice have enhanced acute phase insulin release, which is the primary determinant of the efficacy of glucose clearance...
September 2, 2016: Islets
Rena L Pawlick, John Wink, Andrew R Pepper, Antonio Bruni, Nasser Abualhassen, Yasmin Rafiei, Boris Gala-Lopez, Mariusz Bral, A M James Shapiro
Quality of life in Type 1 diabetic patients may be improved with islet transplantation, but lifelong immunosuppression is required to prevent rejection. Allo-immune response is a key player in graft dysfunction and although the adaptive immune response is well characterized, the effect of the innate immune reaction after transplantation is only recently becoming appreciated. In this study, we address how the innate response affects long-term outcomes in a murine islet allotransplant model. CTLA-4 Ig treatment is known to significantly prolong kidney subcapsular islet allograft survival and enhance glucose tolerance...
September 2, 2016: Islets
Olga Hrytsenko, Bill Pohajdak, James R Wright
Tilapia, a teleost fish, have multiple large anatomically discrete islets which are easy to harvest, and when transplanted into diabetic murine recipients, provide normoglycemia and mammalian-like glucose tolerance profiles. Tilapia insulin differs structurally from human insulin which could preclude their use as islet donors for xenotransplantation. Therefore, we produced transgenic tilapia with islets expressing a humanized insulin gene. It is now known that fish genomes may possess an ancestral duplication and so tilapia may have a second insulin gene...
July 3, 2016: Islets
Antonio Bruni, Andrew R Pepper, Boris Gala-Lopez, Rena Pawlick, Nasser Abualhassan, James D Crapo, Jon D Piganelli, A M James Shapiro
Islet transplantation is a highly effective treatment for stabilizing glycemic control for select patients with type-1 diabetes. Despite improvements to clinical transplantation, single-donor transplant success has been hard to achieve routinely, necessitating increasing demands on viable organ availability. Donation after circulatory death (DCD) may be an alternative option to increase organ availability however, these organs tend to be more compromised. The use of metalloporphyrin anti-inflammatory and antioxidant (MnP) compounds previously demonstrated improved in vivo islet function in preclinical islet transplantation...
July 3, 2016: Islets
Martijn van de Bunt, Majlinda Lako, Amy Barrett, Anna L Gloyn, Mattias Hansson, Mark I McCarthy, Nicola L Beer, Christian Honoré
Directed differentiation of stem cells offers a scalable solution to the need for human cell models recapitulating islet biology and T2D pathogenesis. We profiled mRNA expression at 6 stages of an induced pluripotent stem cell (iPSC) model of endocrine pancreas development from 2 donors, and characterized the distinct transcriptomic profiles associated with each stage. Established regulators of endodermal lineage commitment, such as SOX17 (log2 fold change [FC] compared to iPSCs = 14.2, p-value = 4.9 × 10(-5)) and the pancreatic agenesis gene GATA6 (log2 FC = 12...
April 18, 2016: Islets
You Jeong Kim, Su Min Park, Hye Sook Jung, Eun Ju Lee, Tae Kyoon Kim, Tae-Nyun Kim, Min Jeong Kwon, Soon Hee Lee, Byoung Doo Rhee, Mi-Kyung Kim, Jeong Hyun Park
BACKGROUND: Ginsenoside Rg3 has been proposed to mediate anti-diabetic effects, but their direct effect on pancreatic β cell viability and mechanisms are not clearly understood. Recent studies suggest that intermittent high glucose (IHG) could be more harmful to pancreatic β cells than sustained high glucose. There are few reports about the effect of the ginsenosideRg3 to β cell apoptosis and proliferation against IHG. METHODS: INS-1 cells were treated with alternative glucose concentration with or without ginsenoside Rg3...
April 18, 2016: Islets
Christine A Beamish, Brenda J Strutt, Edith J Arany, David J Hill
Regeneration of insulin-producing β-cells from resident pancreas progenitors requires an understanding of both progenitor identity and lineage plasticity. One model suggested that a rare β-cell sub-population within islets demonstrated multi-lineage plasticity. We hypothesized that β-cells from young mice (postnatal day 7, P7) exhibit such plasticity and used a model of islet dedifferentiation toward a ductal epithelial-cell phenotype to test this theory. RIPCre;Z/AP(+/+) mice were used to lineage trace the fate of β-cells during dedifferentiation culture by a human placental alkaline phosphatase (HPAP) reporter...
April 18, 2016: Islets
Corentin Cras-Méneur, Lynda Elghazi, Patrice Fort, Ernesto Bernal-Mizrachi
The fetal environment plays a decisive role in modifying the risk for developing diabetes later in life. Developing novel methodology for noninvasive imaging of β-cell development in vivo under the controlled physiological conditions of the host can serve to understand how this environment affects β-cell growth and differentiation. A number of culture models have been designed for pancreatic rudiment but none match the complexity of the in utero or even normal physiological environment. Speier et al. recently developed a platform of noninvasive in vivo imaging of pancreatic islets using the anterior chamber of the eye where islets get vascularized, grow and respond to physiological changes...
March 3, 2016: Islets
Quin F Wills, Tobias Boothe, Ali Asadi, Ziliang Ao, Garth L Warnock, Timothy J Kieffer, James D Johnson
Worldwide efforts are underway to replace or repair lost or dysfunctional pancreatic β-cells to cure diabetes. However, it is unclear what the final product of these efforts should be, as β-cells are thought to be heterogeneous. To enable the analysis of β-cell heterogeneity in an unbiased and quantitative way, we developed model-free and model-based statistical clustering approaches, and created new software called TraceCluster. Using an example data set, we illustrate the utility of these approaches by clustering dynamic intracellular Ca(2+) responses to high glucose in ∼300 simultaneously imaged single islet cells...
March 3, 2016: Islets
Takayuki Tanaka, Minoru Fujita, Rita Bottino, Jon D Piganelli, Kevin McGrath, Jiang Li, Whayoung Lee, Hayato Iwase, Martin Wijkstrom, Suzanne Bertera, Cassandra Long, Douglas Landsittel, Ken Haruma, David K C Cooper, Hidetaka Hara
Transplantation of islets into the gastric submucosal space (GSMS) has several advantages (e.g., avoidance of the instant blood-mediated inflammatory response [IBMIR], ability to biopsy). The aim of this study was to determine whether endoscopic biopsy of islet allografts transplanted into the GSMS in diabetic pigs can provide histopathological and immunohistochemical information that correlates with the clinical course (e.g.,, blood glucose level, insulin requirement). Islet allografts (Group1: 10,000 kIEq /kg [n = 4]; Group2: 15,000 kIEq /kg [n = 2]) were transplanted into the GSMS of diabetic pigs under immunosuppression...
2016: Islets
Reshmi Dassaye, Strini Naidoo, Marlon E Cerf
Lineage tracing studies have revealed that transcription factors play a cardinal role in pancreatic development, differentiation and function. Three transitions define pancreatic organogenesis, differentiation and maturation. In the primary transition, when pancreatic organogenesis is initiated, there is active proliferation of pancreatic progenitor cells. During the secondary transition, defined by differentiation, there is growth, branching, differentiation and pancreatic cell lineage allocation. The tertiary transition is characterized by differentiated pancreatic cells that undergo further remodeling, including apoptosis, replication and neogenesis thereby establishing a mature organ...
2016: Islets
Janne Lehtonen, Lauge Schäffer, Morten Grønbech Rasch, Jacob Hecksher-Sørensen, Jonas Ahnfelt-Rønne
Probes based on GLP-1R agonist exendin-4 have shown promise as in vivo β cell tracers. However, questions remain regarding the β cell specificity of exendin-4 probes, and it is unclear if the expression levels of the GLP-1R are affected in a type 2 diabetic state. Using in vivo probing followed by ex vivo imaging we found fluorescent exendin-4 probes to distinctly label the pancreatic islets in mice in a Glp-1r dependent manner. Furthermore, a co-localization study revealed a near 100 percent β cell specificity with less than one percent probing in other analyzed cell types...
2015: Islets
Axel Andres, Scott Livingstone, Tatsuya Kin, Patricia M Campbell, Peter A Senior, Norman M Kneteman, David Bigam, A M James Shapiro
For selected patients with type 1 diabetes, β-cell replacement is the treatment of choice, either by islet transplantation (ITX) or whole pancreas transplantation (PTX). When either modality fails, current practice is to consider retransplantation, or return to exogenous insulin. We investigate outcomes with PTX after failed ITX (PAI), and ITX after failed PTX (IAP). All patients receiving PAI or IAP at a single institution were identified. Donor and recipient variables were documented, including transplant outcomes analyzed for insulin requirement and metabolic control...
2015: Islets
Han-Hung Huang, Lisa Stehno-Bittel
In a variety of mammalian species, small islets secrete more insulin per volume than large islets. This difference may be due to diffusional limitations of large islets, or inherent differences in the insulin production pathways. The purpose of this study was to identify possible differences in the early phase of glucose-stimulated insulin biosynthesis between large and small islets. Isolated small and large rat islets were challenged with 30 minutes of high glucose. The expression of insulin gene transcription factors (MafA, NeuroD/ Beta2, and PDX-1), preproinsulin mRNA, proinsulin and insulin were compared between large and small islets...
2015: Islets
Min Joo Kim, Ok Kyong Choi, Kyung Sil Chae, Hakmo Lee, Sung Soo Chung, Dong-Sik Ham, Ji-Won Kim, Kun-Ho Yoon, Kyong Soo Park, Hye Seung Jung
Incretin-based therapy such as GLP-1 receptor agonists and DPP-4 inhibitors for type 2 diabetes mellitus is characterized by glucose-dependent insulin secretion and glucose-inhibited glucagon secretion. Recently, autophagy deficiency in islet β cells has been shown to contribute to the pathogenesis of type 2 diabetes mellitus however, with the role of incretin has not been established. To evaluate the role of autophagy in incretin effects, 8-week-old male β cell-specific Atg7 knockout (Atg7(Δβ cell)) mice and wild-type mice were administered vildagliptin for 12 weeks...
2015: Islets
Sonja Hänzelmann, Jinling Wang, Emre Güney, Yunzhao Tang, Enming Zhang, Annika S Axelsson, Hannah Nenonen, Albert S Salehi, Claes B Wollheim, Eva Zetterberg, Erik Berntorp, Ivan G Costa, Robert Castelo, Anders H Rosengren
The disease mechanisms underlying type 2 diabetes (T2D) remain poorly defined. Here we aimed to explore the pathophysiology of T2D by analyzing gene co-expression networks in human islets. Using partial correlation networks we identified a group of co-expressed genes ('module') including F2RL2 that was associated with glycated hemoglobin. F2Rl2 is a G-protein-coupled receptor (GPCR) that encodes protease-activated receptor-3 (PAR3). PAR3 is cleaved by thrombin, which exposes a 6-amino acid sequence that acts as a 'tethered ligand' to regulate cellular signaling...
2015: Islets
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