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Islet neogenesis

Nouha Ben-Othman, Andhira Vieira, Monica Courtney, Fabien Record, Elisabet Gjernes, Fabio Avolio, Biljana Hadzic, Noémie Druelle, Tiziana Napolitano, Sergi Navarro-Sanz, Serena Silvano, Keith Al-Hasani, Anja Pfeifer, Sandra Lacas-Gervais, Gunter Leuckx, Laura Marroquí, Julien Thévenet, Ole Dragsbaek Madsen, Decio Laks Eizirik, Harry Heimberg, Julie Kerr-Conte, François Pattou, Ahmed Mansouri, Patrick Collombat
The recent discovery that genetically modified α cells can regenerate and convert into β-like cells in vivo holds great promise for diabetes research. However, to eventually translate these findings to human, it is crucial to discover compounds with similar activities. Herein, we report the identification of GABA as an inducer of α-to-β-like cell conversion in vivo. This conversion induces α cell replacement mechanisms through the mobilization of duct-lining precursor cells that adopt an α cell identity prior to being converted into β-like cells, solely upon sustained GABA exposure...
January 12, 2017: Cell
Sara S Roscioni, Adriana Migliorini, Moritz Gegg, Heiko Lickert
Although β-cell heterogeneity was discovered more than 50 years ago, the underlying principles have been explored only during the past decade. Islet-cell heterogeneity arises during pancreatic development and might reflect the existence of distinct populations of progenitor cells and the developmental pathways of endocrine cells. Heterogeneity can also be acquired in the postnatal period owing to β-cell plasticity or changes in islet architecture. Furthermore, β-cell neogenesis, replication and dedifferentiation represent alternative sources of β-cell heterogeneity...
September 2, 2016: Nature Reviews. Endocrinology
Ansarullah, Colette Free, Jenica Christopherson, Quanhai Chen, Jie Gao, Chengyang Liu, Ali Naji, Alex Rabinovitch, Zhiguang Guo
Using humanized mice with functional human islets, we investigated whether activating GPR119 by PSN632408, a small molecular agonist, can stimulate human β-cell regeneration in vivo. Human islets were transplanted under the left kidney capsule of immunodeficient mice with streptozotocin- (STZ-) induced diabetes. The recipient mice were treated with PSN632408 or vehicle and BrdU daily. Human islet graft function in the mice was evaluated by nonfasting glucose levels, oral glucose tolerance, and removal of the grafts...
2016: Journal of Diabetes Research
Hyo-Sup Kim, Moon-Kyu Lee
Pancreatic progenitor cell research has been in the spotlight, as these cells have the potential to replace pancreatic β-cells for the treatment of type 1 and 2 diabetic patients with the absence or reduction of pancreatic β-cells. During the past few decades, the successful treatment of diabetes through transplantation of the whole pancreas or isolated islets has nearly been achieved. However, novel sources of pancreatic islets or insulin-producing cells are required to provide sufficient amounts of donor tissues...
May 2016: Journal of Diabetes Investigation
Ahmed A M Abdel-Hamid, Alaa El-Din L Firgany
Hydroxychloroquine (HCQ) has been demonstrated to reduce the risk to develop diabetes mellitus (DM). However no previous experimental study had investigated its effect on the structure of the endocrine pancreas, islets of Langerhans (IOL), in insulin resistance (IR). In addition, the mechanism by which HCQ can prevent DM is not well understood. In this study, we hypothesized that the possible favorable outcome of HCQ may be partly achieved by its molecular effect on the endothelial stress markers as well as on the imparied balance of the adipokines that usually accompanies IR...
July 2016: Acta Histochemica
László Gerő
In type 1 diabetic patients perfect normoglycaemia can only be achieved by successful transplantation of the pancreas or Langerhans' islets. Surgical transplantation of the whole pancreas is an invasive operation exerting great burden on the patients. Transplantation of the islets of Langerhans does not burden the patients but the survival of the islet grafts is limited. Both interventions are hampered by the lack of donor organs. However, much of these difficulties could be overcome by the use of "artificial β-cells" which ought to have an ultrastructure identical with that of natural β-cells and produce and secrete insulin in a glucose dependent manner...
May 8, 2016: Orvosi Hetilap
Krishna Prasadan, Chiyo Shiota, Xiao Xiangwei, David Ricks, Joseph Fusco, George Gittes
The insulin-secreting beta cells in the endocrine pancreas regulate blood glucose levels, and loss of functional beta cells leads to insulin deficiency, hyperglycemia (high blood glucose) and diabetes mellitus. Current treatment strategies for type-1 (autoimmune) diabetes are islet transplantation, which has significant risks and limitations, or normalization of blood glucose with insulin injections, which is clearly not ideal. The type-1 patients can lack insulin counter-regulatory mechanism; therefore, hypoglycemia is a potential risk...
October 2016: Cellular and Molecular Life Sciences: CMLS
Gloria Baena-Nieto, Isabel M Lomas-Romero, Rosa M Mateos, Noelia Leal-Cosme, Gonzalo Perez-Arana, Manuel Aguilar-Diosdado, Carmen Segundo, Alfonso M Lechuga-Sancho
BACKGROUND: Ghrelin is a peptide hormone with pleiotropic effects. It stimulates cellular proliferation and inhibits apoptosis-mediated cell death. It prevents diabetes mellitus in several models of pancreas aggression (chemical, surgical and biological toxic insults) in both in vivo and in vitro models, and promotes glucose-stimulated insulin secretion under cytotoxic conditions. It has not yet been tested in vivo in an autoimmune model of diabetes with a persistent insult to the β-cell...
April 22, 2016: Diabetes/metabolism Research and Reviews
Binhai Ren, Chang Tao, Margaret Anne Swan, Nichole Joachim, Rosetta Martiniello-Wilks, Najah T Nassif, Bronwyn A O'Brien, Ann M Simpson
Due to the limitations of current treatment regimes, gene therapy is a promising strategy being explored to correct blood glucose concentrations in diabetic patients. In the current study, we used a retroviral vector to deliver either the human insulin gene alone, the rat NeuroD1 gene alone, or the human insulin gene and rat NeuroD1 genes together, to the rat liver cell line, H4IIE, to determine if storage of insulin and pancreatic transdifferentiation occurred. Stable clones were selected and expanded into cell lines: H4IIEins (insulin gene alone), H4IIE/ND (NeuroD1 gene alone), and H4IIEins/ND (insulin and NeuroD1 genes)...
April 8, 2016: International Journal of Molecular Sciences
Susan Bonner-Weir, Cristina Aguayo-Mazzucato, Gordon C Weir
After birth the endocrine pancreas continues its development, a complex process that involves both the maturation of islet cells and a marked expansion of their numbers. New beta cells are formed both by duplication of pre-existing cells and by new differentiation (neogenesis) across the first postnatal weeks, with the result of beta cells of different stages of maturation even after weaning. Improving our understanding of this period of beta cell expansion could provide valuable therapeutic insights.
May 2016: Upsala Journal of Medical Sciences
Philippe A Lysy, Elisa Corritore, Etienne M Sokal
Since insulin discovery, islet transplantation was the first protocol to show the possibility to cure patients with type 1 diabetes using low-risk procedures. The scarcity of pancreas donors triggered a burst of studies focused on the production of new β cells in vitro. These were rapidly dominated by pluripotent stem cells (PSCs) demonstrating diabetes-reversal potential in diabetic mice. Subsequent enthusiasm fostered a clinical trial with immunoisolated embryonic-derived pancreatic progenitors. Yet safety is the Achilles' heel of PSCs, and a whole branch of β cell engineering medicine focuses on transdifferentiation of adult pancreatic cells...
May 2016: Current Diabetes Reports
Ahmed A M Abdel-Hamid, Alaa El-Din L El-Firgany
Hydroxychloroquine (HCQ) is supposed to have favorable effects in diabetes mellitus (DM). However no previous experimental studies had investigated its effect on the structure of the endocrine pancreas, islets of Langerhans (IOL), in DM. In addition, the mechanism by which HCQ acts in DM is not well understood. In this study, we hypothesized that the possible favorable effects of HCQ in DM at the structural as well as at metabolic levels could be accomplished, in part, by its anti-inflammatory action. A total of 45 rats were divided equally into; control, DM and HCQ + DM groups (received citrate buffer, 27...
April 2016: Journal of Molecular Histology
Lihua Ye, Morgan A Robertson, Teresa L Mastracci, Ryan M Anderson
As one of the key nutrient sensors, insulin signaling plays an important role in integrating environmental energy cues with organism growth. In adult organisms, relative insufficiency of insulin signaling induces compensatory expansion of insulin-secreting pancreatic beta (β) cells. However, little is known about how insulin signaling feedback might influence neogenesis of β cells during embryonic development. Using genetic approaches and a unique cell transplantation system in developing zebrafish, we have uncovered a novel role for insulin signaling in the negative regulation of pancreatic progenitor cell differentiation...
January 15, 2016: Developmental Biology
Teresa Mezza, Gian P Sorice, Caterina Conte, Vinsin A Sun, Chiara M A Cefalo, Simona Moffa, Alfredo Pontecorvi, Andrea Mari, Rohit N Kulkarni, Andrea Giaccari
CONTEXT: Insulin resistance impacts virtually all tissues, including pancreatic β cells. Individuals with insulin resistance, but without diabetes, exhibit an increased islet size because of an elevated number of both β and α cells. Neogenesis from duct cells and transdifferentiation of α cells have been postulated to contribute to the β-cell compensatory response to insulin resistance. OBJECTIVE: Our objective was to explore parameters that could potentially predict altered islet morphology...
February 2016: Journal of Clinical Endocrinology and Metabolism
Béatrice Assouline-Thomas, Daniel Ellis, Maria Petropavlovskaia, Julia Makhlin, Jieping Ding, Lawrence Rosenberg
Regeneration of β-cells in diabetic patients is an important goal of diabetes research. Islet Neogenesis Associated Protein (INGAP) was discovered in the partially duct-obstructed hamster pancreas. Its bioactive fragment, pentadecapeptide 104-118 (INGAP-P), has been shown to reverse diabetes in animal models and to improve glucose homeostasis in patients with diabetes in clinical trials. Further development of INGAP as a therapy for diabetes requires identification of target cells in the pancreas and characterization of the mechanisms of action...
November 2015: Differentiation; Research in Biological Diversity
Himadri Singh, Vikram Parthasarathy, Mohammed Farouk, Vijayalakshmi Venkatesan
Obesity is associated with insulin resistance and type 2 diabetes. Fortunately most obese, insulin-resistant individuals do not develop type 2 diabetes as they can overcome reduced efficiency of insulin action by increasing the functional β-cell mass. Compelling evidences suggest β-cells neogenesis through progenitor/stem cells residing in pancreatic ductal cells and islets, but the role of β-cell regeneration in obesity/insulin resistance from progenitor/stem cells is not clear. Based on many indirect evidences in human studies such as unchanged β-cell replication, apoptosis and size during compensation in insulin resistance in humans, we suggest successful β-cells mass compensation in metabolically healthy obesity is contributed by neoformation of β-cells, through expansion of progenitor cells/stem cells in synergy with β-cell replication...
January 2016: Medical Hypotheses
Colin M Hyslop, Sue Tsai, Vipul Shrivastava, Pere Santamaria, Carol Huang
Type 1 diabetes is caused by autoimmune destruction of β-cells. Although immunotherapy can restore self-tolerance thereby halting continued immune-mediated β-cell loss, residual β-cell mass and function is often insufficient for normoglycemia. Using a growth factor to boost β-cell mass can potentially overcome this barrier and prolactin (PRL) may fill this role. Previous studies have shown that PRL can stimulate β-cell proliferation and up-regulate insulin synthesis and secretion while reducing lymphocytic infiltration of islets, suggesting that it may restore normoglycemia through complementary mechanisms...
January 2016: Endocrinology
Imane Song, Oelfah Patel, Eddy Himpe, Christo J F Muller, Luc Bouwens
One week of treatment with EGF and gastrin (EGF/G) was shown to restore normoglycemia and to induce islet regeneration in mice treated with the diabetogenic agent alloxan. The mechanisms underlying this regeneration are not fully understood. We performed genetic lineage tracing experiments to evaluate the contribution of beta cell neogenesis in this model. One day after alloxan administration, mice received EGF/G treatment for one week. The treatment could not prevent the initial alloxan-induced beta cell mass destruction, however it did reverse glycemia to control levels within one day, suggesting improved peripheral glucose uptake...
2015: PloS One
Lynley D Pound, Christopher Patrick, Chandra E Eberhard, Walid Mottawea, Gen-Sheng Wang, Turki Abujamel, Roxanne Vandenbeek, Alain Stintzi, Fraser W Scott
Cathelicidin antimicrobial peptide (CAMP) is a naturally occurring secreted peptide that is expressed in several organs with pleiotropic roles in immunomodulation, wound healing, and cell growth. We previously demonstrated that gut Camp expression is upregulated when type 1 diabetes-prone rats are protected from diabetes development. Unexpectedly, we have also identified novel CAMP expression in the pancreatic β-cells of rats, mice, and humans. CAMP was present even in sterile rat embryo islets, germ-free adult rat islets, and neogenic tubular complexes...
December 2015: Diabetes
Tiziana Napolitano, Fabio Avolio, Monica Courtney, Andhira Vieira, Noémie Druelle, Nouha Ben-Othman, Biljana Hadzic, Sergi Navarro, Patrick Collombat
The embryonic development of the pancreas is orchestrated by a complex and coordinated transcription factor network. Neurogenin3 (Neurog3) initiates the endocrine program by activating the expression of additional transcription factors driving survival, proliferation, maturation and lineage allocation of endocrine precursors. Among the direct targets of Neurog3, Pax4 appears as one of the key regulators of β-cell specification. Indeed, mice lacking Pax4 die a few days postpartum, as they develop severe hyperglycemia due to the absence of mature pancreatic β-cells...
August 2015: Seminars in Cell & Developmental Biology
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