scholarly journals Morphogenesis of the islets of Langerhans is guided by extra-endocrine Slit2/3 signals

2020 ◽  
pp. MCB.00451-20
Author(s):  
Jennifer M. Gilbert ◽  
Melissa T. Adams ◽  
Nadav Sharon ◽  
Hariharan Jayaraaman ◽  
Barak Blum
Keyword(s):  
Axon Guidance ◽  
Islets Of Langerhans ◽  
Endocrine Cells ◽  
Β Cells ◽  
Robo Receptors ◽  
Correct Function ◽  
Cell Positioning ◽  
Spatial Architecture ◽  
Endocrine Tissues

The spatial architecture of the islets of Langerhans is vitally important for their correct function, and alterations in islet morphogenesis often result in diabetes mellitus. We have previously reported that Roundabout (Robo) receptors are required for proper islet morphogenesis. As part of the Slit-Robo signaling pathway, Robo receptors function in conjunction with Slit ligands to mediate axon guidance, cell migration, and cell positioning in development. However, the role of Slit ligands in islet morphogenesis has not yet been determined. Here we report that Slit ligands are expressed in overlapping and distinct patterns in both endocrine and non-endocrine tissues in late pancreas development. We show that function of either Slit2 or Slit3, which are predominantly expressed in the pancreatic mesenchyme, is required and sufficient for islet morphogenesis, while Slit1, which is predominantly expressed in the β-cells, is dispensable for islet morphogenesis. We further show that Slit functions as a repellent signal to β-cells. These data suggest that clustering of endocrine cells during islet morphogenesis is guided, at least in part, by repelling Slit2/3 signals from the pancreatic mesenchyme.

scholarly journals Morphogenesis of the islets of Langerhans is guided by extra-endocrine Slit2/3 signals

2020 ◽  
Author(s):  
Jennifer M. Gilbert ◽  
Melissa T. Adams ◽  
Nadav Sharon ◽  
Hariharan Jayaraaman ◽  
Barak Blum
Keyword(s):  
Axon Guidance ◽  
Islets Of Langerhans ◽  
Endocrine Cells ◽  
Β Cells ◽  
Robo Receptors ◽  
Correct Function ◽  
Cell Positioning ◽  
Spatial Architecture ◽  
Endocrine Tissues

AbstractThe spatial architecture of the islets of Langerhans is vitally important for their correct function, and alterations in islet morphogenesis often result in diabetes mellitus. We have previously reported that Roundabout (Robo) receptors are required for proper islet morphogenesis. As part of the Slit-Robo signaling pathway, Robo receptors work in conjunction with Slit ligands to mediate axon guidance, cell migration, and cell positioning in development. However, the role of Slit ligands in islet morphogenesis has not yet been determined. Here we report that Slit ligands are expressed in overlapping and distinct patterns in both endocrine and non-endocrine tissues in late pancreas development. We show that function of either Slit2 or Slit3, which are predominantly expressed in the pancreatic mesenchyme, is required and sufficient for islet morphogenesis, while Slit1, which is predominantly expressed in the β cells, is dispensable for islet morphogenesis. We further show that Slit functions as a repellent signal to β cells. These data suggest that clustering of endocrine cells during islet morphogenesis is guided, at least in part, by repelling Slit2/3 signals from the pancreatic mesenchyme.

scholarly journals Regulation of Insulin Secretion and β-Cell Mass by Activating Signal Cointegrator 2

2006 ◽  
Vol 26 (12) ◽  
pp. 4553-4563 ◽  
Author(s):  
Seon-Yong Yeom ◽  
Geun Hyang Kim ◽  
Chan Hee Kim ◽  
Heun Don Jung ◽  
So-Yeon Kim ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Endocrine Cells ◽  
Potential Role ◽  
Cell Mass ◽  
Dominant Negative ◽  
Transcriptional Coactivator ◽  
Β Cells ◽  
Β Cell ◽  
Islet Mass

ABSTRACT Activating signal cointegrator 2 (ASC-2) is a transcriptional coactivator of many nuclear receptors (NRs) and other transcription factors and contains two NR-interacting LXXLL motifs (NR boxes). In the pancreas, ASC-2 is expressed only in the endocrine cells of the islets of Langerhans, but not in the exocrine cells. Thus, we examined the potential role of ASC-2 in insulin secretion from pancreatic β-cells. Overexpressed ASC-2 increased glucose-elicited insulin secretion, whereas insulin secretion was decreased in islets from ASC-2+/− mice. DN1 and DN2 are two dominant-negative fragments of ASC-2 that contain NR boxes 1 and 2, respectively, and block the interactions of cognate NRs with the endogenous ASC-2. Primary rat islets ectopically expressing DN1 or DN2 exhibited decreased insulin secretion. Furthermore, relative to the wild type, ASC-2+/− mice showed reduced islet mass and number, which correlated with increased apoptosis and decreased proliferation of ASC-2+/− islets. These results suggest that ASC-2 regulates insulin secretion and β-cell survival and that the regulatory role of ASC-2 in insulin secretion appears to involve, at least in part, its interaction with NRs via its two NR boxes.

Diabetes as a Paracrinopathy of the Islets of Langerhans

2010 ◽  
Vol 7 (2) ◽  
pp. 79 ◽  
Author(s):  
Pierre Lefèbvre ◽  
Keyword(s):  
Insulin Resistance ◽  
Pancreatic Islets ◽  
Islets Of Langerhans ◽  
Crucial Role ◽  
Cell Types ◽  
Insulin Deficiency ◽  
Metabolic Disturbances ◽  
Β Cells ◽  
Small Clusters

The small clusters of cells scattered in the pancreas and discovered by Langerhans in 1869, currently known as the islets of Langerhans, are at the centre of the pathology of diabetes. Today they appear as sophisticated micro-organs in which various cell types function in a remarkably co-ordinated manner. Until recently, most of the interest has been centred on the β-cells, which synthesise, store and secrete insulin. Insulin deficiency is the hallmark of diabetes, with insulin resistance being associated with some forms of the disease. Although identified more than 40 years ago, a possible role of glucagon in the pathophysiology of diabetes has been largely neglected. Synthesised, stored and released by the α-cells of the islets of Langerhans, glucagon plays a key role in the main metabolic disturbances of diabetes that are hyperglycaemia and excessive lipolysis and ketogenesis. Suggested by Samols et al. decades ago, the possibility of close interactions between α- and β-cells within the islets of Langerhans has recently received considerable experimental support. Unger and Orci have proposed that such paracrine interactions within the pancreatic islets play a crucial role in a vital homoeostatic domain and that disruption or dysfunction of these interactions has to be considered as a key component in the pathophysiology of diabetes. This brief article will present arguments supporting the view of diabetes as a paracrinopathy of the islets of Langerhans.

scholarly journals Philip John Randle. 16 July 1926—26 September 2006

2021 ◽  
Author(s):  
S. J. H. Ashcroft ◽  
R. M. Denton
Keyword(s):  
Pancreatic Islets ◽  
Islets Of Langerhans ◽  
Pyruvate Dehydrogenase ◽  
Glucose Oxidation ◽  
Great Influence ◽  
Β Cells ◽  
Pancreatic Islets Of Langerhans ◽  
Good Research ◽  
Selection Of

Sir Philip Randle, who died aged 80 on 26 September 2006 after a brief illness, was one of the world's foremost researchers into mammalian metabolism. In a career spanning some five decades, he provided a series of brilliant insights into the fundamental mechanisms that determine the selection of metabolic fuels by muscle and other tissues. Many of his findings were concerned with the role of insulin, including the control of its secretion from the β-cells in the pancreatic islets of Langerhans, and with the regulation of glucose oxidation through changes in the activity of pyruvate dehydrogenase. The ideas generated by his investigations laid the foundations for countless subsequent studies and have had a direct bearing on the understanding of diabetes. His lifelong enthusiasm for good research has had a great influence on all who worked with him.

scholarly journals Targeting the SLIT/ROBO pathway in tumor progression: molecular mechanisms and therapeutic perspectives

2019 ◽  
Vol 11 ◽  
pp. 175883591985523 ◽  
Author(s):  
Zhengdong Jiang ◽  
Gang Liang ◽  
Ying Xiao ◽  
Tao Qin ◽  
Xin Chen ◽  
...  
Keyword(s):  
Axon Guidance ◽  
Neuronal Migration ◽  
Molecular Mechanisms ◽  
Vascular System ◽  
Tumor Development ◽  
Tumor Promotion ◽  
Cancer Therapies ◽  
Malignant Cells ◽  
Robo Receptors

The SLITs (SLIT1, SLIT2, and SLIT3) are a family of secreted proteins that mediate positional interactions between cells and their environment during development by signaling through ROBO receptors (ROBO1, ROBO2, ROBO3, and ROBO4). The SLIT/ROBO signaling pathway has been shown to participate in axonal repulsion, axon guidance, and neuronal migration in the nervous system and the formation of the vascular system. However, the role of the SLIT/ROBO pathway has not been thoroughly clarified in tumor development. The SLIT/ROBO pathway can produce both beneficial and detrimental effects in the growth of malignant cells. It has been confirmed that SLIT/ROBO play contradictory roles in tumorigenesis. Here, we discuss the tumor promotion and tumor suppression roles of the SLIT/ROBO pathway in tumor growth, angiogenesis, migration, and the tumor microenvironment. Understanding these roles will help us develop more effective cancer therapies.

scholarly journals Morphofunctional condition of the pancreatic insular apparatus in old rats with alloxan-induced diabetes and its correction with lipoic acid

2020 ◽  
Vol 22 ◽  
pp. 02020
Author(s):  
Yulia Klyueva ◽  
Irina Danilova ◽  
Viktor Emelianov ◽  
Irina Gette ◽  
Ekaterina Trofimova
Keyword(s):  
Islets Of Langerhans ◽  
Lipoic Acid ◽  
Peripheral Blood ◽  
Endocrine Cells ◽  
Glycosylated Hemoglobin ◽  
Sharp Decrease ◽  
Β Cells ◽  
Physiological Aging ◽  
Old Rats

The concentration of glucose and glycosylated hemoglobin in the blood of animals increases as a result of physiological aging. This is due to damage to the pancreatic insular apparatus and a decrease in the number and functioning of active β-cells. The development of alloxan-induced diabetes in old rats is characterized by a decrease in the number of islets of Langerhans, an enlargement of the preserved islets, and a sharp decrease in the number of active endocrine cells. The injection of lipoic acid partially corrected the morphofunctional condition of the islets of Langerhans and the biochemical values of the animals’ peripheral blood.

scholarly journals Tumour suppressor menin is essential for development of the pancreatic endocrine cells

2008 ◽  
Vol 199 (2) ◽  
pp. 287-298 ◽  
Author(s):  
Sandra Fontanière ◽  
Bertrand Duvillié ◽  
Raphaël Scharfmann ◽  
Christine Carreira ◽  
Zhao-Qi Wang ◽  
...  
Keyword(s):  
Endocrine Cells ◽  
Endocrine Pancreas ◽  
Islet Cells ◽  
Specific Effect ◽  
Pancreas Development ◽  
Β Cells ◽  
Neurogenin 3 ◽  
Pancreatic Endocrine Cells ◽  
Endocrine Tissues

Mutations of the multiple endocrine neoplasia type 1 (MEN1) gene predispose patients to MEN1 that affects mainly endocrine tissues, suggesting important physiological functions of the gene in adult endocrine cells. Homozygous disruption of Men1 in mice causes embryonic lethality, whereas the eventual involvement of the gene in embryonic development of the endocrine cells remains unknown. Here, we show that homozygous Men1 knockout mice demonstrate a reduced number of glucagon-positive cells in the E12.5 pancreatic bud associated with apoptosis, whereas the exocrine pancreas development in these mice is not affected. Our data suggest that menin is involved in the survival of the early pancreatic endocrine cells during the first developmental transition. Furthermore, chimerism assay revealed that menin has an autonomous and specific effect on the development of islet cells. In addition, using pancreatic bud culture mimicking the differentiation of α- and β-cells during the second transition, we show that loss of menin leads to the failure of endocrine cell development, altered pancreatic structure and a markedly decreased number of cells expressing neurogenin 3, indicating that menin is also required at this stage of the endocrine pancreas development. Taken together, our results suggest that menin plays an indispensable role in the development of the pancreatic endocrine cells.

scholarly journals Endocannabinoids in the Islets of Langerhans: the ugly, the bad, and the good facts

2018 ◽  
Vol 315 (2) ◽  
pp. E174-E179 ◽  
Author(s):  
Isabel González-Mariscal ◽  
Josephine M. Egan
Keyword(s):  
Islets Of Langerhans ◽  
Endocrine Pancreas ◽  
Endocannabinoid System ◽  
Negative Regulator ◽  
Whole Body ◽  
Β Cells ◽  
Treatment Of Diabetes ◽  
Islet Inflammation ◽  
Whole Body Metabolism

The endocannabinoid system (ECS) regulates cellular homeostasis and whole-body metabolism. There is an autonomous ECS in the endocrine pancreas, including the cannabinoid 1 receptor (CB1R) that is present in β-cells. Here, we discuss conflicts that have arisen with regard to the function(s) of the ECs in the endocrine pancreas and that have caused confusion when defining the role of the ECS in islets of Langerhans, especially the role(s) of CB1R in β-cells. We also discuss the latest data published concerning the ECS in islets. CB1R in particular is not simply a negative modulator of insulin secretion as it is also involved in intra-islet inflammation during high fat-high sugar intake and it is a negative regulator of β-cell viability and turnover. We also discuss the feasibility of using CB1R as a target for the treatment of diabetes.

scholarly journals Synchronized β cell response to glucose is lost concomitant with loss of islet architecture in Robo deficient islets of Langerhans in vivo

2019 ◽  
Author(s):  
Melissa T. Adams ◽  
Christopher A. Reissaus ◽  
JaeAnn M. Dwulet ◽  
Erli Jin ◽  
Joseph M. Szulczewski ◽  
...  
Keyword(s):  
Stem Cells ◽  
Insulin Secretion ◽  
Cell Differentiation ◽  
Islets Of Langerhans ◽  
Β Cells ◽  
Β Cell ◽  
Unique Model ◽  
Spatial Architecture ◽  
Intrinsic Function

AbstractThe spatial architecture of the islets of Langerhans is hypothesized to facilitate synchronized insulin secretion between β cells, yet testing this in vivo in the intact pancreas is challenging. Robo βKO mice, in which the genes Robo1 and Robo2 are deleted selectively in β cells, provide a unique model of altered islet spatial architecture without loss of β cell differentiation or islet damage from diabetes. Combining Robo βKO mice with intravital microscopy, we show here that Robo βKO islets lose synchronized intra-islet Ca2+ oscillations between β cells in vivo. We provide evidence that this loss is not due to a β cell-intrinsic function of Robo, loss of Connexin36 gap junctions, or changes in islet vascularization, suggesting that the islet architecture itself is required for synchronized Ca2+ oscillations. These results have implications for understanding structure-function relationships in the islets during progression to diabetes as well as engineering islets from stem cells.

Synaptotagmins bind calcium to release insulin

2008 ◽  
Vol 295 (6) ◽  
pp. E1279-E1286 ◽  
Author(s):  
Benoit R. Gauthier ◽  
Claes B. Wollheim
Keyword(s):  
Endocrine Cells ◽  
Β Cells ◽  
Attachment Protein ◽  
Receptor Complexes ◽  
Protein Receptor ◽  
Large Dense Core Vesicles ◽  
Sensitive Factor ◽  
Plasma Insulin Levels ◽  
Insulin Exocytosis

Plasma insulin levels are determined mainly by the rate of exocytosis of the insulin-containing large dense core vesicles (LDCVs) of pancreatic islet β-cells. This process involves the recruitment of LDCVs to the plasma membrane, where they are docked by the assembly of multiprotein SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complexes. However, fusion of the two membranes will proceed only in the presence of Ca2+ ions, implicating a Ca2+ sensor protein. The synaptotagmin gene family, comprising 15 members, was proposed to act as such Ca2+ sensor in regulated exocytosis in neurons and neuroendocrine and endocrine cells. Herein, we review the physiological function of the various synaptotagmins with reference to their impact on insulin exocytosis. Cumulating evidence emphasizes the crucial role of synaptotagmin VII and IX as mediators of glucose-induced insulin secretion.

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