scholarly journals Bioengineered Islet Cell Transplantation

2021 ◽  
Author(s):  
Kevin Bellofatto ◽  
Beat Moeckli ◽  
Charles-Henri Wassmer ◽  
Margaux Laurent ◽  
Graziano Oldani ◽  
...  
Keyword(s):  
State Of The Art ◽  
Diabetes Research ◽  
Islet Cell Transplantation ◽  
Β Cell ◽  
Cell Compartment ◽  
Factors Affecting ◽  
Insulin Activity ◽  
On Chip

Abstract Purpose of Review β cell replacement via whole pancreas or islet transplantation has greatly evolved for the cure of type 1 diabetes. Both these strategies are however still affected by several limitations. Pancreas bioengineering holds the potential to overcome these hurdles aiming to repair and regenerate β cell compartment. In this review, we detail the state-of-the-art and recent progress in the bioengineering field applied to diabetes research. Recent Findings The primary target of pancreatic bioengineering is to manufacture a construct supporting insulin activity in vivo. Scaffold-base technique, 3D bioprinting, macro-devices, insulin-secreting organoids, and pancreas-on-chip represent the most promising technologies for pancreatic bioengineering. Summary There are several factors affecting the clinical application of these technologies, and studies reported so far are encouraging but need to be optimized. Nevertheless pancreas bioengineering is evolving very quickly and its combination with stem cell research developments can only accelerate this trend.

scholarly journals ER stress and development of type 1 diabetes

2016 ◽  
Vol 64 (1) ◽  
pp. 2-6 ◽  
Author(s):  
Feyza Engin
Keyword(s):  
Type 1 Diabetes ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Adaptive Responses ◽  
Β Cell ◽  
Cellular Homeostasis ◽  
Unfolded Protein

Type 1 diabetes (T1D) results from an autoimmune-mediated destruction of pancreatic β cells. The incidence of T1D is on the rise globally around 3% to 5% per year and rapidly increasing incidence in younger children is of the greatest concern. currently, there is no way to cure or prevent T1D; hence, a deeper understanding of the underlying molecular mechanisms of this disease is essential to the development of new effective therapies. The endoplasmic reticulum (ER) is an organelle with multiple functions that are essential for cellular homeostasis. Excessive demand on the ER, chronic inflammation, and environmental factors lead to ER stress and to re-establish cellular homeostasis, the adaptive unfolded protein response (UPR) is triggered. However, chronic ER stress leads to a switch from a prosurvival to a proapoptotic UPR, resulting in cell death. Accumulating data have implicated ER stress and defective UPR in the pathogenesis of inflammatory and autoimmune diseases, and ER stress has been implicated in β-cell failure in type 2 diabetes. However, the role of ER stress and the UPR in β-cell pathophysiology and in the initiation and propagation of the autoimmune responses in T1D remains undefined. This review will highlight the current understanding and recent in vivo data on the role of ER stress and adaptive responses in T1D pathogenesis and the potential therapeutic aspect of enhancing β-cell ER function and restoring UPR defects as novel clinical strategies against this disease.

INTRAPERITONEAL TEST OF INSULIN ACTIVITY ON THE RAT DIAPHRAGM IN VIVO: FACTORS CONTROLLING THE VARIABILITY OF RESPONSE

1972 ◽  
Vol 71 (1) ◽  
pp. 103-114 ◽  
Author(s):  
D. A. B. Young ◽  
L. Balant
Keyword(s):  
Body Weight ◽  
Factors Affecting ◽  
Weight Range ◽  
Relative Standard ◽  
Individual Experiment ◽  
Principal Factors ◽  
Insulin Activity ◽  
Sensitivity Changes

ABSTRACT Rafaelsen's intraperitoneal assay of insulin in rats, where the effect measured is the increased incorporation of [U-14C] glucose into diaphragm glycogen, is extremely sensitive and has important advantages over techniques using muscle preparations in vitro, as well as over the more usual techniques in vivo. To make the test more precise and more reproducible from day to day, the optimal conditions have been derived from an examination of each of the principal steps of the technique and from an analysis of the data obtained over a period of 51/2 years. For comparative purposes, the response to a single concentration of insulin, 1 mU/ml, was examined throughout. The principal factors affecting the variability of response are (a) nutritional state of the rats, and (b) weight range of the animals. The proportion of experiments having high relative standard deviations was substantially reduced by fasting the rats for 24 h before the test, and ensuring that they were adequately fed immediately before the fast. It was found that insulin sensitivity changes appreciably with body weight over the complete weight range used (70 to 120 g before fasting) and, consequently, although correcting for variations in body weight reduces variability, the weight range within an individual experiment should be kept as small as possible.

scholarly journals β-Cell Generation: Can Rodent Studies Be Translated to Humans?

2011 ◽  
Vol 2011 ◽  
pp. 1-15 ◽  
Author(s):  
Françoise Carlotti ◽  
Arnaud Zaldumbide ◽  
Johanne H. Ellenbroek ◽  
H. Siebe Spijker ◽  
Rob C. Hoeben ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Cell Mass ◽  
Cell Types ◽  
Organ Donors ◽  
Cell Replacement Therapy ◽  
Β Cell ◽  
Cell Replacement ◽  
Therapeutic Alternatives

β-cell replacement by allogeneic islet transplantation is a promising approach for patients with type 1 diabetes, but the shortage of organ donors requires new sources ofβcells. Islet regenerationin vivoand generation ofβ-cellsex vivofollowed by transplantation represent attractive therapeutic alternatives to restore theβ-cell mass. In this paper, we discuss different postnatal cell types that have been envisaged as potential sources for futureβ-cell replacement therapy. The ultimate goal being translation to the clinic, a particular attention is given to the discrepancies between findings from studies performed in rodents (bothex vivoon primary cells andin vivoon animal models), when compared with clinical data and studies performed on human cells.

scholarly journals Cell Replacement Strategies Aimed at Reconstitution of the β-Cell Compartment in Type 1 Diabetes

Diabetes ◽  
2014 ◽  
Vol 63 (5) ◽  
pp. 1433-1444 ◽  
Author(s):  
Giuseppe Orlando ◽  
Pierre Gianello ◽  
Marcus Salvatori ◽  
Robert J. Stratta ◽  
Shay Soker ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Β Cell ◽  
Cell Compartment ◽  
Cell Replacement

scholarly journals Generation of stem cell-derived β-cells from patients with type 1 diabetes

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Jeffrey R. Millman ◽  
Chunhui Xie ◽  
Alana Van Dervort ◽  
Mads Gürtler ◽  
Felicia W. Pagliuca ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Biology ◽  
Disease Model ◽  
Diabetic Patients ◽  
Β Cells ◽  
Β Cell ◽  
Diabetes Drug

Abstract We recently reported the scalable in vitro production of functional stem cell-derived β-cells (SC-β cells). Here we extend this approach to generate the first SC-β cells from type 1 diabetic patients (T1D). β-cells are destroyed during T1D disease progression, making it difficult to extensively study them in the past. These T1D SC-β cells express β-cell markers, respond to glucose both in vitro and in vivo, prevent alloxan-induced diabetes in mice and respond to anti-diabetic drugs. Furthermore, we use an in vitro disease model to demonstrate the cells respond to different forms of β-cell stress. Using these assays, we find no major differences in T1D SC-β cells compared with SC-β cells derived from non-diabetic patients. These results show that T1D SC-β cells could potentially be used for the treatment of diabetes, drug screening and the study of β-cell biology.

PANC-1 Migration and Cluster Formation is Regulated by Short Range Mechanical Forces

2011 ◽  
Author(s):  
Steven Holfinger ◽  
Rashmeet Reen ◽  
William Ackerman ◽  
Douglas Kniss ◽  
Keith J. Gooch
Keyword(s):  
Cluster Formation ◽  
Cell Types ◽  
Organ Donors ◽  
Islet Cell Transplantation ◽  
Insulin Independence ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Levels ◽  
Alternative Sources

Islet cell transplantation has already shown improved control of glucose levels and the potential to achieve insulin independence in type 1 diabetes mellitus, however there is a shortage of organ donors needed to match patient needs [1–2]. In the search for alternative sources of islets, many cell types have shown signs of β-cell differentiation by secreting c-peptide, insulin, and glucagon [3–5]. When maintained in serum-free medium, human epithelial-like pancreatic adenocarcinoma (PANC-1) cells and human-islet derived precursor cells (hIPCs) can go through a morphological transition and cluster [6]. These islet-like cell aggregates subsequently express glucagon, somatostatin, and insulin, indicating that clustering may play an important role in differentiation towards β-cells [7].

scholarly journals The Many Lives of Myc in the Pancreatic β-Cell

2020 ◽  
pp. jbc.REV120.011149
Author(s):  
Carolina Rosselot ◽  
Sharon Baumel-Alterzon ◽  
Yansui Li ◽  
Gabriel Brill ◽  
Luca Lambertini ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcription Factor ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Diabetic Patients ◽  
Cell Regeneration ◽  
Diabetes Research ◽  
Β Cells ◽  
Β Cell

Diabetes results from insufficient numbers of functional pancreatic β-cells. Thus, increasing the number of available functional β-cells ex vivo for transplantation, or regenerating them in situ in diabetic patients, is a major focus of diabetes research. The transcription factor, Myc, discovered decades ago, lies at the nexus of most, if not all, known proliferative pathways. Based on this, many studies in the 1990’s and early 2000’s explored the potential of harnessing Myc expression to expand β-cells for diabetes treatment. Nearly all these studies in β-cells used pathophysiological or supraphysiological levels of Myc and reported enhanced β-cell death, de-differentiation or the formation of insulinomas if co-overexpressed with Bcl-xL, an inhibitor of apoptosis. This obviously reduced the enthusiasm for Myc as a therapeutic target for β-cell regeneration. However, recent studies indicate that “gentle” induction of Myc expression enhances β-cell replication without induction of cell death or loss of insulin secretion, suggesting that appropriate levels of Myc could have therapeutic potential for β-cell regeneration. Furthermore, although it has been known for decades that Myc is induced by glucose in β-cells very little is known about how this essential anabolic transcription factor perceives and responds to nutrients and increased insulin demand in vivo. Here we summarize the previous and recent knowledge of Myc in the β-cell, its potential for β-cell regeneration and its physiological importance for neonatal and adaptive β-cell expansion.

Using Mass Spectrometry to Detect, Differentiate, and Semiquantitate Closely Related Peptide Hormones in Complex Milieu: Measurement of IGF-II and Vesiculin

Endocrinology ◽  
2015 ◽  
Vol 156 (3) ◽  
pp. 1194-1199 ◽  
Author(s):  
Kate L. Lee ◽  
Martin J. Middleditch ◽  
Geoffrey M. Williams ◽  
Margaret A. Brimble ◽  
Garth J. S. Cooper
Keyword(s):  
Mass Spectrometry ◽  
Secretory Granules ◽  
Prenatal Development ◽  
Mouse Serum ◽  
Diabetes Research ◽  
Β Cell ◽  
Murine Cell Line ◽  
Liquid Chromatography Tandem Mass

Abstract The search for an islet β-cell growth factor has been a key objective in recent diabetes research, because the ability to regenerate and/or protect the functioning β-cell population in patients could result in a great advancement for diabetes treatment. IGF-I and IGF-II are known to play crucial roles in fetal growth and prenatal development, and there is growing evidence that IGF-II increases β-cell proliferation and survival in vitro and in vivo. A search for the source of IGF-II–like immunoreactivity in isolated β-cell secretory granules from the murine cell line βTC6-F7 revealed a novel 2-chain IGF-II–derived peptide, which we named vesiculin and which has been shown to be a full insulin agonist. Here, we present a liquid chromatography–tandem mass spectrometry method that enables selective detection and semiquantitation of the highly related IGF-II and vesiculin molecules. We have used this method to measure these 2 peptides in conditioned media from 2 β-cell lines, produced under increasing glucose concentrations. This technique detected both IGF-II and vesiculin in media conditioned by MIN6 and βTC6-F7 cells at levels in the range of 0 to 6 μM (total insulin, 80–450 μM) and revealed a glucose-stimulated increase in insulin, IGF-II, and vesiculin. IGF-II was detected in adult human and neonatal mouse serum in high levels, but vesiculin was not present. The methodology we present herein has utility for detecting and differentiating active peptides that are highly related and of low abundance.

scholarly journals Mitophagy protects beta cells from inflammatory damage in diabetes

2020 ◽  
Author(s):  
Vaibhav Sidarala ◽  
Gemma L. Pearson ◽  
Vishal S. Parekh ◽  
Benjamin Thompson ◽  
Lisa Christen ◽  
...  
Keyword(s):  
Β Cells ◽  
Β Cell ◽  
Inflammatory Signaling ◽  
Protective Response ◽  
Inflammatory Stress ◽  
Inflammatory Conditions ◽  
Inflammatory Damage ◽  
Pro Inflammatory Cytokines

AbstractInflammatory damage contributes to β-cell failure in type 1 and 2 diabetes (T1D and T2D). Mitochondria are damaged by inflammatory signaling in β-cells, resulting in impaired bioenergetics and initiation of pro-apoptotic machinery. Hence, the identification of protective responses to inflammation could lead to new therapeutic targets. Here we report that mitophagy serves as a protective response to inflammatory stress in both human and rodent β-cells. Utilizing in vivo mitophagy reporters, we observed that diabetogenic pro-inflammatory cytokines induced mitophagy in response to nitrosative/oxidative mitochondrial damage. Mitophagy-deficient β-cells were sensitized to inflammatory stress, leading to the accumulation of fragmented dysfunctional mitochondria, increased β-cell death, and hyperglycemia. Overexpression of CLEC16A, a T1D gene and mitophagy regulator whose expression in islets is protective against T1D, ameliorated cytokine-induced human β-cell apoptosis. Thus, mitophagy promotes β-cell survival and prevents diabetes by countering inflammatory injury. Targeting this pathway has the potential to prevent β-cell failure in diabetes and may be beneficial in other inflammatory conditions.

scholarly journals Longitudinal Intravital Imaging of Biosensor-labeled In Situ Islet Beta Cells

2019 ◽  
Author(s):  
Christopher A. Reissaus ◽  
Ashley N. Twigg ◽  
Kara S. Orr ◽  
Abass M. Conteh ◽  
Michelle M. Martinez ◽  
...  
Keyword(s):  
Β Cells ◽  
Dynamic Nature ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Longitudinal Measurements ◽  
Ros Accumulation

AbstractImpaired function and apoptosis of insulin-secreting islet β-cells is central to disease progression in both type 1 and type 2 diabetes. Oxidative damage resulting from excess reactive oxygen species (ROS) is a central factor in β-cell dysfunction and death, but the dynamic nature of ROS accumulation and its depletion pose a problem for mechanistic studies in vivo. Biosensors, including the redox-sensitive GFP (roGFPs), coupled with intravital microscopy provide a sensitive and dynamic solution to this problem. Here, we utilize a virally-delivered roGFP2-containing human glutaredoxin-1 (Grx1-roGFP2) to selectively monitor β-cell ROS dynamics in vivo in response to toxic glucose analogs. We paired viral biosensor delivery with implanted abdominal imaging windows over the pancreas, thus allowing longitudinal measurements of β-cell ROS and islet area during and after streptozotocin (STZ) exposure. The studies presented here represent a robust experimental platform that could be readily adapted to various transgenic or physiological mouse models in conjunction with any number of available biosensors, and thus opens a vast realm of potential for discovery in islet biology in vivo.

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