scholarly journals Pancreatic Pseudoislets: An Organoid Archetype for Metabolism Research

2021 ◽  
Author(s):  
Mollie S.H. Friedlander ◽  
Vy M. Nguyen ◽  
Seung K. Kim ◽  
Romina J. Bevacqua
Keyword(s):  
Islet Cell ◽  
Islet Cells ◽  
Glucagon Secretion ◽  
Human Islets ◽  
Human Islet ◽  
International Programs ◽  
Islet Cell Transplantation ◽  
Cellular Mechanisms ◽  
Insulin And Glucagon Secretion ◽  
Experimental Approaches

Pancreatic islets are vital endocrine regulators of systemic metabolism, and recent investigations have increasingly focused on understanding human islet biology. Studies of isolated human islets have advanced understanding of the development, function, and regulation of cells comprising islets, especially pancreatic α- and β-cells. However, the multicellularity of the intact islet has stymied specific experimental approaches—particularly in genetics and cell signaling interrogation. This barrier has been circumvented by the observation that islet cells can survive dispersion and reaggregate to form ‘pseudoislets’, organoids that retain crucial physiological functions, including regulated insulin and glucagon secretion. Recently, exciting advances in the use of pseudoislets for genetics, genomics, islet cell transplantation, and studies of intra-islet signaling and islet cell interactions have been reported by investigators worldwide. Here we review molecular and cellular mechanisms thought to promote islet cell reaggregation, summarize methods that optimize pseudoislet development, and detail recent insights about human islet biology from genetic and transplantation-based pseudoislet experiments. Owing to robust, international programs for procuring primary human pancreata, pseudoislets should serve as both a durable paradigm for primary organoid studies and as an engine of discovery for islet biology, diabetes, and metabolism research.

scholarly journals Pancreatic Pseudoislets: An Organoid Archetype for Metabolism Research

2021 ◽  
Author(s):  
Mollie S.H. Friedlander ◽  
Vy M. Nguyen ◽  
Seung K. Kim ◽  
Romina J. Bevacqua
Keyword(s):  
Islet Cell ◽  
Islet Cells ◽  
Glucagon Secretion ◽  
Human Islets ◽  
Human Islet ◽  
International Programs ◽  
Islet Cell Transplantation ◽  
Cellular Mechanisms ◽  
Insulin And Glucagon Secretion ◽  
Experimental Approaches

Pancreatic islets are vital endocrine regulators of systemic metabolism, and recent investigations have increasingly focused on understanding human islet biology. Studies of isolated human islets have advanced understanding of the development, function, and regulation of cells comprising islets, especially pancreatic α- and β-cells. However, the multicellularity of the intact islet has stymied specific experimental approaches—particularly in genetics and cell signaling interrogation. This barrier has been circumvented by the observation that islet cells can survive dispersion and reaggregate to form ‘pseudoislets’, organoids that retain crucial physiological functions, including regulated insulin and glucagon secretion. Recently, exciting advances in the use of pseudoislets for genetics, genomics, islet cell transplantation, and studies of intra-islet signaling and islet cell interactions have been reported by investigators worldwide. Here we review molecular and cellular mechanisms thought to promote islet cell reaggregation, summarize methods that optimize pseudoislet development, and detail recent insights about human islet biology from genetic and transplantation-based pseudoislet experiments. Owing to robust, international programs for procuring primary human pancreata, pseudoislets should serve as both a durable paradigm for primary organoid studies and as an engine of discovery for islet biology, diabetes, and metabolism research.

scholarly journals Premises for Cholecystokinin and Gastrin Peptides in Diabetes Therapy

2019 ◽  
Vol 12 ◽  
pp. 117955141988360 ◽  
Author(s):  
Jens F Rehfeld
Keyword(s):  
Drug Targets ◽  
Islet Cell ◽  
Active Sites ◽  
Developmental Stages ◽  
Gut Hormones ◽  
Glucagon Secretion ◽  
Human Islets ◽  
The Body ◽  
Pancreatic Islet Cell ◽  
Insulin And Glucagon Secretion

Gastrin and cholecystokinin (CCK) are classical gastrointestinal peptide hormones. Their biogenesis, structures, and intestinal secretory patterns are well-known with the striking feature that their receptor-bound ‘active sites’ are highly homologous and that this structure is conserved for more than 500 million years during evolution. Consequently, gastrin and CCK are agonists for the same receptor (the CCK2 receptor). But in addition, tyrosyl O-sulphated CCK are also bound to the specific CCK1 receptor. The receptors are widely expressed in the body, including pancreatic islet-cell membranes. Moreover, CCK and gastrin peptides are at various developmental stages and diseases expressed in pancreatic islets; also in human islets. Accordingly, bioactive gastrin and CCK peptides stimulate islet-cell growth as well as insulin and glucagon secretion. In view of their insulinotropic effects, gastrin and CCK peptides have come into focus as drug targets, either alone or in combination with other insulinotropic gut hormones or growth factors. So far, modified CCK and gastrin peptides are being examined as potential drugs for therapy of type 1 as well as type 2 diabetes mellitus.

REGULATION OF INSULIN AND GLUCAGON SECRETION FROM A HUMAN ISLET CELL ADENOMA

1977 ◽  
Vol 74 (2) ◽  
pp. 273-280 ◽  
Author(s):  
A. J. BONE ◽  
R. W. GUMPERT ◽  
S. L. HOWELL ◽  
J. SHELDON ◽  
M. TELLEZ-YUDILEVICH ◽  
...  
Keyword(s):  
B Cells ◽  
Islet Cell ◽  
Glucagon Secretion ◽  
Pancreatic Tissue ◽  
Tumour Cells ◽  
Human Islet ◽  
Insulin Content ◽  
Insulin Biosynthesis ◽  
Cell Adenoma ◽  
Insulin And Glucagon Secretion

The regulation of insulin biosynthesis, and insulin and glucagon secretion have been investigated in a human islet cell adenoma, by incubation of tumour fragments. Both biosynthesis and secretion of insulin were strongly stimulated by incubation of islet tumour cells in the presence of increasing glucose concentrations in the range 2–8 mmol/l. However, 20 mm-glucose or 20 mm-glucose plus isobutyl methylxanthine (IBMX), both of which provide potent secretagogues for normal B cells, failed to stimulate proinsulin biosynthesis and secretion from the tumour cells. Overall rates of secretion, expressed as a proportion of total insulin content, were up to 20-fold higher than those expected for normal pancreatic tissue. Glucagon secretion from the tumour was stimulated by low glucose concentrations; normal A cells also respond in this way under these conditions. However, no stimulation of glucagon secretion occurred in the presence of IBMX. There was therefore a major alteration in the regulation both of insulin and glucagon secretion, in that release of neither hormone was stimulated by cyclic AMP. Ultrastructural examination showed the tumour to be rather heterogeneous. A and B cells with normal storage granule content and structure were seen, as well as a rather larger number of B cells containing some granules of atypical appearance. The insulin content of the tumour (13 i.u./g wet wt) was consistent with 6–8% of the tumour cells being B cells.

Role of the Interventional Radiologist in Pancreatic Whole Organ and Islet Cell Transplantation

2019 ◽  
Vol 03 (04) ◽  
pp. 314-325
Author(s):  
Ketan Y. Shah ◽  
Russell O. Simpson ◽  
Yifan Wang ◽  
Obi T. Okoye ◽  
Mithil B. Pandhi ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Islet Cell ◽  
Islet Cells ◽  
Portal System ◽  
Cell Transplant ◽  
Pancreatic Islet Cells ◽  
Islet Cell Transplantation ◽  
Image Guided ◽  
Treatment Of Diabetes

AbstractPancreas transplantation is an exciting therapy which has been used for several decades in the treatment of diabetes mellitus. It can be performed as either a whole organ or islet cell transplant. The role of interventional radiologists in the management of whole organ transplants is evolving and includes treatment of postoperative complications and graft biopsy to evaluate for rejection. An in-depth understanding of the transplant anatomy and variations is a fundamental tool in performing these interventions successfully. Islet cell transplantation entails delivery of purified donor pancreatic islet cells into the recipient portal vein. Because of their expertise in image-guided access to the portal system, interventional radiologists play a crucial role in this procedure. The purpose of this article is to review the indications, anatomy, complications, and outcomes of both whole organ and islet cell pancreas transplants, followed by a discussion of the role of interventional radiologists in each procedure.

scholarly journals Interleukin-22 reverses human islet dysfunction and apoptosis triggered by hyperglycemia and LIGHT

2018 ◽  
Vol 60 (3) ◽  
pp. 171-183
Author(s):  
Shadab Abadpour ◽  
Bente Halvorsen ◽  
Afaf Sahraoui ◽  
Olle Korsgren ◽  
Pål Aukrust ◽  
...  
Keyword(s):  
Islet Cells ◽  
Harmful Effect ◽  
Human Islets ◽  
Protective Role ◽  
Human Islet ◽  
Islet Function ◽  
Post Transplantation ◽  
Interleukin 22 ◽  
Glucose Stimulated Insulin Secretion

Interleukin (IL)-22 has recently been suggested as an anti-inflammatory cytokine that could protect the islet cells from inflammation- and glucose-induced toxicity. We have previously shown that the tumor necrosis factor family member, LIGHT, can impair human islet function at least partly via pro-apoptotic effects. Herein, we aimed to investigate the protective role of IL-22 on human islets exposed to the combination of hyperglycemia and LIGHT. First, we found upregulation of LIGHT receptors (LTβR and HVEM) in engrafted human islets exposed to hyperglycemia (>11 mM) for 17 days post transplantation by using a double islet transplantation mouse model as well as in human islets cultured with high glucose (HG) (20 mM glucose) + LIGHT in vitro, and this latter effect was attenuated by IL-22. The effect of HG + LIGHT impairing glucose-stimulated insulin secretion was reversed by IL-22. The harmful effect of HG + LIGHT on human islet function seemed to involve enhanced endoplasmic reticulum stress evidenced by upregulation of p-IRE1α and BiP, elevated secretion of pro-inflammatory cytokines (IL-6, IL-8, IP-10 and MCP-1) and the pro-coagulant mediator tissue factor (TF) release and apoptosis in human islets, whereas all these effects were at least partly reversed by IL-22. Our findings suggest that IL-22 could counteract the harmful effects of LIGHT/hyperglycemia on human islet cells and potentially support the strong protective effect of IL-22 on impaired islet function and survival.

scholarly journals In vivo studies of glucagon secretion by human islets transplanted in mice

2019 ◽  
Author(s):  
Krissie Tellez ◽  
Yan Hang ◽  
Xueying Gu ◽  
Roland W. Stein ◽  
Seung K. Kim
Keyword(s):  
Insulin Secretion ◽  
Islet Transplantation ◽  
Glucagon Secretion ◽  
Human Islets ◽  
Human Islet ◽  
In Vivo Studies ◽  
Cell Regulation ◽  
Cell Hyperplasia ◽  
Human Islet Transplantation

AbstractRelatively little is known about regulated glucagon secretion by human islet α cells compared to insulin secretion from β cells, despite conclusive evidence of dysfunction in both cell types in diabetes mellitus. Distinct insulin sequences in humans and mice permit in vivo studies of β cell regulation after human islet transplantation in immunocompromised mice, whereas identical glucagon sequences prevent analogous in vivo measures of glucagon output from human α cells. We used CRISPR/Cas9 genome editing to remove glucagon-encoding codons 2-29 in immunocompromised (NSG) mice, preserving production of other proglucagon-derived hormones, like Glucagon-like-peptide 1. These NSG-Glucagon knockout (NSG-GKO) mice had phenotypes associated with glucagon signaling deficits, including hypoglycemia, hyperaminoacidemia, hypoinsulinemia, and islet α cell hyperplasia. NSG-GKO host metabolic and islet phenotypes reverted after human islet transplantation, and human islets retained regulated glucagon and insulin secretion. NSG-GKO mice provide an unprecedented resource to investigate unique, species-specific human α cell regulation in vivo.

scholarly journals The Effect of Recovery Warm-up Time Following Cold Storage on the Dynamic Glucose-stimulated Insulin Secretion of Isolated Human Islets

2020 ◽  
Vol 29 ◽  
pp. 096368972090827
Author(s):  
Oscar Alcazar ◽  
Alejandro Alvarez ◽  
Camillo Ricordi ◽  
Elina Linetsky ◽  
Peter Buchwald
Keyword(s):  
Insulin Secretion ◽  
Cold Storage ◽  
Islet Cell ◽  
Cell Function ◽  
Human Islets ◽  
Second Phase ◽  
Islet Cell Transplantation ◽  
Warm Up ◽  
Recovery Times ◽  
Glucose Stimulated Insulin Secretion

Standardized islet characterization assays that can provide results in a timely manner are essential for successful islet cell transplantation. A critical component of islet cell quality is β-cell function, and perifusion-based assessments of dynamic glucose-stimulated insulin secretion (GSIS) are the most informative method to assess this, as they provide the most complex in vitro evaluation of GSIS. However, protocols used vary considerably among centers and investigators as they often use different low- and high-glucose concentrations, exposure-times, flow-rates, oxygen concentrations, islet numbers, analytical methods, measurement units, and instruments, which result in different readouts and make comparisons across platforms difficult. Additionally, the conditions of islet storage and shipment prior to assessment may also affect islet function. Establishing improved standardized protocols for perifusion GSIS assays should be an integral part of the ongoing effort to increase the rigor of human islet studies. Here, we performed detailed evaluation of GSIS of human islets using a fully automated multichannel perifusion instrument following various warm-up recovery times after cold storage that corresponds to current shipping conditions (8°C). We found that recovery times shorter than 18 h (overnight) resulted in impaired insulin secretion. While the effects were relatively moderate on second-phase insulin secretion, first-phase peaks were restored only following 18-h incubation. Hence, the biphasic profile of dynamic GSIS was considerably affected when islets were not allowed to recover for a sufficient time after being maintained in cold. Accordingly, while cold storage might improve islet cell survival during shipment and prolong the length of culture, functional assessments should be performed only after allowing for at least overnight recovery at physiological temperatures.

scholarly journals Potential Benefits of Nrf2/Keap1 Targeting in Pancreatic Islet Cell Transplantation

Antioxidants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 321 ◽  
Author(s):  
Alberto Jarrin Lopez ◽  
Hien Lau ◽  
Shiri Li ◽  
Hirohito Ichii
Keyword(s):  
Cell Transplantation ◽  
Pancreatic Islet ◽  
Islet Cell ◽  
Islet Cells ◽  
Therapeutic Option ◽  
Inflammatory Cells ◽  
Cell Integrity ◽  
Islet Cell Transplantation ◽  
Pancreatic Islet Cell ◽  
Antioxidant Genes

Permanent pancreatic islet cell destruction occurs in type 1 diabetes mellitus (T1DM) through the infiltration of inflammatory cells and cytokines. Loss of β-cell integrity secondary to oxidation leads to an inability to appropriately synthesize and secrete insulin. Allogenic islet cell transplantation (ICT) has risen as a therapeutic option to mitigate problematic hypoglycemia. Nevertheless, during the process of transplantation, islet cells are exposed to oxidatively caustic conditions that severely decrease the islet cell yield. Islet cells are at a baseline disadvantage to sustain themselves during times of metabolic stress as they lack a robust anti-oxidant defense system, glycogen stores, and vascularity. The Nrf2/Keap1 system is a master regulator of antioxidant genes that has garnered attention as pharmacologic activators have shown a protective response and a low side effect profile. Herein, we present the most recently studied Nrf2/Keap1 activators in pancreas for application in ICT: Dh404, dimethyl fumarate (DMF), and epigallocatechin gallate (EGCG). Furthermore, we discuss that Nrf2/Keap1 is a potential target to ameliorate oxidative stress at every step of the Edmonton Protocol.

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