From:
Sukie Crandall
Date: 2011-08-08 17:25:12 UTC
Subject: Re: [ferrethealth] Insulinoma...
To: ferrethealth@yahoogroups.com
Also in here are some recent insulinoma imaging info.
I do NOT have time to Search PLOS or PubMed right now unless this comes up immediately but here there was the conversational note which looks like maybe it was in 2008 or before, so if someone has time to look at more recent info on Beta Cell generation that would make sense, especially if it has something in common with the origin modality possibility discussed in the recent Sci Am article, in which case the problem MIGHT be either with the Alpha calls OR EVEN ULTIMATELY WITH THE CELLS THAT CREATE THE ALPHA CELLS (spacing purposely done this way to make caps readable):
> PLOS if I recall right
> indicates that it appears that a number of them develop at the same
> time in waves -- which may help explain why insulinoma can be seeded
> in many locations in the pancreas), etc.
Hopefully, someone here can do a search on Beta Cell Generation in Pub Med and PLOS from 2007 till now for more data.
Where not abstracts and minimal quotes in this the words are mine:
> <http://www.sciencenews.org/view/generic/id/57902/title/Insulin-producing_cells_can_renegerate_in_diabetic_mice
>>
>
> Not work in ferrets, but a shift in the data, so if it also applies to
> ferrets it may help with future understanding of pancreatic diseases
> that affect them.
>
>> Alpha cells in the pancreas can spontaneously transform into insulin-
>> producing beta cells, researchers from the University of Geneva in
>> Switzerland report online in Nature April 4.
>
>
> Okay, yes, they have and guess what they found:
>
> http://www.ncbi.nlm.nih.gov/pubmed/20138042
>
>> Gastroenterology. 2010 Feb 2. [Epub ahead of print]
>> alpha Cell-Specific Men1 Ablation Triggers the Transdifferentiation
>> of Glucagon-Expressing Cells and Insulinoma Development.
>> Lu J, Herrera PL, Carreira C, Bonnavion R, Seigne C, Calender A,
>> Bertolino P, Zhang CX.
>> Laboratoire Génétique Moléculaire, Signalisation et Cancer, Centre
>> National de la Recherche Scientifique, UMR5201, Faculté de Médecine,
>> Université Claude Bernard Lyon1, Centre LEON-BERARD, Lyon, France.
>> BACKGROUND & AIMS: The tumor suppressor menin is recognized as a key
>> regulator of pancreatic islet development, proliferation, and beta-
>> cell function, whereas its role in alpha cells remains poorly
>> understood. The purpose of the current study was to address this
>> issue in relation to islet tumor histogenesis. METHODS: We generated
>> alpha cell-specific Men1 mutant mice with Cre/loxP technology and
>> carried out analyses of pancreatic lesions developed in the mutant
>> mice during aging. RESULTS: We showed that, despite the alpha-cell
>> specificity of the GluCre transgene, both glucagonomas and a large
>> amount of insulinomas developed in mutant mice older than 6 months,
>> accompanied by mixed islet tumors. Interestingly, the cells sharing
>> characteristics of both alpha and beta cells were identified shortly
>> after the appearance of menin-deficient alpha cells but well before
>> the tumor onset. Using a genetic cell lineage tracing analysis, we
>> demonstrated that insulinoma cells were directly derived from
>> transdifferentiating glucagon-expressing cells. Furthermore, our
>> data indicated that the expression of Pdx1, MafA, Pax4, and Ngn3 did
>> not seem to be required for the initiation of this
>> transdifferentiation. CONCLUSIONS: Our work shows cell
>> transdifferentiation as a novel mechanism involved in islet tumor
>> development and provides evidence showing that menin regulates the
>> plasticity of differentiated pancreatic alpha cells in vivo,
>> shedding new light on the mechanisms of islet tumorigenesis.
>> Copyright © 2010 AGA Institute. Published by Elsevier Inc. All
>> rights reserved.
>> PMID: 20138042 [PubMed - as supplied by publisher]
>
> Also interesting in relation to slowed rates of cellular death of such
> cells:
>
>> Endocrinology. 2010 Mar 10. [Epub ahead of print]
>> Exendin-4 Prevents c-Jun N-Terminal Protein Kinase Activation by
>> Tumor Necrosis Factor-{alpha} (TNF{alpha}) and Inhibits TNF{alpha}-
>> Induced Apoptosis in Insulin-Secreting Cells.
>> Natalicchio A, De Stefano F, Orlando MR, Melchiorre M, Leonardini A,
>> Cignarelli A, Labarbuta R,Marchetti P, Perrini S, Laviola L,
>> Giorgino F.
>> Department of Emergency and Organ Transplantation (A.N., F.D.S.,
>> M.R.O., M.M., A.L., A.C., R.L., S.P., L.L., F.G.), Section on
>> Internal Medicine, Endocrinology, Andrology, and Metabolic Diseases,
>> University of Bari, I-70124 Bari, Italy; and Endocrinology and
>> Metabolism of Transplantation (P.M.), Azienda Ospedaliera
>> Universitaria Pisa, 56126 Pisa, Italy.
>>
>> PMID: 20219981 [PubMed - as supplied by publisher]
>
> and
>
> http://www.ncbi.nlm.nih.gov/pubmed/20110682
>
>> Cell Physiol Biochem. 2010;25(2-3):211-20. Epub 2010 Jan 12.
>> Protective role of glucagon-like peptide-1 against glucosamine-
>> induced cytotoxicity in pancreatic beta cells.
>> Kim YK, Park JH, Park SH, Lim B, Baek WK, Suh SI, Lim JG, Ryu GR,
>> Song DK.
>> Department of Physiology & Chronic Disease Research Center, Daegu
>> 700-712, Republic of Korea.
>>
>> PMID: 20110682 [PubMed - in process]
>
> and imaging:
>
> http://www.ncbi.nlm.nih.gov/pubmed/20111963
>
>> Eur J Nucl Med Mol Imaging. 2010 Jan 29. [Epub ahead of print]
>> (68)Ga-labelled exendin-3, a new agent for the detection of
>> insulinomas with PET.
>> Brom M, Oyen WJ, Joosten L, Gotthardt M, Boerman OC.
>> Department of Nuclear Medicine, Radboud University Nijmegen Medical
>> Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands
>> PURPOSE: Insulinomas are neuroendocrine tumours derived from
>> pancreatic beta-cells. The glucagon-like peptide 1 receptor (GLP-1R)
>> is expressed with a high incidence (>90%) and high density in
>> insulinomas. Glucagon-like peptide 1 (GLP-1), the natural ligand of
>> GLP-1R, is rapidly degraded in vivo. A more stable agonist of GLP-1R
>> is exendin-3. We investigated imaging of insulinomas with DOTA-
>> conjugated exendin-3 labelled with (68)Ga. METHODS: Targeting of
>> insulinomas with [Lys(40)(DOTA)]exendin-3 labelled with either
>> (111)In or (68)Ga was investigated in vitro using insulinoma tumour
>> cells (INS-1). [Lys(40)((111)In-DTPA)]Exendin-3 was used as a
>> reference in this study. In vivo targeting was investigated in BALB/
>> c nude mice with subcutaneous INS-1 tumours. PET imaging was
>> performed using a preclinical PET/CT scanner. RESULTS: In vitro
>> exendin-3 specifically bound and was internalized by GLP-1R-positive
>> cells. In BALB/c nude mice with subcutaneous INS-1 tumours a high
>> uptake of [Lys(40)((111)In-DTPA)]exendin-3 in the tumour was
>> observed (33.5 +/- 11.6%ID/g at 4 h after injection). Uptake was
>> specific, as determined by coinjection of an excess of unlabelled
>> [Lys(40)]exendin-3 (1.8 +/- 0.1%ID/g). The pancreas also exhibited
>> high and specific uptake (11.3 +/- 1.0%ID/g). High uptake was also
>> found in the kidneys (144 +/- 24%ID/g) and this uptake was not
>> receptor-mediated. In this murine tumour model optimal targeting of
>> the GLP-1R expressing tumour was obtained at exendin doses </=0.1
>> microg. Remarkably, tumour uptake of (68)Ga-labelled [Lys(40)
>> (DOTA)]exendin-3 was lower (8.9 +/- 3.1%ID/g) than tumour uptake of
>> (111)In-labelled [Lys(40)(DTPA)]exendin-3 (25.4 +/- 7.2%ID/g). The
>> subcutaneous tumours were clearly visualized by small-animal PET
>> imaging after injection of 3 MBq of [Lys(40)((68)Ga-DOTA)]exendin-3.
>> CONCLUSION: [Lys(40)((68)Ga-DOTA)]Exendin-3 specifically accumulates
>> in insulinomas, although the uptake is lower than that of [Lys(40)
>> ((111)In-DTPA)]exendin-3. Therefore, [Lys(40)((68)Ga-DOTA)]exendin-3
>> is a promising tracer to visualize insulinomas with PET.
>> PMID: 20111963 [PubMed - as supplied by publisher]
>
> http://www.ncbi.nlm.nih.gov/pubmed/20056547
>
>> Bioorg Med Chem. 2010 Feb;18(3):1265-72. Epub 2009 Dec 16.
>> Design, synthesis and in vitro characterization of Glucagon-Like
>> Peptide-1 derivatives for pancreatic beta cell imaging by SPECT.
>> Behnam Azad B, Rota VA, Breadner D, Dhanvantari S, Luyt LG.
>> Departments of Chemistry, The University of Western Ontario, 1151
>> Richmond Street, London, Ontario, Canada.
>> Novel Glucagon-Like Peptide-1 (GLP-1) derivatives containing the
>> metal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-
>> tetraacetic acid) and naturally occurring Indium ((113/115)In) were
>> prepared using solid-phase Fmoc methods. All synthesized peptides
>> contained d-Ala-8, a modification known to improve resistance
>> towards degradation by dipeptidyl peptidase-IV. The effect of
>> increased distance between DOTA and the peptide chain was
>> investigated using an (aminoethyl) ethoxy acetyl linker, in order to
>> reduce steric effects imposed by DOTA. Placement of linker and DOTA
>> moieties were also varied within the GLP-1 sequence to test for
>> optimal metal-complex location. The binding affinity of the peptide
>> derivatives was determined in vitro with Chinese hamster ovary cells
>> stably transfected with a human GLP-1 receptor (CHO/GLP-1R) cell
>> line and was shown to be in the nM range. Gamma camera imaging of an
>> insulinoma cell line was carried out using (111)In-labeled peptides.
>> Our results suggest that the prepared GLP-1 derivatives are suitable
>> imaging probes for studying pancreatic islet function in vivo.
>> Copyright (c) 2009 Elsevier Ltd. All rights reserved.
>> PMID: 20056547 [PubMed - in process]
Sukie (not a vet)
Recommended ferret health links:
http://pets.groups.yahoo.com/group/ferrethealth/
http://ferrethealth.org/archive/
http://www.afip.org/ferrets/index.html
http://www.miamiferret.org/
http://www.ferrethealth.msu.edu/
http://www.ferretcongress.org/
http://www.trifl.org/index.shtml
http://homepage.mac.com/sukie/sukiesferretlinks.html
all ferret topics:
http://listserv.ferretmailinglist.org/archives/ferret-search.html
"All hail the procrastinators for they shall rule the world tomorrow."
(2010, Steve Crandall)
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