From:
Sukie Crandall
Date: 2010-04-05 06:00:40 UTC
Subject: [ferrethealth] beta cells arising from Alpha cells instead of from stem cells
To: fhl <ferrethealth@yahoogroups.com>
<http://www.sciencenews.org/view/generic/id/57902/title/Insulin-producing_c=
ells_can_renegerate_in_diabetic_mice
>
Not work in ferrets, but a shift in the data, so if it also applies to=20
ferrets it may help with future understanding of pancreatic diseases=20
that affect them.
> Alpha cells in the pancreas can spontaneously transform into insulin-
> producing beta cells, researchers from the University of Geneva in=20
> Switzerland report online in Nature April 4.
...
> The exciting discovery from this study is that alpha cells can=20
> spontaneously convert to beta cells without any interference...
> it opens up the idea that reprogramming is not just something we=20
> have to force cells to do, that it=92s an intrinsic property of the=20
> cells...
> some of the insulin-producing cells also made glucagon, which is=20
> normally made by alpha cells...
In the mice that creation required most beta cells to first be killed=20
off, but I wonder if anyone has considered looking at it from the=20
opposite vantage point, to see if insulinomae also contain cells that=20
produce glucagon in any species because if so that could point to a=20
genetic component, or if to a trigger component then it could allow=20
better formation of hypotheses about mechanisms.
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=20
> of Glucagon-Expressing Cells and Insulinoma Development.
> Lu J, Herrera PL, Carreira C, Bonnavion R, Seigne C, Calender A,=20
> Bertolino P, Zhang CX.
> Laboratoire G=E9n=E9tique Mol=E9culaire, Signalisation et Cancer, Centre =
> National de la Recherche Scientifique, UMR5201, Facult=E9 de M=E9decine, =
> Universit=E9 Claude Bernard Lyon1, Centre LEON-BERARD, Lyon, France.
> BACKGROUND & AIMS: The tumor suppressor menin is recognized as a key=20
> regulator of pancreatic islet development, proliferation, and beta-
> cell function, whereas its role in alpha cells remains poorly=20
> understood. The purpose of the current study was to address this=20
> issue in relation to islet tumor histogenesis. METHODS: We generated=20
> alpha cell-specific Men1 mutant mice with Cre/loxP technology and=20
> carried out analyses of pancreatic lesions developed in the mutant=20
> mice during aging. RESULTS: We showed that, despite the alpha-cell=20
> specificity of the GluCre transgene, both glucagonomas and a large=20
> amount of insulinomas developed in mutant mice older than 6 months,=20
> accompanied by mixed islet tumors. Interestingly, the cells sharing=20
> characteristics of both alpha and beta cells were identified shortly=20
> after the appearance of menin-deficient alpha cells but well before=20
> the tumor onset. Using a genetic cell lineage tracing analysis, we=20
> demonstrated that insulinoma cells were directly derived from=20
> transdifferentiating glucagon-expressing cells. Furthermore, our=20
> data indicated that the expression of Pdx1, MafA, Pax4, and Ngn3 did=20
> not seem to be required for the initiation of this=20
> transdifferentiation. CONCLUSIONS: Our work shows cell=20
> transdifferentiation as a novel mechanism involved in islet tumor=20
> development and provides evidence showing that menin regulates the=20
> plasticity of differentiated pancreatic alpha cells in vivo,=20
> shedding new light on the mechanisms of islet tumorigenesis.=20
> Copyright =A9 2010 AGA Institute. Published by Elsevier Inc. All=20
> rights reserved.
> PMID: 20138042 [PubMed - as supplied by publisher]
Also interesting in relation to slowed rates of cellular death of such=20
cells:
> Endocrinology. 2010 Mar 10. [Epub ahead of print]
> Exendin-4 Prevents c-Jun N-Terminal Protein Kinase Activation by=20
> 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,=20
> Cignarelli A, Labarbuta R,Marchetti P, Perrini S, Laviola L,=20
> Giorgino F.
> Department of Emergency and Organ Transplantation (A.N., F.D.S.,=20
> M.R.O., M.M., A.L., A.C., R.L., S.P., L.L., F.G.), Section on=20
> Internal Medicine, Endocrinology, Andrology, and Metabolic Diseases,=20
> University of Bari, I-70124 Bari, Italy; and Endocrinology and=20
> Metabolism of Transplantation (P.M.), Azienda Ospedaliera=20
> Universitaria Pisa, 56126 Pisa, Italy.
> Glucagon-like peptide-1 and its analogs may preserve pancreatic beta-
> cell mass by promoting resistance to cytokine-mediated apoptosis.=20
> The mechanisms of TNFalpha-induced apoptosis and of its inhibition=20
> by exendin-4 were investigated in insulin-secreting cells. INS-1 and=20
> MIN6 insulinoma cells were exposed to 20 ng/ml TNFalpha, with or=20
> without pretreatment with 10 nM exendin-4. Treatment with TNFalpha=20
> increased c-Jun N-terminal protein kinase (JNK) phosphorylation 2-
> fold, reduced inhibitor-kappaBalpha (IkappaBalpha) protein content=20
> by 50%, induced opposite changes in caspase-3 and Bcl-2 protein=20
> content, and increased cellular apoptosis. Moreover, exposure to=20
> TNFalpha resulted in increased serine phosphorylation of both=20
> insulin receptor substrate (IRS)-1 and IRS-2 and reduced basal and=20
> insulin-induced Akt phosphorylation. However, in the presence of a=20
> JNK inhibitor, TNFalpha-induced apoptosis was diminished and serine=20
> phosphorylation of IRS proteins was prevented. When cells were=20
> pretreated with exendin-4, TNFalpha-induced JNK and IRS-1/2 serine=20
> phosphorylation was markedly reduced, Akt phosphorylation was=20
> increased, caspase-3 and Bcl-2 protein levels were restored to=20
> normal, and TNFalpha-induced apoptosis was inhibited by 50%. This=20
> was associated with a 2-fold increase in IRS-2 expression levels. A=20
> similar ability of exendin-4 to prevent TNFalpha-induced JNK=20
> phosphorylation was found in isolated pancreatic human islets. The=20
> inhibitory effect of exendin-4 on TNFalpha-induced JNK=20
> phosphorylation was abrogated in the presence of the protein kinase=20
> A inhibitor H89. In conclusion, JNK activation mediates TNFalpha-
> induced apoptosis and impairment of the IRS/Akt signaling pathway in=20
> insulin-secreting cells. By inhibiting JNK phosphorylation in a PKA-
> dependent manner, exendin-4 counteracts TNFalpha-mediated apoptosis=20
> and reverses the inhibitory events in the IRS/Akt pathway, resulting=20
> in promotion of cell survival.
> 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,=20
> Song DK.
> Department of Physiology & Chronic Disease Research Center, Daegu=20
> 700-712, Republic of Korea.
> High doses of glucosamine have been known to induce apoptosis of=20
> pancreatic beta cells. The mechanism for this phenomenon has not=20
> been clearly elucidated. We aimed to explore the potential=20
> mechanisms for glucosamine toxicity in the rat insulinoma cell line=20
> INS-1 and in rat native beta cells. We also investigated whether=20
> glucagon-like peptide (GLP)-1 could be protective against=20
> glucosamine. Glucosamine exhibited dose-dependent inhibition of cell=20
> survival and an increase in the cell population at the sub-G1 phase.=20
> Glucosamine was revealed to inhibit cellular glucose uptake,=20
> resulting in the activation of AMP-activated protein kinase (AMPK).=20
> Accordingly, phosphorylation of P70S6K and ribosomal protein S6=20
> (S6RP) was decreased. Protein glycosylation appeared not to be=20
> involved in this cytotoxicity. Pretreatment with GLP-1 alleviated=20
> glucosamine-mediated inhibition of glucose uptake and lessened AMPK=20
> activation, thus allowing recovery of the phosphorylation levels of=20
> P70S6K and S6RP. The effect of GLP-1 was blocked by the adenylyl=20
> cyclase inhibitor MDL12330A but not by the protein kinase A=20
> inhibitor H89. Taken together, these data demonstrate that=20
> glucosamine may inhibit beta-cell survival by diminishing cellular=20
> glucose uptake independent of glycosylation. This glucosamine=20
> toxicity can be blocked by GLP-1, which leads to recovery of the=20
> glucose uptake through a PKA-independent, cAMP-dependent mechanism.=20
> Copyright 2010 S. Karger AG, Basel.
> 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=20
> insulinomas with PET.
> Brom M, Oyen WJ, Joosten L, Gotthardt M, Boerman OC.
> Department of Nuclear Medicine, Radboud University Nijmegen Medical=20
> Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands
> PURPOSE: Insulinomas are neuroendocrine tumours derived from=20
> pancreatic beta-cells. The glucagon-like peptide 1 receptor (GLP-1R)=20
> is expressed with a high incidence (>90%) and high density in=20
> insulinomas. Glucagon-like peptide 1 (GLP-1), the natural ligand of=20
> GLP-1R, is rapidly degraded in vivo. A more stable agonist of GLP-1R=20
> is exendin-3. We investigated imaging of insulinomas with DOTA-
> conjugated exendin-3 labelled with (68)Ga. METHODS: Targeting of=20
> insulinomas with [Lys(40)(DOTA)]exendin-3 labelled with either=20
> (111)In or (68)Ga was investigated in vitro using insulinoma tumour=20
> cells (INS-1). [Lys(40)((111)In-DTPA)]Exendin-3 was used as a=20
> reference in this study. In vivo targeting was investigated in BALB/
> c nude mice with subcutaneous INS-1 tumours. PET imaging was=20
> performed using a preclinical PET/CT scanner. RESULTS: In vitro=20
> exendin-3 specifically bound and was internalized by GLP-1R-positive=20
> cells. In BALB/c nude mice with subcutaneous INS-1 tumours a high=20
> uptake of [Lys(40)((111)In-DTPA)]exendin-3 in the tumour was=20
> observed (33.5 +/- 11.6%ID/g at 4 h after injection). Uptake was=20
> specific, as determined by coinjection of an excess of unlabelled=20
> [Lys(40)]exendin-3 (1.8 +/- 0.1%ID/g). The pancreas also exhibited=20
> high and specific uptake (11.3 +/- 1.0%ID/g). High uptake was also=20
> found in the kidneys (144 +/- 24%ID/g) and this uptake was not=20
> receptor-mediated. In this murine tumour model optimal targeting of=20
> the GLP-1R expressing tumour was obtained at exendin doses </=3D0.1=20
> 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=20
> (111)In-labelled [Lys(40)(DTPA)]exendin-3 (25.4 +/- 7.2%ID/g). The=20
> subcutaneous tumours were clearly visualized by small-animal PET=20
> imaging after injection of 3 MBq of [Lys(40)((68)Ga-DOTA)]exendin-3.=20
> CONCLUSION: [Lys(40)((68)Ga-DOTA)]Exendin-3 specifically accumulates=20
> 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=20
> 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=20
> 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=20
> Richmond Street, London, Ontario, Canada.
> Novel Glucagon-Like Peptide-1 (GLP-1) derivatives containing the=20
> metal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-
> tetraacetic acid) and naturally occurring Indium ((113/115)In) were=20
> prepared using solid-phase Fmoc methods. All synthesized peptides=20
> contained d-Ala-8, a modification known to improve resistance=20
> towards degradation by dipeptidyl peptidase-IV. The effect of=20
> increased distance between DOTA and the peptide chain was=20
> investigated using an (aminoethyl) ethoxy acetyl linker, in order to=20
> reduce steric effects imposed by DOTA. Placement of linker and DOTA=20
> moieties were also varied within the GLP-1 sequence to test for=20
> optimal metal-complex location. The binding affinity of the peptide=20
> derivatives was determined in vitro with Chinese hamster ovary cells=20
> stably transfected with a human GLP-1 receptor (CHO/GLP-1R) cell=20
> line and was shown to be in the nM range. Gamma camera imaging of an=20
> insulinoma cell line was carried out using (111)In-labeled peptides.=20
> Our results suggest that the prepared GLP-1 derivatives are suitable=20
> imaging probes for studying pancreatic islet function in vivo.=20
> Copyright (c) 2009 Elsevier Ltd. All rights reserved.
> PMID: 20056547 [PubMed - in process]
So, insulinoma tumors may be due to alpha cells gone wrong. The risk=20
of that can have a genetic component, and such cells are resistant to=20
normal modes of cellular death.
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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