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J Clin Invest. 01/2012; eLetters.
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ABSTRACT: A major problem in medical research is to translate in vitro observations into the living organism. In this perspective, we discuss ongoing efforts to non-invasively image pancreatic islets/β-cells by techniques, such as magnetic resonance imaging and positron emission tomography, and present an experimental platform, which allows in vivo imaging of pancreatic β-cell mass and function longitudinally and at the single-cell level. Following transplantation of pancreatic islets into the anterior chamber of the eye of mice and rats, these islets are studied by functional microscopic imaging. This imaging platform can be utilized to address fundamental aspects of pancreatic islet cell biology in vivo in health and disease. These include the dynamics of pancreatic islet vascularization, islet cell innervation, signal-transduction, change in functional β-cell mass and immune responses. Moreover, we discuss the feasibility of studying human islet cell physiology and pathology in vivo as well as the potential of using the anterior chamber of the eye as a site for therapeutic transplantation in type 1 diabetes mellitus.
Acta Physiologica 04/2011; 204(2):178-85. · 3.09 Impact Factor
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V L Perez,
A Caicedo,
D M Berman,
E Arrieta,
M H Abdulreda,
R Rodriguez-Diaz,
A Pileggi,
E Hernandez,
S R Dubovy,
J M Parel,
C Ricordi,
N M Kenyon,
N S Kenyon, P O Berggren
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ABSTRACT: The aim of this study was to provide evidence that the anterior chamber of the eye serves as a novel clinical islet implantation site.
In a preclinical model, allogeneic pancreatic islets were transplanted into the anterior chamber of the eye of a baboon model for diabetes, and metabolic and ophthalmological outcomes were assessed.
Islets readily engrafted on the iris and there was a decrease in exogenous insulin requirements due to insulin secretion from the intraocular grafts. No major adverse effects on eye structure and function could be observed during the transplantation period.
Our study demonstrates the long-term survival and function of allogeneic islets after transplantation into the anterior chamber of the eye. The safety and simplicity of this procedure provides support for further studies aimed at translating this technology into the clinic.
Diabetologia 03/2011; 54(5):1121-6. · 6.81 Impact Factor
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M. H. Abdulreda,
G. Faleo,
R. D. Molano,
J. Molina,
Y. H. Tan,
O. A. R. Echeverria,
E. Zahr,
R. Rodriguez-Diaz,
P. K. Edlund,
I. Leibiger,
A. Bayer,
V. L. Perez,
C. Ricordi, P. O. Berggren,
A. Pileggi,
A. Caicedo
Diabetes 01/2010; 59:A39-A39. · 8.29 Impact Factor
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American Journal of Transplantation. 01/2010; 10:229-229.
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M. H. Abdulreda,
G. Faleo,
R. D. Molano,
J. Molina,
Y. H. Tan,
O. A. Ron-Echeverria,
E. Zahr,
R. Rodriguez-Diaz,
I. Leibiger,
A. L. Bayer,
V. L. Perez,
C. Ricordi, P. O. Berggren,
A. Caicedo,
A. Pileggi
American Journal of Transplantation. 01/2010; 10:202-202.
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Diabetes 01/2010; 59:A360-A360. · 8.29 Impact Factor
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M. Abdulreda,
G. Faleo,
R. D. Molano,
J. Molina,
Y. H. Tan,
E. Zahr,
A. Bayer,
V. Perez,
C. Ricordi, P. O. Berggren,
A. Caicedo,
A. Pileggi
American Journal of Transplantation. 01/2010; 10:56-56.
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American Journal of Transplantation. 01/2009; 9:725-725.
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Diabetes 01/2009; 58:A499-A499. · 8.29 Impact Factor
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Xenotransplantation 01/2009; 16(5):415-415. · 2.33 Impact Factor
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Diabetes 01/2009; 58:A102-A103. · 8.29 Impact Factor
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American Journal of Transplantation. 01/2009; 9:726-727.
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Diabetes 01/2009; 58:A57-A57. · 8.29 Impact Factor
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ABSTRACT: An insufficient number of insulin-producing beta-cells is a major cause of defective control of blood glucose in both type 1 and type 2 diabetes. The aim of this study was to clarify whether the insulinotropic imidazolines can affect the survival of highly proliferating insulin-secreting cells, here exemplified by the MIN6 cell line. Our data demonstrate that RX871024, but not efaroxan, triggered MIN6 cell death and potentiated death induced by a combination of the pro-inflammatory cytokines interleukin-1beta, interferon- gamma and tumor necrosis factor-alpha. These effects did not involve changes in nitric oxide production but correlated with stimulation of c-jun N-terminal kinase (JNK) activity and activation of caspases-1, -3, -8 and -9. Our results suggest that the imidazoline RX871024 causes death of highly proliferating insulin-secreting cells, putatively via augmentation of JNK activity, a finding that may impact on the possibility of using compounds of similar activity in the treatment of diabetes.
Cellular and Molecular Life Sciences CMLS 05/2008; 65(7-8):1248-55. · 6.57 Impact Factor
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N Dekki,
R Nilsson,
S Norgren,
S M Rössner,
I Appelskog,
C Marcus,
O Simell,
A Pugliese,
R Alejandro,
C Ricordi, P O Berggren,
L Juntti-Berggren
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ABSTRACT: The aim of this study was to clarify the frequency of patients with type 1 diabetes that have serum that increases pancreatic beta-cell cytoplasmic free Ca(2+) concentration, [Ca(2+)](i), and if such an effect is also present in serum from first-degree relatives. We also studied a possible link between the serum effect and ethnic background as well as presence of autoantibodies. Sera obtained from three different countries were investigated as follows: 82 Swedish Caucasians with newly diagnosed type 1 diabetes, 56 Americans with different duration of type 1 diabetes, 117 American first-degree relatives of type 1 diabetic patients with a mixed ethnic background and 31 Caucasian Finnish children with newly diagnosed type 1 diabetes. Changes in [Ca(2+)](i) , upon depolarization, were measured in beta-cells incubated overnight with sera from type 1 diabetic patients, first-degree relatives or healthy controls. Our data show that there is a group constituting approximately 30% of type 1 diabetic patients of different gender, age, ethnic background and duration of the disease, as well as first-degree relatives of type 1 diabetic patients, that have sera that interfere with pancreatic beta-cell Ca(2+)-handling. This effect on beta-cell [Ca(2+)](i) could not be correlated to the presence of autoantibodies. In a defined subgroup of patients with type 1 diabetes and first-degree relatives a defect Ca(2+)-handling may aggravate development of beta-cell destruction.
Bioscience Reports 01/2008; 27(6):321-6. · 2.38 Impact Factor
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Purinergic Signalling 01/2008; 4:S49-S49. · 3.16 Impact Factor
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ABSTRACT: The mechanism by which the novel, pure glucose-dependent insulinotropic, imidazoline derivative BL11282 promotes insulin secretion in pancreatic islets has been investigated. The roles of KATP channels, alpha2-adrenoreceptors, the I1-receptor-phosphatidylcholine-specific phospholipase (PC-PLC) pathway and arachidonic acid signaling in BL11282 potentiation of insulin secretion in pancreatic islets were studied. Using SUR1(-/-) deficient mice, the previous notion that the insulinotropic activity of BL11282 is not related to its interaction with KATP channels was confirmed. Insulinotropic activity of BL11282 was not related to its effect on alpha2-adrenoreceptors, I1-imidazoline receptors or PC-PLC. BL11282 significantly increased [3H]arachidonic acid production. This effect was abolished in the presence of the iPLA2 inhibitor, bromoenol lactone. The data suggest that potentiation of glucose-induced insulin release by BL11282, which is independent of concomitant changes in cytoplasmic free Ca2+ concentration, involves release of arachidonic acid by iPLA2 and its metabolism to epoxyeicosatrienoic acids through the cytochrome P-450 pathway.
Cellular and Molecular Life Sciences CMLS 12/2007; 64(22):2985-93. · 6.57 Impact Factor
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ABSTRACT: The pancreatic beta cell ATP-sensitive potassium (K(ATP)) channel, composed of the pore-forming alpha subunit Kir6.2, a member of the inward rectifier K+channel family, and the regulatory beta subunit sulfonylurea receptor 1 (SUR1), a member of the ATP-binding cassette superfamily, couples the metabolic state of the cell to electrical activity. Several endogenous compounds are known to modulate K(ATP) channel activity, including ATP, ADP, phosphatidylinositol diphosphates and long-chain acyl coenzyme A (LC-CoA) esters. LC-CoA esters have been shown to interact with Kir6.2, but the mechanism and binding site(s) have yet to be identified.
Using multiple sequence alignment of known acyl-CoA ester interacting proteins, we were able to identify four conserved amino acid residues that could potentially serve as an acyl-CoA ester-binding motif. The motif was also recognised in the C-terminal region of Kir6.2 (R311-332) but not in SUR1.
Oocytes expressing Kir6.2DeltaC26 K332A repeatedly generated K(+)currents in inside-out membrane patches that were sensitive to ATP, but were only weakly activated by 1 mumol/l palmitoyl-CoA ester. Compared with the control channel (Kir6.2DeltaC26), Kir6.2DeltaC26 K332A displayed unaltered ATP sensitivity but significantly decreased sensitivity to palmitoyl-CoA esters. Coexpression of Kir6.2DeltaC26 K332A and SUR1 revealed slightly increased activation by palmitoyl-CoA ester but significantly decreased activation by the acyl-CoA esters compared with the wild-type K(ATP) channel and Kir6.2DeltaC26+SUR1. Computational modelling, using the crystal structure of KirBac1.1, suggested that K332 is located on the intracellular domain of Kir6.2 and is accessible to intracellular modulators such as LC-CoA esters.
These results verify that LC-CoA esters interact at the pore-forming subunit Kir6.2, and on the basis of these data we propose an acyl-CoA ester binding motif located in the C-terminal region.
Diabetologia 09/2007; 50(8):1670-7. · 6.81 Impact Factor
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Diabetologia 08/2007; 50(7):1559-60. · 6.81 Impact Factor
