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1.
Am J Transplant ; 17(9): 2444-2450, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28489277

ABSTRACT

Islet transplantation offers a minimally invasive approach for ß cell replacement in diabetic patients with hypoglycemic unawareness. Attempts at insulin independence may require multiple islet reinfusions from distinct donors, increasing the risk of allogeneic sensitization. Currently, solid organ pancreas transplant is the only remaining surgical option following failed islet transplantation in the United States; however, the immunologic impact of repeated exposure to donor antigens on subsequent pancreas transplantation is unclear. We describe a case series of seven patients undergoing solid organ pancreas transplant following islet graft failure with long-term follow-up of pancreatic graft survival and renal function. Despite highly variable panel reactive antibody levels prior to pancreas transplant (mean 27 ± 35%), all seven patients achieved stable and durable insulin independence with a mean follow-up of 6.7 years. Mean hemoglobin A1c values improved significantly from postislet, prepancreas levels (mean 8.1 ± 1.5%) to postpancreas levels (mean 5.3 ± 0.1%; p = 0.0022). Three patients experienced acute rejection episodes that were successfully managed with thymoglobulin and methylprednisolone, and none of these preuremic type 1 diabetic recipients developed stage 4 or 5 chronic kidney disease postoperatively. These results support pancreas-after-islet transplantation with aggressive immunosuppression and protocol biopsies as a viable strategy to restore insulin independence after islet graft failure.


Subject(s)
Diabetes Mellitus, Type 1/surgery , Graft Rejection/prevention & control , Islets of Langerhans Transplantation , Pancreas Transplantation , Adult , Female , Follow-Up Studies , Graft Survival , Humans , Immunosuppressive Agents/therapeutic use , Insulin/blood , Male , Middle Aged , Prognosis , Risk Factors , Young Adult
3.
Am J Physiol ; 276(1): G211-8, 1999 01.
Article in English | MEDLINE | ID: mdl-9886998

ABSTRACT

In a rabbit model of chronic ileal inflammation, we previously demonstrated inhibition of Na-glucose cotransport (SGLT-1). The mechanism of inhibition was secondary to a decrease in the number of cotransporters and not solely secondary to an inhibition of Na-K-ATPase or altered affinity for glucose. In this study, we determined the effect of methylprednisolone (MP) on SGLT-1 inhibition during chronic ileitis. Treatment with MP almost completely reversed the reduction in SGLT-1 in villus cells from the chronically inflamed ileum. MP also reversed the decrease in Na-K-ATPase activity in villus cells during chronic ileitis. However, MP treatment reversed the SGLT-1 inhibition in villus cell brush-border membrane vesicles from the inflamed ileum, which suggested an effect of MP at the level of the cotransporter itself. Kinetic studies demonstrated that the reversal of SGLT-1 inhibition by MP was secondary to an increase in the maximal velocity for glucose without a change in the affinity. Analysis of immunoreactive protein levels of the cotransporter demonstrated a restoration of the cotransporter numbers after MP treatment in the chronically inflamed ileum. Thus MP treatment alleviates SGLT-1 inhibition in the chronically inflamed ileum by increasing the number of cotransporters and not solely secondary to enhancing the activity of Na-K-ATPase or by altering the affinity for glucose.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Ileitis/metabolism , Ileum/metabolism , Membrane Glycoproteins/antagonists & inhibitors , Methylprednisolone/pharmacology , Monosaccharide Transport Proteins/antagonists & inhibitors , Animals , Blotting, Western , Chronic Disease , Ileitis/pathology , Ileum/drug effects , Ileum/pathology , Membrane Glycoproteins/metabolism , Microvilli/metabolism , Monosaccharide Transport Proteins/metabolism , Rabbits , Sodium-Glucose Transporter 1 , Sodium-Potassium-Exchanging ATPase/metabolism
4.
Am J Physiol ; 275(6): G1259-65, 1998 12.
Article in English | MEDLINE | ID: mdl-9843761

ABSTRACT

In the chronically inflamed ileum, unique mechanisms of alteration of similar transport processes suggest regulation by different immune-inflammatory mediator pathways. In a rabbit model of chronic ileitis, we previously demonstrated that Na+-glucose cotransport was inhibited by a decrease in the cotransporter numbers, whereas Na+-amino acid cotransport was inhibited by a decrease in the affinity for the amino acid. In this study, we demonstrated that Na+-bile acid cotransport was reduced in villus cells from the chronically inflamed ileum. In villus cell brush-border membrane vesicles from the chronically inflamed ileum, Na+-bile acid cotransport was reduced as well, suggesting a direct effect at the cotransporter itself. Kinetic studies demonstrated that Na+-bile acid cotransport was inhibited by both a decrease in the affinity as well as a decrease in the maximal rate of uptake of the bile acid. Analysis of steady-state mRNA and immunoreactive protein levels of the Na+-bile acid cotransporter also demonstrated some reduction during chronic ileitis. Thus, in the chronically inflamed ileum, the mechanisms of inhibition of Na+-glucose, Na+-amino acid, and Na+-bile acid cotransport are different. These data suggest that different cotransporters are uniquely altered either secondary to their intrinsic differences or by different immune-inflammatory mediators during chronic ileitis.


Subject(s)
Carrier Proteins/antagonists & inhibitors , Ileitis/metabolism , Organic Anion Transporters, Sodium-Dependent , Symporters , Animals , Bile Acids and Salts/metabolism , Carrier Proteins/genetics , Carrier Proteins/metabolism , Chronic Disease , Homeostasis/physiology , Ileitis/pathology , Ileum/metabolism , Ileum/pathology , Kinetics , Microvilli/metabolism , RNA, Messenger/metabolism , Rabbits
5.
Am J Physiol ; 275(3): G483-9, 1998 09.
Article in English | MEDLINE | ID: mdl-9724259

ABSTRACT

In the chronically inflamed ileum, unique mechanisms of alteration of transport processes suggest regulation by different immune-inflammatory mediator pathways. We previously demonstrated that Na+-glucose cotransport in the chronically inflamed ileum was inhibited by a decrease in cotransporter number without a change in glucose affinity. The aim of this study was to determine the alterations in Na+-amino acid cotransport in chronically inflamed ileum produced by coccidial infection in rabbits. [3H]alanine uptake was performed in cells and vesicles by rapid filtration. In villus cells from chronically inflamed ileum, Na+-K+-ATPase was reduced 50% and Na+-alanine cotransport was also reduced (5.8 +/- 1.2 in normal and 1.4 +/- 0.5 nmol/mg protein in inflamed; n = 6, P < 0.05). [3H]alanine uptake in brush-border membrane vesicles was reduced in chronically inflamed ileum (73.2 +/- 1.2 in normal and 21.5 +/- 3.2 pmol/mg protein in inflamed; n = 3, P < 0.05), suggesting a direct effect on the cotransporter itself. Na+-amino acid cotransport in chronically inflamed ileum was inhibited by a decrease in affinity without a change in the maximal rate of uptake, and unaltered steady-state mRNA levels also suggested that the number of cotransporters was unchanged. Thus the mechanisms of inhibition of Na+-amino acid cotransport and Na+-glucose cotransport in chronically inflamed ileum are different. These observations suggest that different immune-inflammatory mediators may regulate different transport pathways during chronic ileitis.


Subject(s)
Alanine/metabolism , Amino Acid Transport Systems , Carrier Proteins/metabolism , Coccidiosis/metabolism , Eimeria , Ileal Diseases/metabolism , Inflammation/metabolism , Intestinal Mucosa/metabolism , Microvilli/metabolism , Sodium/metabolism , Symporters , Amino Acid Transport Systems, Neutral , Animals , Biological Transport , Carrier Proteins/genetics , Chronic Disease , Ileal Diseases/parasitology , Ileum , Intestinal Mucosa/parasitology , Kinetics , Polymerase Chain Reaction , RNA, Messenger/biosynthesis , Rabbits , Transcription, Genetic
6.
Am J Physiol ; 273(4): G913-9, 1997 10.
Article in English | MEDLINE | ID: mdl-9357835

ABSTRACT

In a rabbit model of chronic ileal inflammation, we previously demonstrated that coupled NaCl absorption was reduced because of an inhibition of Cl-/HCO3- but not Na+/H+ exchange on the brush-border membrane (BBM) of villus cells. In this study we determined the alterations in Na+-stimulated glucose [Na+-O-methyl-D-glucose (Na+-OMG)] absorption during chronic ileitis. Na+-OMG uptake was reduced in villus cells from the chronically inflamed ileum. Na+-K+-adenosinetriphosphatase (ATPase), which provides the favorable Na+ gradient for this cotransporter in intact cells, was found to be reduced also. However, in villus cell BBM vesicles from the inflamed ileum Na+-OMG uptake was reduced as well, suggesting an effect at the level of the cotransporter itself. Kinetic studies demonstrated that Na+-OMG uptake in the inflamed ileum was inhibited by a decrease in the maximal rate of uptake for OMG without a change in the affinity. Analysis of steady-state mRNA and immunoreactive protein levels of this cotransporter demonstrates reduced expression. Thus Na+-glucose cotransport was inhibited in the chronically inflamed ileum, and the inhibition was secondary to a decrease in the number of cotransporters and not solely secondary to an inhibition of Na+-K--ATPase or altered affinity for glucose.


Subject(s)
Coccidiosis/physiopathology , Ileitis/physiopathology , Intestinal Mucosa/metabolism , Membrane Glycoproteins/biosynthesis , Monosaccharide Transport Proteins/biosynthesis , Monosaccharide Transport Proteins/metabolism , Sodium/metabolism , Animals , Coccidiosis/pathology , Eimeria , Ileitis/parasitology , Ileum , Inflammation , Intestinal Absorption , Intestinal Mucosa/pathology , Kinetics , Methylglucosides/metabolism , Microvilli/metabolism , Monosaccharide Transport Proteins/antagonists & inhibitors , RNA, Messenger/biosynthesis , Rabbits , Sodium-Glucose Transporter 1 , Sodium-Potassium-Exchanging ATPase/metabolism , Transcription, Genetic
7.
Ann N Y Acad Sci ; 779: 46-57, 1996 Apr 15.
Article in English | MEDLINE | ID: mdl-8659862

ABSTRACT

We describe an analysis of the NCX1 gene and show that various tissues express different alternatively spliced forms of the gene. Alternative splicing has been confirmed by the genomic analysis of the Na(+)-Ca2+ exchanger gene. We also describe the Drosophila Na(+)-Ca2+ exchanger as having many of the same structural characteristics of the mammalian exchangers and this locus as possibly undergoing alternative splicing in the same region that has been described in the NCX1 gene. The general structure of the exchangers is similar to that of the alpha-subunit of the (Na(+)+ K+)-A Pase. Finally, sequence comparison of the various molecules demonstrates that structural characteristics of these molecules are more strongly conserved than the primary sequence of these products.


Subject(s)
Alternative Splicing , Carrier Proteins/genetics , Amino Acid Sequence , Animals , Calcium/metabolism , Humans , Molecular Sequence Data , Sequence Homology , Sodium/metabolism , Sodium-Calcium Exchanger , Transfection
8.
Am J Pathol ; 144(2): 383-92, 1994 Feb.
Article in English | MEDLINE | ID: mdl-7508685

ABSTRACT

The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein (alpha 2MR/LRP) and its 39-kd receptor-associated protein (RAP) were identified by indirect immunofluorescence in human extravillous and villous trophoblast cells at different stages of pregnancy. The alpha 2MR/LRP was detected in invading trophoblast cells and in some instances these invading cells did not express RAP. In chorionic villi of first and second trimester placenta, alpha 2MR/LRP and RAP were found in cytotrophoblast and syncytiotrophoblast. With advancing pregnancy alpha 2MR/LRP became primarily localized to the apical surface of the syncytiotrophoblast, while RAP was present in the cytoplasm. Villous cytotrophoblast cells lost both proteins by the third trimester. Isolated cytotrophoblast cells that undergo spontaneous differentiation into syncytiotrophoblast in culture increased expression of both alpha 2MR/LRP and RAP. With syncytium formation, alpha 2MR/LRP became localized to the plasma membrane in cup-like structures. Changes in the mRNAs for alpha 2MR/LRP and RAP paralleled the changes in relative abundance of the proteins assessed by immunofluorescence. cAMP treatment suppressed both alpha 2MR/LRP and RAP in the cultured trophoblasts, but alpha 2MR/LRP was reduced to a greater extent than RAP. We conclude that alpha 2MR/LRP and RAP are developmentally regulated in human trophoblast cells, that the temporal and spatial patterns of expression of these proteins can be dissociated, and that cAMP modulates both alpha 2MR/LRP and RAP in human trophoblast. The patterns of alpha 2MR/LRP and RAP expression in trophoblast cells are consistent with roles for the receptor in trophoblast invasion and transport of molecules across the syncytiotrophoblast.


Subject(s)
Carrier Proteins/metabolism , Glycoproteins/metabolism , Receptors, Immunologic/metabolism , Trophoblasts/metabolism , Cell Division , Cells, Cultured , Chorionic Villi/metabolism , Cytoplasm/metabolism , Female , Fluorescent Antibody Technique , Humans , Immunoblotting , LDL-Receptor Related Protein-Associated Protein , Low Density Lipoprotein Receptor-Related Protein-1 , Pregnancy , RNA, Messenger/metabolism , Receptors, Immunologic/genetics , alpha-Macroglobulins/genetics , alpha-Macroglobulins/metabolism
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