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PubMedDate not supplied

Determination of the osmotic characteristics of hamster pancreatic islets and isolated pancreatic islet cells.

The ability to store pancreatic islets using cryopreservation methodology would greatly assist the application of clinical islet transplantation to Type 1 (insulin-dependent) diabetics. It is our working thesis that the illumination of fundamental biophysical characteristics of these cells will lead to increased cryosurvival rates through theoretically predicted and experimental testing of optimal freezing protocol; as has been found for cells and tissues such as mammalian and Drosophila embryos. Pancreatic islets were isolated from Golden hamsters and their osmometric behavior, including inactive cell volume (Vb), was determined for either whole islets or isolated individual islet cells. When islets or islet cells were exposed to various concentrations of NaCl, they were found to exhibit a "classic" "Boyle-Van't Hoff" osmometric response. The Boyle-Van't Hoff representation of the volume curve (relative cell volume vs. 1/osmolality) yields a linear response with r values of .99 for each curve. Extrapolations to the normalized osmotically inactive volumes (Vb) were .43 and .22 for whole islets and individual islet cells, respectively. These data regarding the fundamental cryobiological characteristics of islets and islet cells should provide the foundation upon which to further the investigation of osmotic parameters of these cells and eventually lead to the determination of optimal freezing protocols.

Animals↗

PubMed1993

Effects of steroid and lactogenic hormones on islets of Langerhans: a new hypothesis for the role of pregnancy steroids in the adaptation of islets to pregnancy.

Adaptive changes that occur in islets of Langerhans during pregnancy include enhanced insulin secretion, insulin synthesis, beta-cell proliferation, gap-junctional coupling among beta-cells, and glucose oxidation. We have determined that elevated lactogenic activity is directly responsible for these changes in beta-cell function. Recently, we showed that two of the principal adaptive characteristics (insulin secretion and beta-cell proliferation) of rat pregnancy peaked on day 15 and returned to control levels by day 20. As placental lactogen remains elevated during late gestation, it was of interest to determine whether pregnancy steroids could reverse the effects of lactogen on islets. In this study, rat islets were cultured with progesterone, estradiol, rat PRL (rPRL), or combinations of these hormones (progesterone and rPRL, estradiol and rPRL, or progesterone and estradiol and rPRL). Insulin secretion was examined for 8 days, and beta-cell proliferation by 2-bromo-5'-deoxyuridine (BrdU) incorporation on days 4 and 8. rPRL treatment resulted in a time-dependent increase in insulin secretion that was 3-fold greater than that from control islets by day 8. Progesterone and estradiol had minimal effects on insulin secretion. Estradiol had no effect on the increased insulin secretion observed with rPRL during the first 6 days and a small inhibitory effect on days 7 and 8. Although progesterone treatment had no effect on the increased insulin secretion induced by rPRL during the first 3 days, it subsequently resulted in a decline in insulin secretion to that from control islets. The combination of progesterone and estradiol was more effective than either steroid by itself in reversing the effects of rPRL on insulin secretion. Similar results were obtained in the BrdU labeling experiments: 1) a 7-fold increase in the number of BrdU-labeled nuclei per islet was observed after culture in the presence of rPRL; and 2) estradiol had a small inhibitory effect on the increased BrdU labeling observed with rPRL; however, 3) progesterone completely reversed the effect of rPRL on islet beta-cell division. These results demonstrate that progesterone counterregulates the effects of PRL on insulin secretion and islet beta-cell division. The temporal changes observed in islets in vitro under the influence of PRL and progesterone mimic those seen in islets during pregnancy. We conclude that progesterone, which increases in the later stages of gestation, is the primary hormone responsible for counteracting the stimulatory effects of elevated lactogenic activity on islets during late pregnancy.

Animals↗

PubMed1998

Progressive pancreatic islet hyperplasia in the islet-targeted, parathyroid hormone-related protein-overexpressing mouse.

PTH-related protein (PTHrP) is a paracrine/autocrine factor produced in most cell types in the body. Its functions include the regulation of cell cycle, of differentiation, of apoptosis, and of developmental events. One of the cells which produces PTHrP is the pancreatic beta cell. We have previously described a transgenic mouse model of targeted overexpression of PTHrP in the beta cell, the RIP-PTHrP mouse. These studies showed that PTHrP overexpression markedly increased islet mass and insulin secretion and resulted in hypoglycemia. Those studies were limited to RIP-PTHrP mice of 8-12 weeks of age. In the current report, we demonstrate that PTHrP overexpression induces a progressive increase in islet mass over the life of the RIP-PTHrP mouse, and that, in contrast to some other models of targeted PTHrP overexpression, the phenotype is not developmental, but occurs postnatally. The marked increase in islet mass is not associated with a measurable increase in beta cell replication rates. A further slowing in the normally low islet apoptosis rate could not be demonstrated in the RIP-PTHrP islet. Thus, the marked increase in islet mass in the RIP-PTHrP mouse is unexplained in mechanistic terms. Finally, RIP-PTHrP mice are resistant to the diabetogenic effects of streptozotocin. The mechanisms responsible for the increase in islet mass in the RIP-PTHrP mouse likely lie in either very subtle changes in islet turnover or in early steps in islet differentiation and development. The ability of PTHrP to increase islet mass and function, as well as its ability to attenuate the diabetogenic effects of streptozotocin, indicate that further study of PTHrP on islet development and function are important and may lead to therapeutic strategies in diabetes mellitus.

Animals↗

PubMed2006

Pancreatic islet production of vascular endothelial growth factor--a is essential for islet vascularization, revascularization, and function.

To investigate molecular mechanisms controlling islet vascularization and revascularization after transplantation, we examined pancreatic expression of three families of angiogenic factors and their receptors in differentiating endocrine cells and adult islets. Using intravital lectin labeling, we demonstrated that development of islet microvasculature and establishment of islet blood flow occur concomitantly with islet morphogenesis. Our genetic data indicate that vascular endothelial growth factor (VEGF)-A is a major regulator of islet vascularization and revascularization of transplanted islets. In spite of normal pancreatic insulin content and beta-cell mass, mice with beta-cell-reduced VEGF-A expression had impaired glucose-stimulated insulin secretion. By vascular or diffusion delivery of beta-cell secretagogues to islets, we showed that reduced insulin output is not a result of beta-cell dysfunction but rather caused by vascular alterations in islets. Taken together, our data indicate that the microvasculature plays an integral role in islet function. Factors modulating VEGF-A expression may influence islet vascularity and, consequently, the amount of insulin delivered into the systemic circulation.

Animals↗

PubMed2005

Individual mice can be distinguished by the period of their islet calcium oscillations: is there an intrinsic islet period that is imprinted in vivo?

Pulsatile insulin secretion in vivo is believed to be derived, in part, from the intrinsic glucose-dependent intracellular calcium concentration ([Ca2+]i) pulsatility of individual islets. In isolation, islets display fast, slow, or mixtures of fast and slow [Ca2+]i oscillations. We show that the period of islet [Ca2+]i oscillations is unique to each mouse, with the islets from an individual mouse demonstrating similar rhythms to one another. Based on their rhythmic period, mice were broadly classified as being either fast (0.65 +/- 0.1 min; n = 6 mice) or slow (4.7 +/- 0.2 min; n = 15 mice). To ensure this phenomenon was not an artifact of islet-to-islet communication, we confirmed that islets cultured in isolation (period: 2.9 +/- 0.1 min) were not statistically different from islets cultured together from the same mouse (3.1 +/- 0.1 min, P > 0.52, n = 5 mice). We also compared pulsatile insulin patterns measured in vivo with islet [Ca2+]i patterns measured in vitro from six mice. Mice with faster insulin pulse periods corresponded to faster islet [Ca2+]i patterns, whereas slower insulin patterns corresponded to slower [Ca2+]i patterns, suggesting that the insulin rhythm of each mouse is preserved to some degree by its islets in vitro. We propose that individual mice have characteristic oscillatory [Ca2+]i patterns, which are imprinted in vivo through an unknown mechanism.

Animals↗

PubMed2006

CD4+ CD25+ regulatory T-cells inhibit the islet innate immune response and promote islet engraftment.

Early islet cell loss is a significant problem in clinical islet cell transplantation. Diverse stress stimuli induce innate immune responses in islets that contribute to beta-cell dysfunction, inflammation, and loss. Here, we show that cytokine-stimulated murine islets express multiple inflammatory chemokines that recruit T-cells and thereby impair islet function in vitro and in vivo. Both nonislet ductal and exocrine elements and the individual islet cellular components contribute to this innate immune response. CD4+ CD25+ regulatory T-cells inhibit islet chemokine expression through a cell contact-dependent, soluble factor-independent mechanism and inhibit effector T-cell migration to the islet. Regulatory T-cells can also migrate to stimulated islets. Cotransfer of regulatory T-cells with islets in a transplantation model prevents islet innate immune responses and inflammation and preserves normal architecture and engraftment. Regulatory T-cell inhibition of multiple components of innate immune responses may be a fundamental aspect of their function that influences ischemia-reperfusion injury and adaptive immunity.

Animals↗

PubMed1990

Islet cell thymidine kinase activity as indicator of islet cell proliferation in rat pancreas.

The activity of thymidine kinase (TK;EC 2.7.1.21) in homogenates of isolated rat islets of Langerhans was measured and correlated with the DNA replicatory activity of the islet cells. Adult and fetal rat islets were cultured in medium with 2.7 or 16.7 mM glucose or 16.7 mM glucose and 1 microgram/ml human growth hormone. In both types of islets, 16.7 mM glucose doubled [3H]thymidine incorporation compared with 2.7 mM glucose, and the addition of growth hormone caused a further increase in DNA replication. TK activity in the islets showed similar changes in response to glucose and growth hormone. The correlation between [3H]thymidine incorporation and TK activity was thus highly significant. Cell-cycle analysis of cultured fetal rat islets showed that TK activity was preferentially expressed during the S phase of the cell cycle. TK activity of freshly isolated islets declined with the age of the animal. In pancreatic sections, the islet cell autoradiographic labeling index after [3H]thymidine administration in vivo likewise declined with age and was correlated with the TK activity in freshly isolated islets. It is suggested that measurements of islet TK activity can be used as index of islet cell proliferation; this method has the distinct advantage of avoiding the cumbersome procedure of preparing and scoring autoradiograms.

Animals↗

PubMed1986

Effects of islet cell surface antibodies on isolated neonatal rat islets of Langerhans in vitro.

Islet cell surface antibodies (ICSA) were raised by immunization of rabbits with viable neonatal rat pancreatic islet cell suspensions. By absorption with liver powder and spleen cells unspecific cytotoxic components were removable from the sera. Cytotoxic effect of islet cell antiserum against islet cells was indicated by 51Cr-release. In dependence on serum concentration beta-cell damage induced by ICSA-positive serum was detectable by insulin leakage from neonatal rat islets of Langerhans. The immune cytolytic effect of rabbit anti-rat islet cell surface serum was accompanied by morphological alterations of the islet surface structure as revealed by scanning electron microscopy. Pretreatment of pancreatic islets with cytotoxic islet cell antiserum results in an increased insulin leakage even after the removal of the cytotoxic conditions suggesting the persistence of cell membrane lesions. Insulin secretion of islets of Langerhans first exposed to cytotoxic ICSA-positive serum is still stimulated by 15 mmol/1 glucose plus 0.1 mmol/1 3-isobutyl-1-methylxanthine (IBMX) but taking into account the increased insulin leakage the secretory capacity of these islets is significantly diminished.

Animals↗

PubMed1994

Free intraperitoneal islet autografts in pancreatectomized dogs--impact of islet purity and posttransplantation exogenous insulin.

BACKGROUND: We compared the ability of impure, dispersed pancreatic islet tissue (DPIT) and purified islets to engraft in the peritoneal cavity of dogs. We also tested whether posttransplantation insulin therapy affects islet engraftment. METHODS: Thirty-two dogs underwent total pancreatectomy. DPIT was autotransplanted intraperitoneally in nine dogs. Purified islets were autotransplanted intraperitoneally in 13 dogs and intraportally in seven dogs. Dogs received comparable islet mass. One half of the recipients of intraperitoneal grafts received 12 days of posttransplantation exogenous insulin. Three dogs did not undergo transplantation. Intravenous glucose tolerance tests were done at 60 and 180 days. RESULTS: The long-term graft functional survival rate of intraperitoneal DPIT graft was significantly better than the rate of intraperitoneal purified islets (p < 0.01) and was as good as the rate of intraportal purified islets. Purified islets transplanted intraperitoneally failed early compared with other groups, with only 46% functioning at 3 weeks (p = 0.05); exogenous insulin reduced this early failure rate (p = 0.05). At 6 months 67% of intraperitoneal DPIT and 86% of intraportal purified grafts were functioning. Glucose disposal did not differ between groups. CONCLUSIONS: The peritoneal cavity is a safe, practical site for islet transplantation, particularly for high-volume DPIT grafts. DPIT may provide a larger, more viable beta-cell mass than purified islets, or the acinar-ductal tissue may have a positive effect on engraftment. Exogenous insulin may promote engraftment of transplanted islets with a marginal beta-cell mass.

Animals↗

PubMed1999

Immunocytochemical Localization of Glucose Transporter-2 (GLUT-2) in Pancreatic Islets and Islet Cell Tumors.

Glucose is a major metabolic fuel in mammals and is transported into organs and cells by a facilitated diffusion which involves binding of glucose to glucose transporters (GLUTs). Among several GLUTs so far indentified, GLUT-2 is specifically localized immunocytochemV cally in beta-islet cells. Using immunocytochemical staining, normal pancreases and 27 cases of islet cell tumors, including insulinomas, gastrinomas, glucagonomas, pancreatic polypeptide-omas (PPomas), and a nonfunctioning islet cells tumor, were systematically stained for four different pancreatic hormones, gastrin, and GLUT-2. GLUT-2 staining in beta-islet cells was more diffuse than that of insulin immunostaining, and corresponded with the positive staining in the lateral segments of beta-cell plasma membrane, that faced adjacent beta-cells. Glucagon, somatostatin (SRIF) and PP cells stained weakly for GLUT-2, weaker than that of beta-cells. Some nonbeta cells, especially extra-islet PP cells were not stained for GLUT-2. Among islet cell tumors, insulinomas stained less strongly for GLUT-2 than normal beta-cells from the adjacent normal pancreas. Gastrinomas, glucagonomas, and PPomas stained weaker than insulinomas. Even nonfunctioning islet cell tumors were weakly stained for GLUT-2. The positive staining for GLUT-2 observed for islets cells and all islet tumors is consistent with the notion that all pancreatic islet cells and islet cell tumors utilize glucose as a major fuel, requiring transporter-facilitated diffusion of glucose into the cells of normal organ and their tumors.

Journal Article↗

PubMed2002

Islet yield remains a problem in islet autotransplantation.

For patients with chronic pancreatitis whose pain is inadequately controlled with opiate analgesia, surgical resection offers a good chance of symptomatic relief. However, the inevitable sequela is type 1 diabetes mellitus and its attendant long-term complications. Islet cell autotransplantation offers a theoretical "cure" for this iatrogenic diabetes but this end point has not been produced consistently in clinical practice. The main factor determining the likelihood of insulin independence after islet autotransplantation is the islet mass that is transplanted. This review examines the factors that affect the functional islet mass available for transplantation. Original articles and reviews from peer-reviewed journals were analyzed following a computer search of the MEDLINE database from 1966 to the present, we extracted mainly level 2 and level 3 data. Although improvements in collagenase consistency and purification techniques and reductions in cold ischemic times have all been shown to improve islet yield, there is still the need to optimize every stage in the islet isolation process. Increasing the proportion of potential islets in the final isolate is of particular importance in chronic pancreatitis because the total mass of islets initially available in the gland might be just sufficient to produce insulin independence after islet autotransplantation. We believe that reducing the warm ischemic time might significantly increase the likelihood of insulin independence after islet autotransplantation.

Chronic Disease↗

PubMed1995

Clinical islet transplantation experience of the University of California Islet Transplant Consortium.

BACKGROUND: The University of California Islet Transplant Consortium was formed to evaluate the feasibility of performing clinical islet transplantation at different transplant centers by using a single centralized islet isolation laboratory. METHODS: From July 1992 through February 1995 seven adult islet transplantations were performed, six allografts and one autograft. Once procured, human pancreata were brought to the UCLA-VA Islet Core Laboratory for islet isolation and purification, which were then transported to different centers for transplantation. Patients 1 through 3 received their transplants in Los Angeles, patient 4 received her islet transplant in Torrance, and patients 5 through 7 received their transplants in San Francisco. RESULTS: Although none of these patients achieved insulin independence, four of seven had functioning grafts longer than 6 months as indicated by circulating C-peptide level greater than 0.7 ng/ml. Furthermore, improved glucose control as shown by a decreased insulin requirement was seen in 57% (four of seven patients) of these patients. The ability to isolate islets at a single laboratory and transport them long distances to different centers was shown in patients 4 through 7. CONCLUSIONS: Islet transplantation can be performed with improvements in blood glucose control, and islets can be isolated at a centralized location and successfully transported to different centers for transplantation.

Adult↗

PubMed2002

New markers for pancreatic islets and islet cell tumors.

Islets of Langerhans account for 2 g of endocrine tissue in the pancreas, comprising approximately one million islets, with each containing 1000 endocrine cells. The major hormone secreted from the islets is insulin, which regulates blood glucose, the main fuel of the body. Islets also secrete glucagon, somatostatin and pancreatic polypeptide and all are involved in the paracrine mechanism. Islet cells can be stained immunohistochemically for the general endocrine markers, chromogranin A, synaptophysin, neuron-specific enolase and Leu7. Beta islet cells are well equipped with glucose transporter 2, which binds to glucose and regulates diffusion of glucose through the beta cell membrane. As all four islet hormones are initially synthesized as prohormones, all islet cells are equipped with prohormone convertase 1/3 and 2. In addition, islet cells also contain zinc-containing matrix metalloproteinases and their inhibitors, metallothionein, cyclin-dependent kinases and insulin-like growth factors, and many more hormones, peptides and enzymes. Thus, islets not only secrete insulin and other pancreatic hormones but are a complex organ whose major function is glucose homeostasis.

Adult↗

PubMed1991

Islet transplantation in experimental diabetes of the rat. XIII. Cryopreservation reduces MHC class II but not class I antigens of rat pancreatic islets.

Pretreatment of islet allografts prior to transplantation may reduce islet immunogenicity and prolong graft acceptance. We have studied the MHC antigen reducing effect of cryopreservation onto rat pancreatic islets performing indirect immunofluorescence tests and peroxidase-anti-peroxidase staining (PAP). Three different freezing programs were used. Program A: 0.5 degrees C/min to -35 degrees C and 1 degree C/min from -35 to -100 degrees C. Program B: 2 degrees C/min to -35 degrees C and 6 degrees C/min from -35 to -100 degrees C. Program C: 0.25 degrees C/min to -40 degrees C. Cryopreservation clearly reduced the number of class II antigen positive cells per islet in all cases. Program A was most effective with 45.5% of class II antigen negative islets compared to 6.4% of class II antigen negative fresh islets as shown by indirect immunofluorescence. The class II antigen reducing effect of cryopreservation proved to be permanent and not only temporary. Reduced class II antigen expression of cryopreserved islets could not be reestablished by incubation of the islets with rat IFN. A combination of cryopreservation followed by a 10 day culture period proved to be most effective with 85.6% of class II antigen negative islets. In contrast, we could not show any effect of cryopreservation on class I antigen expression. Viability of the cryopreserved rat islets was shown in-vitro by glucose stimulated insulin secretion.

Animals↗

PubMed2002

Adenovirus-mediated hepatocyte growth factor expression in mouse islets improves pancreatic islet transplant performance and reduces beta cell death.

Hepatocyte growth factor (HGF) increases beta cell proliferation and function in rat insulin promoter (RIP)-targeted transgenic mice. RIP-HGF mouse islets also function superiorly to normal islets in a transplant setting. Here, we aimed to determine whether viral gene transfer of the HGF gene into mouse islets ex vivo could enhance the performance of normal islets in a streptozotocin-diabetic severe combined immunodeficient mouse marginal islet mass model in which 300 uninfected or adenovirus (Adv) LacZ-transduced islet equivalents were insufficient to correct hyperglycemia. In dramatic contrast, 300 AdvHGF-transduced islet equivalents promptly (day 1) and significantly (p < 0.01) decreased random non-fasting blood glucose levels, from 351 +/- 20 mg/dl to an average of 191 +/- 7 mg/dl over 8 weeks. At day 1 post-transplant, beta cell death was significantly (p < 0.05) decreased, and the total insulin content was significantly (p < 0.05) increased in AdvHGF-transduced islets containing grafts. This anti-beta cell death action of HGF was independently confirmed in RIP-HGF mice and in INS-1 cells, both treated with streptozotocin. Activation of the phosphatidylinositol 3-kinase/Akt intracellular-signaling pathway appeared to be involved in this beta cell protective effect of HGF in vitro. In summary, adenoviral delivery of HGF to murine islets ex vivo improves islet transplant survival and blood glucose control in a subcapsular renal graft model in immuno-incompetent diabetic mice.

Adenoviridae↗

PubMed1994

The role of nitric oxide in IL-1 beta-mediated dysfunction of rodent islets of Langerhans. Implications for the function of intrahepatic islet grafts.

Products of inflammation, such as interleukin-1 beta (IL-1 beta) and nitric oxide (NO), may impair early function of pancreatic islet grafts. In in vitro studies, freshly isolated rat islets of Langerhans cultured for 24 hr (10 islets/well) in the presence of 20 IU/ml of IL-1 beta released 57% less insulin (mean +/- S.E. of 151 +/- 61 microU) on the average than control (385 +/- 89 microU) cultures (n = 9, P = 0.08). Nitrite levels in the medium (indirect measure of NO) after islets were cultured for a 24-hr period were nearly 3-fold greater in IL-1 beta-exposed islets than control islet cultures (5.8 +/- 1.0 microM vs. 2.2 +/- 0.3 microM, P = 0.03). Production of nitrite by islet cells in the presence of IL-1 beta was inhibited in cultures also containing 2 mM L-NG-monomethyl-Arginine (L-NMMA) (3.4 +/- 0.4 microM, n = 9, P = 0.09 vs. control). When islets were maintained for 1 hr in 30 mg/dl glucose followed by 300 mg/dl for 1 hr, insulin release (stimulated) increased 6-fold (from 7 +/- 2 to 45 +/- 11 microU) in control cultures but only 3-fold (from 4 +/- 2 to 12 +/- 4 microU) in IL-1 beta-exposed cultures (n = 9, P = .01). Addition of 2 mM L-NMMA to islet cultures in the presence of IL-1 beta (20 IU/ml) (n = 9) restored insulin release to normal (from 6 +/- 2 to 38 +/- 9 microU, P > or = 0.6), suggesting that NO mediates the inhibitory effect of IL-1 beta on beta-cell function. In in vivo studies, rats with streptozotocin-induced diabetes (blood glucose > 400 mg/dl) received minimal (750 hand-picked islets) intraportal beta cell mass isografts with (n = 5) or without (n = 9) treatment with 100 mg/7 days of L-NMMA from 3 days before transplantation to 4 days after transplantation (POD -3 to +4). L-NMMA-treated rats became euglycemic (glucose < 200 mg/dl) earlier than nontreated rats (mean +/- SD of 6.4 +/- 2.5 vs. 16.7 +/- 4.7 days posttransplant, P = 0.001). These findings support the hypothesis that NO is a mediator of beta cell dysfunction after intraportal transplantation of freshly isolated islets of Langerhans.

Animals↗

PubMed2002

17beta-Estradiol protects isolated human pancreatic islets against proinflammatory cytokine-induced cell death: molecular mechanisms and islet functionality.

INTRODUCTION: Proinflammatory cytokines (PIC) (interleukin-1beta, interferon-gamma, and tumor necrosis factor alpha) are released after intraportal islet transplantation lead to functional suppression and islet apoptosis. Estradiol has been shown to promote survival of cells undergoing PIC-induced apoptosis. In this study, we evaluated the effects of estradiol on isolated human pancreatic islet (IHPI) survival after exposure to PIC and analyzed potential mechanisms of action. METHODS: Hand-picked, freshly isolated IHPI were incubated with PIC and estradiol. Viability was analyzed from single islet cells stained with ethidium bromide and acridine orange, apoptosis using a quantitative kit, NF-kappaB nuclear translocation using a promoter-Luciferase NF-kappaB responsive construct, mitochondrial permeability transition using the ApoAlert Mitochondrial kit, and caspase 9 by a fluorometric assay. In vitro functionality was examined by static incubation, and a limited number of islets were transplanted in nonobese diabetic, severe combined immunodeficient mice. RESULTS: 17beta-Estradiol induced a dose-dependent increase in islet viability, an effect partially reversed by the estrogen receptor antagonist ICI 182,780. In vitro, islets treated with estradiol presented higher stimulation index. Euglycemia was achieved in 6 of 12 animals that received estradiol-treated islets compared with 1 of 12 control animals. Lower NF-kappaB nuclear translocation, cytochrome release, and caspase 9 activation occurred in islets treated with estradiol. CONCLUSIONS: Estradiol promoted IHPI survival and improved functionality after PIC exposure in vitro and in vivo after transplantation. The molecular mechanisms involved included a decrease in NF-kappaB nuclear translocation, decrease in mitochondrial cytochrome release, and caspase 9 activation. The use of estradiol might be beneficial in clinical islet transplantation.

Animals↗

PubMed2006

Characterisation of collagen VI within the islet-exocrine interface of the human pancreas: implications for clinical islet isolation?

BACKGROUND: To optimize the methods used for human islet isolation for transplantation, it is important to improve our understanding of the structure of the islet-exocrine interface. In this study, the composition of collagen subtypes in the interface have been characterized and quantified in human pancreas. METHODS: Human adult pancreases were retrieved from older (mean age 55.7+/-3.0 yrs) and young donors (mean age 21.8+/-3.2 yrs). Tissue from the body of each pancreas was examined by quantitative immunohistochemistry. Collagen within the islet-exocrine interface was identified by immunolabeling for collagen I, IV, V or VI and islets identified either morphologically or by immunolabeling for insulin. Collagen subtypes were quantified and data expressed as collagen area at the interface relative to the islet area. Statistical analysis was by ANOVA or Mann Whitney U test. RESULTS: In older pancreases, collagen IV, V and VI were present throughout the islet-exocrine interface, whereas collagen I was more variable. The mean peri-islet collagen VI proportion was significantly greater than that of collagen I or IV. Mean islet area and the proportional collagen VI content in specimens from younger subjects were not significantly different to those in older subjects. CONCLUSIONS: Collagen VI is a major component of the islet-exocrine interface of the adult pancreas, the content being more than double that of collagen I or IV. However, the proportional collagen VI content was not dependent on the age of the donor. These data may facilitate the design of new collagenases, targeting major substrates such as collagen VI in order to improve clinical islet isolation.

Adult↗