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PubMed2003

The effect of apolipoprotein E deficiency on islet amyloid deposition in human islet amyloid polypeptide transgenic mice.

AIMS/HYPOTHESIS: Islet amyloid deposits are present in over 85% of Type 2 diabetic patients and have been suggested to be pathogenic. The mechanism that converts islet amyloid polypeptide (IAPP), the unique component of these deposits, into amyloid fibrils in vivo is not known. The amino acid sequence of IAPP is critical but insufficient for beta-pleated sheet formation. As apolipoprotein E (apoE), another component of islet amyloid deposits, plays a critical role in amyloid formation in Alzheimer's disease, we hypothesised that apoE could play an important role in islet amyloid formation. METHODS: Transgenic mice expressing the human form of IAPP ( hIAPP (+/0)) were crossbred with apoE deficient ( apoE (-/-)) mice and followed for 12 months, at which time the prevalence and severity of islet amyloid, as well as plasma glucose, hIAPP, immunoreactive insulin (IRI) and lipid concentrations were measured. RESULTS: The prevalence and severity of islet amyloid after one year of follow up were comparable among hIAPP (+/0) mice that were apoE (+/+), apoE (+/-) or apoE (-/-). Differences in glucose tolerance, lipid abnormalities or changes in pancreatic content or plasma concentrations of hIAPP and/or IRI did not account for these findings. CONCLUSION/INTERPRETATION: Our data shows that, unlike in the localized amyloidosis in the brain characteristic of Alzheimer's disease, apoE is not critical for islet amyloid formation in a transgenic mouse model of Type 2 diabetes mellitus. These results indicate that the mechanisms of localised amyloid formation probably vary among different amyloid-associated disorders. Therefore, therapeutic strategies targeting apoE might not apply equally to patients with different amyloid associated diseases.

Amyloid↗

PubMed1994

Islet amyloid polypeptide and its N-terminal and C-terminal flanking peptides' immunoreactivity in islet amyloid of diabetic patients.

We determined immunohistochemically whether the islet amyloid polypeptide (IAPP)/amylin precursor is one component of islet amyloid, using polyclonal antibodies specific for human IAPP8-17 and amino (N)-terminal and carboxy (C)-terminal flanking peptides. To enhance immunostaining of the amyloid, we pretreated the pancreatic tissue sections with 100% formic acid. In three non-diabetic subjects, pancreatic islet cells were immunoreactive to anti-IAPP8-17 and anti-N-terminal and C-terminal flanking peptide antibodies and the reactivity was enhanced with formic acid pretreatment. In six type 2 diabetic subjects and a subject with type A insulin resistance, islet amyloid deposits were reactive to anti-IAPP8-17 antibody, but not to anti-N-terminal and C-terminal flanking peptide antibodies. Formic acid pretreatment markedly enhanced the reactivity to anti-IAPP8-17 antibody; however, it failed to show the reactivity to anti-N-terminal and C-terminal flanking peptide antibodies. Formic acid pretreatment of pancreatic tissue sections prepared for immunostaining is useful for visualization of buried epitopes of mature IAPP and its precursor molecules, either in islet amyloid deposits or in the islet cells. We conclude that the IAPP precursor and N-terminal and C-terminal flanking peptides are not constituents of human islet amyloid.

Adult↗

PubMed2005

Kyoto islet isolation method: the optimized one for non-heart-beating donors with highly efficient islet retrieval.

The availability of pancreata for clinical cadaveric islet transplantation is restricted to non-heart-beating donors (NHBDs) in Japan. This forced us to modify the current standard islet isolation protocol that was made up for brain-dead donors and make it suitable for NHBDs. The Kyoto islet isolation method is the one with induction of several steps based on the ideas both already reported literally and invented originally by ourselves. Using this islet isolation method, we isolated islets from 13 human pancreata of NHBDs and transplanted 11 preparations to six type-1 diabetic patients. The rate to meet release criteria of Edmonton protocol was 84.6%. Establishment of this method allowed us to begin a clinical islet transplantation program in Japan and to continue to perform the preparation of islets from NHBDs with high rate to meet the release criteria of the Edmonton protocol.

Brain Death↗

PubMed1996

Normalization of diabetes by xenotransplantation of cryopreserved microencapsulated pancreatic islets. Application of a new strategy in islet banking.

To develop a requisite islet bank for the clinical implementation of an injectable bioartificial endocrine pancreas, microencapsulated islets were cryopreserved and assessed both in vitro by static glucose challenge and in a transplantation study. The insulin response of cryopreserved encapsulated rat islets was comparable with fresh islets. Transplantation of 800-900 banked rat islets resulted in the normalization of the metabolic blood glucose perturbation, body weight, and general health characteristics in 8 out of 8 diabetic mice for the study duration of 90 days. Whereas free islets are easily fragmented and lost during the freezing process, the capsule protects the fragile islets from freezing damage, increasing the retrieval rate from 79.5 +/- 9.8% to 97.2 +/- 1.3.

Animals↗

PubMed2000

Recognition of islet-directed peripheral blood lymphocytes in vitro before rejection of allogeneic grafted islets.

A co-culture of splenic lymphocytes with allogeneic pancreatic islets [i.e., mixed lymphocyte islet co-culture (MLIC)] for 96 hr leads to reduction of beta-cells and to an allospecific induction of major histocompatibility complex (MHC) class II antigens on beta-cells. The intent of our investigation was to determine whether peripheral blood lymphocytes (PBL) obtained from allogeneic islet-grafted BB/OK rats (=sensitization in vivo) cause similar alterations to donor-specific islet cells. PBL prepared before transplantation, before (at day 7) and after islet rejection were co-cultured for 24 hr with donor-specific islets. PBL obtained at any time before and after transplantation caused reduction of beta-cells and enhancement of intercellular adhesion molecule-1(+)/beta-cells. Induction of MHC class II+ beta-cells was most pronounced with PBL obtained before rejection. Down-regulation of major histocompatibility complex class I+ beta-cells was caused by PBL that had been obtained from grafted animals only; it was most pronounced before islet rejection and has never been observed with lymphocytes from nongrafted normoglycemic rats. The 24-hr MLIC is capable of recognizing functionally active, donor-specific lymphocytes and is able to distinguish between the effects of sensitized and nonsensitized lymphocytes.

Animals↗

PubMed1995

Vascular endothelial growth factor and its receptors, flt-1 and flk-1, are expressed in normal pancreatic islets and throughout islet cell tumorigenesis.

Endocrine organs, such as the pancreatic islets of Langerhans, contain permeable, fenestrated endothelium that allows direct access of endocrine cells to the blood stream. Factors that control differentiation and maintenance of this highly specialized endothelium remain unknown. Vascular endothelial growth factor (VEGF) is a multifunctional growth factor that may be responsible for the homeostasis of endocrine endothelium; it is a selective mitogen for endothelial cells and is able to permeabilize endothelium. We have analyzed the expression of VEGF mRNA and protein in pancreatic islet cells of normal mice and during the different stages of tumor progression in a transgenic mouse model of beta-cell carcinogenesis. The 120-amino acid and the 164-amino acid isoforms of VEGF are expressed in normal islets of Langerhans and are moderately up-regulated during the stages of tumor development. Two high-affinity receptors for VEGF, flt-1 and flk-1, are expressed by endothelial cells both in normal islets and in the stages of tumorigenesis; these receptors are not up-regulated during this process. Our data raise the possibility that VEGF is involved in the maintenance of permeable endothelium in islets of Langerhans, an observation that may have implications for islet cell physiology and diabetes. While VEGF may also play an important role in the growth of new blood vessels during islet cell tumorigenesis, it cannot be the only factor required for the activation of tumor angiogenesis.

Adenoma, Islet Cell↗

PubMed2000

Pro islet amyloid polypeptide (ProIAPP) immunoreactivity in the islets of Langerhans.

Islet amyloid is typically found in type 2 diabetes mellitus and is believed to participate in the beta cell deterioration. The islet amyloid fibril consists of the 37-amino-acid islet amyloid polypeptide (IAPP) but its pathogenesis is only partly understood. We developed several different rabbit antisera against the flanking peptides of the IAPP precursor (proIAPP) and the proIAPP processing sites in order to study the possible occurrence of unprocessed proIAPP or parts thereof in islet amyloid. We applied these antisera in an immunohistochemical study on, islet amyloid deposits present in a newly generated mouse strain that over-expresses human IAPP but is devoid of mouse IAPP. Male mice of this strain develop severe islet amyloidosis when given a high fat diet. Generally, the antisera showed no immunoreactivity with the amyloid. However, in scattered single beta cells, where amyloid could be seen intracellularly, immunoreactivity with one or more of the antisera co-localized with the amyloid. Although virtually all amyloid in human islets of Langerhans is found extracellularly, we propose that the initial amyloid formation occurs intracellularly, perhaps by not fully processed or folded (pro)IAPP. This amyloid, which may develop rapidly under certain circumstances, probably leads to cell death. If not degraded these amyloid spots may then act as nidus for further amyloid formation from fully processed IAPP, secreted from surrounding beta cells.

Amino Acid Sequence↗

PubMed1989

Persistent impairment of the insulin response to glucose both in vivo and in vitro after streptozotocin exposure: studies with grafted pancreatic islets and islets maintained in culture.

The functional responses of the pancreatic B-cells after cytotoxic damage are still largely unknown. Using in vitro models to clarify this issue, we have recently observed a preferential reduction of glucose-stimulated insulin production and release in mouse pancreatic islets maintained in culture after in vitro exposure to streptozotocin. In order to evaluate the relevance of these findings in vivo, two sets of experiments were performed. First, mouse pancreatic islets were exposed in vitro to 2.2 mmol/l streptozotocin or vehicle alone, cultured for 6 days, and finally grafted under the kidney capsule of normoglycemic nude mice. Two weeks after transplantation there was no difference in the total DNA and insulin content between the two groups of islet grafts, but the insulin concentration, as expressed per microgram DNA, was decreased by 40% in the streptozotocin-treated islets. The insulin release of the grafts, during perfusion of the graft-bearing kidney in situ with 16.7 mmol/l glucose was diminished in the streptozotocin group, whilst perfusion with 16.7 mmol/l glucose plus 5 mmol/l theophylline was able partially to counteract the reduction in insulin release. In the second set of experiments, NMRI mice were injected iv with 160 mg/kg streptozotocin or vehicle alone, and their islets isolated 15 min after the injections. After 6 days in culture, there was no decrease in DNA, glucagon and somatostatin contents, but the insulin content was decreased by 40% in the streptozotocin exposed islets. These islets also showed a 60% decrease in the insulin response to glucose, which was partly counteracted by incubation with 16.7 mmol/l glucose plus 5 mmol/l theophylline.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1982

Tissue culture reduces Ia antigen-bearing cells in rat islets and prolongs islet allograft survival.

Prolongation of rat pancreatic islet allograft survival by a prior 7-day period of tissue culture was demonstrated, confirming previous reports by others. We then sought to identity those cells in islets capable of stimulating allograft rejection (Ia antigen-bearing cells) and to determine whether such cells and/or their Ia antigens might be reduced by tissue culture. Freshly isolated and 7-day-cultured Wistar-Furth rat islets were incubated with a mouse anti-rat Ia nonpolymorphic monoclonal antibody, then with peroxidase-conjugated goat anti-mouse antibody, and processed for electron microscopy. Peroxidase (Ia)-positive lymphocytes, macrophages, and capillary endothelial cells were identified in fresh but not in cultured islets. A radioligand assay, using 125I-protein A, revealed a 45% decrease in binding of Ia antibody to cultured compared with fresh islet cells. We conclude that Ia antigen-bearing lymphocytes, macrophages, and capillary endothelial cells in rat islets are reduced by tissue culture and that this may account, at least in part, for the decreased immunogenicity of cultured islet allografts.

Animals↗

PubMed2003

Pancreatic precursors and differentiated islet cell types from murine embryonic stem cells: an in vitro model to study islet differentiation.

Embryonic stem (ES) cells differentiating in vitro reproduce many facets of early embryonic development, including the expression of developmentally regulated transcription factors and the differentiation of multipotent precursor cells. ES cells were evaluated for their ability to differentiate into pancreatic and islet lineage-restricted stages including pancreatic duodenal homeobox 1 (PDX1)-positive pancreatic precursor cells, early endocrine cell progenitors, and islet hormone-producing cells. Following growth and differentiation in nonselective medium containing serum, murine ES cells spontaneously differentiated into cells individually expressing each of the four major islet hormones: insulin, glucagon, somatostatin, and pancreatic polypeptide. PDX1 immunostaining cells appeared first, before hormone-positive cells had emerged. Hormone-positive cells appeared within focal clusters of cells coexpressing PDX1 and the nonclassical hormone markers peptide YY (YY) and islet amyloid polypeptide (IAPP) in combination with the definitive hormones, characteristic of endocrine cells appearing during early pancreaticogenesis. This system allows the investigation of many facets of islet development since it promotes the appearance of the complete range of islet phenotypes and reproduces important developmental stages of normal islet cytodifferentiation in differentiating ES cell cultures.

Amyloid↗

PubMed2002

Islet redox stress: the manifold toxicities of insulin resistance, metabolic syndrome and amylin derived islet amyloid in type 2 diabetes mellitus.

CONTEXT: Redox stress, reactive oxygen species, reactive nitrogen species, and oxygen free radicals ("toxic oxygen") are increasingly being reported as important cellular signaling mechanisms. It has been known for over a hundred years that type 2 diabetes mellitus is a manifold disease, not only in its etiology, but also in its associated manifold toxicities and multiple complications of the diabetic opathies. The presence of islet amyloid has also been described in association with type 2 diabetes mellitus for a century. OBJECTIVE: This review will attempt to remain focused on the relationship between redox stress, the reactive oxygen species and the reactive nitrogen species in the islet, and how these interact with the multiplicative effect of the toxicities of insulin resistance, metabolic syndrome, amylin (hyperamylinemia), amylin derived islet amyloid and type 2 diabetes mellitus. CONCLUSIONS: Redox sensitive cellular signaling systems play an important role in the development, progressive nature (remodeling) and damaging effects on the beta cell within the islet of the pancreas. Furthermore, redox stress may play an important role in the remodeling and development of islet amyloid creating a space-occupying lesion with a resultant secretory and absorptive defect within the islet. The presence of manifold toxicities necessitates an approach of global risk reduction in the prevention and treatment of type 2 diabetes mellitus. An improved understanding of the dynamic relationship between these toxicities and redox stress within the islet will aid both the researcher and the clinician.

Amyloid↗

PubMed2002

Effects of free fatty acid on polymerization of islet amyloid polypeptide (IAPP) in vitro and on amyloid fibril formation in cultivated isolated islets of transgenic mice overexpressing human IAPP.

BACKGROUND: Islet amyloid polypeptide (IAPP) is deposited as amyloid in the islets of Langerhans in type 2 diabetes. The mechanism behind the formation of the cytotoxic fibrils is unknown. Islet amyloid develops in a mouse IAPP null mouse strain that expresses human IAPP (+hIAPP/-mIAPP) after 9 months on a high-fat diet. Herein we investigate the effect that individual free fatty acids (FFAs) exert on formation of amyloid-like fibrils from synthetic IAPP and the effects of FFAs on IAPP polymerization in +hIAPP/-mIAPP islets cultivated in vitro. MATERIALS AND METHODS: In the study myristic acid, palmitic acid, stearic acid, oleic acid, and linoleic acid were used together with albumin. Thioflavin T (Th T) assay was used for quantification of amyloid-like fibrils. Islets were isolated from the +hIAPP/-mIAPP transgenic strain and cultured in the presence of the FFAs for 2 days. Immuno-electron microscopy was used for evaluation. RESULTS: The Th T assay showed that all studied FFAs potentiated fibril formation but that myristic acid revealed the highest capacity. In some cells from cultured islets, intragranular aggregates were present. These aggregates had a filamentous appearance and labeled with antibodies against IAPP. In some cells cultured in the presence of linoleic acid, large amounts of intracellular amyloid were present. Earlier, this has not been observed after such a short incubation period. CONCLUSIONS: Our studies suggest that FFAs can potentiate amyloid formation in vitro, probably without being integrated in the fibril. Cultivation of +hIAPP/-mIAPP transgenic mouse islets with FFAs results in altered morphology of the secretory granules with appearance of IAPP- immunoreactive fibrillar material. We suggest that such fibrillar material may seed extracellular amyloid formation after exocytosis.

Amyloid↗

PubMed1998

Islet injury induces neurotrophin expression in pancreatic cells and reactive gliosis of peri-islet Schwann cells.

Pancreatic islets are enveloped by a sheath of Schwann cells, the glial cells of the peripheral nervous system (PNS). The fact that Schwann cells of the PNS become reactive and express nerve growth factor (NGF) and other growth factors following axotomy suggested the possibility that peri-islet Schwann cells could become activated by islet injury. To test this hypothesis, we examined two animal models of islet injury. The first model was mice and rats injected with streptozotocin (SZ), a specific beta-cell toxin. The second model was NOD mice, a strain in which beta cells are deleted by an autoimmune process. We found that peri-islet Schwann cells became reactive following islet injury and began to express increased levels of NGF and the neurotrophin receptor p75. Lesions to the pancreas also markedly induced NGF expression by exocrine and endocrine cells. Neurotrophin expression was not unique to adult tissues since pancreatic cells transiently expressed p75, the NGF receptor Trk A, and NGF during development. These observations suggest that NGF could play an important role in pancreas during embryogenesis and in processes leading to repair following islet injury in adults.

Animals↗

PubMed1997

Pathological changes in the islet milieu precede infiltration of islets and destruction of beta-cells by autoreactive lymphocytes in a transgenic model of virus-induced IDDM.

RIP-LCMV transgenic mice that express the viral glycoprotein (GP) or nucleoprotein (NP) from lymphocytic choriomeningitis virus (LCMV) under control of the rat insulin promoter (RIP) in pancreatic beta-cells develop autoimmune diabetes (IDDM) after infection with LCMV. Previous reports have described that the viral infection activates naive, potentially autoreactive CD8+ cytotoxic T-lymphocytes (CTL) that are present in the periphery of these mice, thus leading to the breaking of immunological unresponsiveness to the viral self-antigen expressed on beta-cells. However, we find that adoptive transfer of such CTL that were active in vitro and in vivo into uninfected RIP-LCMV recipients rarely resulted in hyperglycemia nor in insulitis, despite their ability to home to the islets and induce peri-insulitis. These observations indicated that, in addition to activated autoreactive lymphocytes, other factor(s) were required for beta-cell destruction. The present study shows that upregulation of MHC class II molecules associated with the attraction/activation of antigen presenting cells (APCs) to the islets occurs as soon as 2 days after LCMV inoculation of transgenic mice, clearly before CD4+ and CD8+ lymphocytes are found entering the islets (days 6 and 7 after LCMV inoculation). In contrast, although some MHC class II upregulation is also found in islets of non-transgenic mice 2-4 days after LCMV infection, no insulitis or IDDM develops and MHC is downregulated to normal (pre-infection) levels by day 7-10 in these mice. Associated with the activation of APCs and MHC upregulation observed in transgenic mice, viral (LCMV) infection of islets was detectable 2 days post-viral inoculation in some mice. Thus, beta-cell destruction by activated autoreactive lymphocytes is a multifactorial process that is likely to require changes within the islet milieu or dysfunction of islets.

Adoptive Transfer↗

PubMed1989

Localisation of islet amyloid peptide in lipofuscin bodies and secretory granules of human B-cells and in islets of type-2 diabetic subjects.

Islet amyloid peptide (or diabetes-associated peptide), the major component of pancreatic islet amyloid found in type-2 diabetes, has been identified by electron-microscopic immunocytochemistry in pancreatic B-cells from five non-diabetic human subjects, and in islets from five type-2 diabetic patients. The greatest density of immunoreactivity for islet amyloid peptide was found in electron-dense regions of some lysosomal or lipofuscin bodies. The peptide was also localised by quantification of immunogold in the secretory granules of B-cells, and was present in cytoplasmic lamellar bodies. Acid phosphatase activity was also demonstrated in these organelles. Immunoreactivity for insulin was found in some lysosomes. These results suggest that islet amyloid peptide is a constituent of normal pancreatic B-cells, and accumulates in lipofuscin bodies where it is presumably partially degraded. In islets from type-2 diabetic subjects, amyloid fibrils and lipofuscin bodies in B-cells showed immunoreactivity for the amyloid peptide. Abnormal processing of the peptide within B-cells could lead to the formation of islet amyloid in type-2 diabetes.

Adolescent↗

PubMed1993

Lymphoid activation by micro- and macroencapsulated islets during mixed lymphocyte islet culture.

We have recently demonstrated long-lasting normoglycaemia after transplantation of barium alginate microencapsulated rat and porcine islets. Nevertheless the transplantation results obtained with different microencapsulation techniques have been controversial. Little is known about possible immune interactions between host and encapsulated islet. This study demonstrates in vitro stimulation of lymphoid cells by encapsulated islets that is similar to that of unencapsulated islets. This stimulation was reduced by a 4-day culture with unencapsulated islets only. After macroencapsulation of islets in hollow fibres a stimulatory effect was also observed, but this was less pronounced than after microencapsulation. Empty microcapsules as well as macrocapsules induced lymphoid proliferation as a result of mitogenic impurities in the encapsulation materials themselves. In the same donor-recipient combination in which we have shown successful transplantation, we found activation of the sensibilization arm of the immune system. This suggests that microencapsulation results in protection of the transplanted islets from the action of the effector arm. This lymphoid activation could be triggered by the mitogeniticity of the encapsulation material itself. In the case of alginates these mitogenic factors could not be abolished by culture (i.e. dialysis).

Alginates↗

PubMed1978

Isolated mouse pancreatic islets in culture: effects of serum and different culture media on the insulin production of the islets.

Various conditions for tissue culture of collangenase-isolated mouse pancreatic islets were studied in an attempt to optimize the maintenance of glucose stimulated insulin biosynthesis and release in the cultured specimens. Islets which had been cultured at a physiological glucose concentration (5.5 mmol/1) in the absence of serum had an impaired glucose-stimulated insulin biosynthesis and release as well as a reduced insulin content. Thus, insulin biosynthesis was three times higher after culture in a serum supplemented medium. Further, the insulin secretion of islets cultured in the presence of serum was markedly enhanced in acute incubations with high concentrations of glucose. This response was most pronounced in islets which had been cultured free-floating. A comparison between different culture media showed that islets cultured in RPMI 1640 had the highest insulin production. The present data suggest that the most favourable conditions for long-term storage of isolated islets in culture may be obtained when the islets are maintained as free-floating explants in a culture medium consisting of RPMI 1640 supplemented with serum.

Animals↗

PubMed1994

Inflammatory islet damage in patients bearing HLA-DR 3 and/or DR 4 haplotypes does not lead to islet autoimmunity.

The hypothesis was tested that islet autoimmunity is induced by ongoing islet cell destruction in subjects with susceptibility genes HLA-DR 3 and/or DR 4. Sixty-one patients with confirmed chronic pancreatitis were analysed, 30 of whom expressed HLA-DR 3 and/or DR 4. Electron microscopy studies in 10 patients showed that the inflammatory process also affected islets, as recognisable from islet cell lysis, intrainsular fibrosis and immune cell infiltrates. None of the sera tested contained any of three markers of islet autoimmunity, ICA, IAA or GAD antibodies. A correlation was seen between the loss of exocrine function, as determined by the ALTAB-test, and of beta-cell function, as determined by the C-peptide response to i.v. glucagon. However, there was no preferential loss of beta-cell function in patients with HLA-DR 3 and/or DR 4. We conclude that islet cell destruction occurs during chronic pancreatitis, but does not trigger islet autoimmunity, even in the presence of HLA-DR 3 and/or DR 4.

Adult↗