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PubMed1996

Induction of islet cell differentiation and new islet formation in the hamster--further support for a ductular origin.

Partial obstruction of the adult hamster pancreas leads to islet cell differentiation and new islet formation. From morphologic and morphometric observations, we have tentatively identified the source of the new islet tissue to be from cells in the ducts. In this study, in vivo labeling with a single pulse of tritiated thymidine after partial duct obstruction was used to ascertain whether newly formed islet cells were in fact derived from cells in the ductal epithelium. Supportive evidence for this formulation was also sought using immunocytochemistry for islet hormones and in situ hybridization for glucagon and insulin mRNA to probe areas of proliferating duct cells. Endocrine cell differentiation was observed as a migration of cells out from small ducts beginning at about 10 days after obstruction. Duct and islet cell labeling indices (LI;%) in control animals remained at a low level (0.25 +/- 0.01 and 0.26 +/- 0.03, respectively) throughout the experiment. In contrast, at 2 weeks after partial obstruction, the duct and islet cell LI were 4.2 +/- 0.7 and 0.80 +/- 0.1 (p < 0.05 vs. control). After 2 weeks, there was a rapid and significant 86% decline in the duct cell LI to a low of 0.6 +/- 0.2 at 8 weeks, which was accompanied by a comparable, but reciprocal, 113% increase in the islet cell LI to a high of 1.7 +/- 0.8 (p < 0.05). In situ hybridization demonstrated glucagon and insulin mRNA-positive cells within intralobular ducts as early as 6 and 8 days, respectively, after obstruction. Glucagon and insulin peptides appeared in these cells at approximately 8 and 10 days, respectively, as cells migrated out from the duct wall. This study provides additional evidence that further supports our concept that pancreatic endocrine cell differentiation in this model reiterates the normal ontogeny of beta cell differentiation from cells in the ductular epithelium.

Age Factors↗

PubMed2003

Insulin independence following isolated islet transplantation and single islet infusions.

OBJECTIVE: To restore islet function in patients whose labile diabetes subjected them to frequent dangerous episodes of hypoglycemic unawareness, and to determine whether multiple transplants are always required to achieve insulin independence. SUMMARY BACKGROUND DATA: The recent report by the Edmonton group documenting restoration of insulin independence by islet transplantation in seven consecutive patients with type 1 diabetes differed from previous worldwide experience of only sporadic success. In the Edmonton patients, the transplanted islet mass critical for success was approximately more than 9,000 IEq/kg of recipient body weight and required two or three separate transplants of islets isolated from two to four cadaveric donors. Whether the success of the Edmonton group can be recapitulated by others, and whether repeated transplants using multiple donors will be a universal requirement for success have not been reported. METHODS: The authors report their treatment with islet transplantation of nine patients whose labile type 1 diabetes was characterized by frequent episodes of dangerous hypoglycemia. RESULTS: In each of the seven patients who have completed the treatment protocol (i.e., one or if necessary a second islet transplant), insulin independence has been achieved. In five of the seven patients only a single infusion of islets was required. To date, only one recipient has subsequently lost graft function, after an initially successful transplant. This patient suffered recurrent hyperglycemia 9 months after the transplant. CONCLUSIONS: This report confirms the efficacy of the Edmonton immunosuppressive regimen and indicates that insulin independence can often be achieved by a single transplant of sufficient islet mass.

Adult↗

PubMed2006

Successful islet transplantation from nonheartbeating donor pancreata using modified Ricordi islet isolation method.

BACKGROUND: Current success of islet transplantation has led to donor shortage and the need for marginal donor utilization to alleviate this shortage. The goal of this study was to improve the efficacy of islet transplantation using nonheartbeating donors (NHBDs). METHODS: First, we used porcine pancreata for the implementation of several strategies and applied to human pancreata. These strategies included ductal injection with trypsin inhibitor for protection of pancreatic ducts, ET-Kyoto solution for pancreas preservation, and Iodixanol for islet purification. RESULTS: These strategies significantly improved both porcine and human islet isolation efficacy. Average 399,469+/-36,411 IE human islets were obtained from NHBDs (n=13). All islet preparations met transplantation criteria and 11 out of 13 cases (85%) were transplanted into six type 1 diabetic patients for the first time in Japan. All islets started to secrete insulin and all patients showed better blood glucose control without hypoglycemic loss of consciousness. The average HbA1c levels of the six recipients significantly improved from 7.5+/-0.4% at transplant to 5.1+/-0.2% currently (P<0.0003). The average insulin amounts of the six recipients significantly reduced from 49.2+/-3.3 units at transplant to 11+/-4.4 units (P<0.0005) and five out of six patients reduced to less than half dose. The first patient is now insulin free, the first such case in Japan. CONCLUSION: This demonstrates that our current protocol makes it feasible to use NHBDs for islet transplant into type 1 diabetic patients efficiently.

Adult↗

PubMed2000

Chronic blockade of NO synthase paradoxically increases islet NO production and modulates islet hormone release.

Islet production of nitric oxide (NO) and CO in relation to islet hormone secretion was investigated in mice given the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) in their drinking water. In these mice, the total islet NO production was paradoxically increased, reflecting induction of inducible NOS (iNOS) in background of reduced activity and immunoreactivity of constitutive NOS (cNOS). Unexpectedly, normal mice fasted for 24 h also displayed iNOS activity, which was further increased in L-NAME-drinking mice. Glucose-stimulated insulin secretion in vitro and in vivo was increased in fasted but unaffected in fed mice after L-NAME drinking. Glucagon secretion was increased in vitro. Control islets incubated with different NOS inhibitors at 20 mM glucose displayed increased insulin release and decreased cNOS activity. These NOS inhibitors potentiated glucose-stimulated insulin release also from islets of L-NAME-drinking mice. In contrast, glucagon release was suppressed. In islets from L-NAME-drinking mice, cyclic nucleotides were upregulated, and forskolin-stimulated hormone release, CO production, and heme oxygenase (HO)-2 expression increased. In conclusion, chronic NOS blockade evoked iNOS-derived NO production in pancreatic islets and elicited compensatory mechanisms against the inhibitory action of NO on glucose-stimulated insulin release by inducing upregulation of the islet cAMP and HO-CO systems.

Animals↗

PubMed2000

Feeding a protective hydrolysed casein diet to young diabetic-prone BB rats affects oxidation of L[U-14C]glutamine in islets and Peyer's patches, reduces abnormally high mitotic activity in mesenteric lymph nodes, enhances islet insulin and tends to normalize NO production.

The present studies were undertaken to examine concomitant diet-induced changes in pancreatic islets and cells of the gut immune system of diabetes-prone BB rats in the period before classic insulitis. Diabetes-prone (BBdp) and control nondiabetes prone (BBc) BB rats were fed for approximately 17 days either a mainly plant-based standard laboratory rodent diet associated with high diabetes frequency, NIH-07 (NIH) or a protective semipurified diet with hydrolyzed casein (HC) as the amino acid source. By about 7 weeks of age, NIH-fed BBdp rats had lower plasma insulin and insulin/glucose ratio, lower insulin content of isolated islets, lower basal levels of NO but higher responsiveness of NO production to IL-1beta in cultured islets, and higher Con A response and biosynthetic activities in mesenteric lymphocytes than control rats fed the same diet. In control rats, the HC diet caused only minor changes in most variables, except for a decrease in oxidation of L-[U-14C]glutamine in Peyer's patch (PP) cells and an increase in protein biosynthesis in mesenteric lymphocytes. In BBdp rats, however, the HC diet increased plasma insulin concentration, islet insulin/protein ratio, and tended to normalize the basal and IL-1beta-stimulated NO production by cultured islets. The HC diet decreased oxidation of L[U-14C]glutamine in BBdp pancreatic islets, whereas oxidation of L-[U-14C]glutamine in PP cells was increased, and the basal [Methyl-3H]thymidine incorporation in mesenteric lymphocytes was decreased. These findings are compatible with the view that alteration of nutrient catabolism in islet cells as well as key cells of the gut immune system, particularly changes in mitotic and biosynthetic activities in mesenteric lymphocytes, as well as basal and IL-1beta stimulated NO production, participate in the sequence of events leading to autoimmune diabetes in BB rats. Thus, the protection afforded by feeding a hydrolysed casein-based diet derives from alterations in both the target islet tissue and key cells of the gut immune system in this animal model of type 1 diabetes.

Administration, Oral↗

PubMed1992

Adaptation of islets of Langerhans to pregnancy: increased islet cell proliferation and insulin secretion correlates with the onset of placental lactogen secretion.

To elucidate the temporal profile of adaptive changes of the islets of Langerhans to the increased insulin demands of pregnancy, we have studied islet cell proliferation and insulin secretion during gestation in the rat. 5-Bromo-2'-deoxyuridine incorporation into dividing islet cells was significantly (P less than 0.05) increased over age-matched controls by day 10, rose continuously to a peak at day 14, and then returned to control levels by day 18. By day 20, cell division was significantly inhibited (P less than 0.05). The pattern of changes in insulin secretory profiles observed with perfused pancreata of pregnant animals was similar to that obtained for islet cell proliferation. Both the threshold of glucose-stimulated insulin secretion and the amount of above threshold insulin secretion began to diverge from controls by day 10. By day 12, the glucose-stimulation threshold was significantly decreased from 5.7 mM glucose to 3.3 mM (P less than 0.05), remained at this low level through day 15, and returned toward normal by day 20. Concomitant with the increased sensitivity of B cells to glucose, the above threshold insulin secretion was significantly increased by day 12 (P less than 0.05), peaked at day 15, and returned to control levels by day 20. This insulin secretory data demonstrates that the increased sensitivity of B cells to glucose is an important component of the adaptation of islets during pregnancy to the increased demand for insulin at physiological concentrations of plasma glucose. To correlate the above changes in islet cell proliferation and insulin secretion with levels of placental lactogen (PL), serum lactogenic hormone activity was measured by Nb2 lymphoma cell replication assays. This analysis revealed the expected biphasic pattern: a midpregnancy peak at day 12, followed by a nadir at day 14, and then continuously elevated levels until term. The bioassay data agreed with the known secretory profiles of rat (r) PL-I (midpregnancy) and rPL-II (late pregnancy). Our results provide the first systematic evaluation of changes in islet function during pregnancy in the rat. In addition, they provide evidence that rPL-I may be the critical hormonal signal which triggers the primary adaptive changes in islet function characteristic of pregnancy. The return to normal values of insulin secretion and inhibition of cell division observed at day 20 in the presence of high concentrations of rPL-II suggests that other inhibitory influences become dominant in the later stages of rat pregnancy.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1996

Inducible nitric oxide synthase (iNOS) in pancreatic islets of nonobese diabetic mice: identification of iNOS- expressing cells and relationships to cytokines expressed in the islets.

Inflammatory cytokines and nitric oxide (NO) are candidate mediators of pancreatic islet beta-cell destruction in insulin-dependent diabetes mellitus. In this study, we used a semiquantitative PCR assay to measure levels of messenger RNA (mRNA) expression of the inflammatory cytokines, interleukin-1 alpha (IL-1 alpha), tumor necrosis factor-alpha, and interferon-gamma (IFN gamma), and of the inducible form of NO synthase (iNOS) in mononuclear leukocytes isolated from pancreatic islets of autoimmune diabetes-prone nonobese diabetic (NOD) female mice. We found that mRNA levels of iNOS, IL-1 alpha, and IFN gamma in islet mononuclear leukocytes increased from 5 weeks of age to onset of diabetes ( > 13 weeks of age). To determine whether increased iNOS, IL-1 alpha, and IFN gamma mRNA expressions were related to diabetes development, we compared mRNA levels of these molecules in mononuclear leukocytes from islets of 12 week-old diabetes-prone NOD female mice and three groups of 12-week-old mice with low diabetes risk: NOD female mice injected with complete Freund's adjuvant at 4 weeks of age, NOD male mice, and BALB/c female mice that do not develop diabetes. We found that iNOS, IL-1 alpha, and IFN gamma mRNA levels were higher in mononuclear leukocytes from islets of diabetes-prone NOD female mice than in those from mice correlated with IL-1 alpha and IFN gamma mRNA levels. By using specific antibodies and immunohistochemical methods, we localized iNOS in macrophages as well as in beta-cells of islets from diabetes-prone NOD female mice. These findings suggest that IL-1 alpha and IFN gamma may promote islet beta-cell destruction at least in part by up-regulating iNOS expression an No production by both macrophages and beta-cells in the islets of autoimmune diabetes-prone NOD mice.

Animals↗

PubMed2000

Persistent expression of HNF6 in islet endocrine cells causes disrupted islet architecture and loss of beta cell function.

We used transgenesis to explore the requirement for downregulation of hepatocyte nuclear factor 6 (HNF6) expression in the assembly, differentiation, and function of pancreatic islets. In vivo, HNF6 expression becomes downregulated in pancreatic endocrine cells at 18. 5 days post coitum (d.p.c.), when definitive islets first begin to organize. We used an islet-specific regulatory element (pdx1(PB)) from pancreatic/duodenal homeobox (pdx1) gene to maintain HNF6 expression in endocrine cells beyond 18.5 d.p.c. Transgenic animals were diabetic. HNF6-overexpressing islets were hyperplastic and remained very close to the pancreatic ducts. Strikingly, alpha, delta, and PP cells were increased in number and abnormally intermingled with islet beta cells. Although several mature beta cell markers were expressed in beta cells of transgenic islets, the glucose transporter GLUT2 was absent or severely reduced. As glucose uptake/metabolism is essential for insulin secretion, decreased GLUT2 may contribute to the etiology of diabetes in pdx1(PB)-HNF6 transgenics. Concordantly, blood insulin was not raised by glucose challenge, suggesting profound beta cell dysfunction. Thus, we have shown that HNF6 downregulation during islet ontogeny is critical to normal pancreas formation and function: continued expression impairs the clustering of endocrine cells and their separation from the ductal epithelium, disrupts the spatial organization of endocrine cell types within the islet, and severely compromises beta cell physiology, leading to overt diabetes.

Animals↗

PubMed1994

Expression of neural cell adhesion molecule (N-CAM) in rat islets and its role in islet cell type segregation.

Endocrine cell types are non-randomly distributed within pancreatic islets of Langerhans. In the rat, insulin-secreting B-cells occupy the core of the islets and are surrounded by A-, D- and PP-cells, secreting glucagon, somatostatin and pancreatic polypeptide, respectively. Furthermore, dissociated islet cells have the ability in vitro to form aggregates with the same cell-type organization as native islets (pseudoislets). These observations suggest that a differential expression of cell adhesion molecules (CAMs) might characterize B- and non-B-cells (A-, D- and PP-cells), and be in part responsible for the establishment and maintenance of islet architecture. Indirect immunofluorescence using antibodies against CAMs and islet hormones was performed on serial sections of the splenic and duodenal parts of the rat pancreas. Staining for the Ca(2+)-dependent CAM E-cadherin was detected on both exocrine and endocrine tissue and was uniform over the entire islet section, in both pancreatic regions. By contrast, staining for the Ca(2+)-independent neural CAM (N-CAM) was restricted to endocrine tissue and nerve endings. Furthermore, N-CAM staining of endocrine cells was stronger in the islet periphery, a region composed mostly of non-B-cells. Serial sections demonstrate that cells staining strongly for N-CAM in the splenic part correspond to glucagon cells and in the duodenal part to pancreatic polypeptide cells. Within pseudoislets in vitro a stronger staining for N-CAM was also observed on peripheral cells, corresponding to non-B-cells.

Animals↗

PubMed2001

The pancreatic islets in spontaneously hypertensive rats: islet blood flow and insulin production.

The aim of the study was to investigate if hypertension affects pancreatic islet blood flow and endocrine function. For this purpose, spontaneously hypertensive rats (SHR) were compared with normotensive control Wistar-Kyoto rats (WKY). Both islet size and islet cell replication in 4-month-old SHR was increased compared with WKY. The (pro)insulin biosynthesis was reduced in islets isolated from SHR, whereas the insulin content was unchanged. A hyperinsulinemic response to glucose in vivo was observed in 4- and 12-month-old SHR. Pancreatic blood flow, measured using a microsphere technique, was lower in SHR than in WKY in rats aged 5 weeks, 4 months or 1 year. Islet blood flow was lower in 4-month-old and 1-year-old SHR. In 4-month-old animals, islet blood flow was unaffected by administration of enalaprilate and prazosin in both strains, but was markedly decreased by the administration of N(G)-methyl-L-arginine. It was concluded that the islets of SHR have a decreased insulin production in vitro and a decreased islet blood perfusion. The reasons for this are likely to be multifactorial. Because SHR maintained an essentially normal glucose tolerance, an adaptation of the beta-cells to the metabolic and hemodynamic changes imposed by hypertension occurred.

Adrenergic alpha-Antagonists↗

PubMed2000

Possible relationship between changes in islet neogenesis and islet neogenesis-associated protein-positive cell mass induced by sucrose administration to normal hamsters.

The possible relationship between changes in islet cell mass and in islet neogenesis-associated protein (INGAP)-cell mass induced by sucrose administration to normal hamsters was investigated. Normal hamsters were given sucrose (10% in drinking water) for 5 (S8) or 21 (S24) weeks and compared with control (C) fed hamsters. Serum glucose and insulin levels were measured and quantitative immunocytochemistry of the endocrine pancreas was performed. Serum glucose levels were comparable among the groups, while insulin levels were higher in S hamsters. There was a significant increase in beta-cell mass (P<0.02) and in beta-cell 5-bromo-2'-deoxyuridine index (P<0.01), and a significant decrease in islet volume (P<0.01) only in S8 vs C8 hamsters. Cytokeratin (CK)-labelled cells were detected only in S8 hamsters. INGAP-positive cell mass was significantly larger only in S8 vs C8 hamsters. Endocrine INGAP-positive cells were located at the islet periphery ( approximately 96%), spread within the exocrine pancreas ( approximately 3%), and in ductal cells (<1%) in all groups. INGAP positivity and glucagon co-localization varied according to topographic location and type of treatment. In C8 hamsters, 49.1+/-6. 9% cells were INGAP- and glucagon-positive in the islets, while this percentage decreased by almost half in endocrine extra-insular and ductal cells. In S8 animals, co-expression increased in endocrine extra-insular cells to 36.3+/-9.5%, with similar figures in the islets, decreasing to 19.7+/-6.9% in ductal cells. INGAP-positive cells located at the islet periphery also co-expressed CK. In conclusion, a significant increase of INGAP-positive cell mass was only observed at 8 weeks when neogenesis was present, suggesting that this peptide might participate in the control of islet neogenesis. Thus, INGAP could be a potentially useful tool to treat conditions in which there is a decrease in beta-cell mass.

Animals↗

PubMed2005

Lack of compensatory increase in islet blood flow and islet mass in GK rats following 60% partial pancreatectomy.

The effects of a 60% partial pancreatectomy were studied in hyperglycemic GK (Goto-Kakizaki) rats. Partial pancreatectomy or a sham operation was performed on 12-week-old female Wistar rats, GK rats or hybrids between male GK rats and female Wistar rats. Measurements of pancreatic blood flow and islet blood flow were performed by a microsphere technique 2 weeks after surgery. Glucose tolerance was decreased in hybrid compared with Wistar rats, and in GK rats compared with both hybrid and Wistar rats before surgery. Partial pancreatectomy induced minor changes in glucose tolerance. Wistar rats had a decreased islet mass following partial pancreatectomy. Both hybrid and GK rats showed a significant decrease in relative islet volume, but only GK rats in total islet mass, compared with Wistar rats 2 weeks after surgery. Pancreatic blood flow and islet blood flow did not significantly differ between sham-operated Wistar, hybrid or GK rats. After partial pancreatectomy, islet blood flow in relation to islet mass increased 3-fold in Wistar rats and 2-fold in hybrid rats. In contrast, GK rats showed no increase in islet blood flow following partial pancreatectomy. It is concluded that compensatory mechanisms after partial pancreatectomy are operating less efficiently in hybrid and GK rats.

Animals↗

PubMed1996

Induction of allogeneic islet survival by intrahepatic islet preimmunization and transient immunosuppression.

Induction of tolerance to fully major histocompatibility complex (MHC)-mismatched rat islet allografts implanted at two different islet transplant sites (liver and kidney capsule [KC]) was examined. Streptozotocin-induced diabetic Lewis (RT1(1)) rats remained hyperglycemic (> 200 mg/dl) after intrahepatic preimmunization by injection of 200 low-temperature cultured (24 degrees C for 7 days) Wistar-Furth (WF, RT1u) rat islets into the portal vein with one injection (1 ml) of rat antilymphocyte serum intraperitoneally. Three weeks later, 1,200 WF islets that had been cultured to remove passenger lymphoid cells were transplanted into the liver via the portal vein or under the KC. The intrahepatic transplants survived 60.2 +/- 11.9 days, and all six of the KC transplants maintained normoglycemia for > 100 days after the preimmunization regimen. In contrast, survival of fresh islet transplants was not significantly improved by this preimmunization protocol at either transplantation site. This study demonstrates that indefinite islet allograft survival can be achieved across a full MHC mismatch by intrahepatic preimmunization with a small number of cultured donor islets and a brief period of immunosuppression followed by transplantation of low-temperature cultured donor islets.

Animals↗

PubMedDate not supplied

Isolation of islets of Langerhans from the rat and pig pancreas using a modified UW solution from organ storage to islet purification.

The aim of this work was to determine the possibility of using the organ preservation solution UW for the enzymatic collagenase digestion step of the isolation of islets of Langerhans, although this solution is a calcium-free medium (collagenase being a calcium-dependent enzyme), high sodium and low potassium medium, which may be toxic for cells at the temperature needed for islet isolation. The rationale behind this work was that porcine islets are fragile, and that islets are poorly protected against oxidative stress: thus the cytoprotective properties of UW solution might be able to protect the islets during the digestion step, and improve the function of the isolated islets. As a first step, we verified that pancreas digestion with collagenase in a modified (i.e. hydroxyethyl starch deprived) UW solution was feasible: islets were randomly isolated from rat pancreas under either conventional conditions (usual ionic solution, IS), when the pancreas was inflated with UW solution (UW), and again when the pancreas was incubated for an additional hour (UW + 1) after inflation with UW and before the digestion step, thus simulating the time lapse between pancreas collection and islet isolation. In the last two conditions, collagenase was dissolved in UW solution for the digestion step.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

PubMed1994

Isolation of porcine pancreatic islets: low trypsin activity during the isolation procedure guarantees reproducible high islet yields.

During the past few years, interest in xenotransplantation of porcine islets of Langerhans for the future therapy of type I diabetes has increased markedly. Therefore, we established a semiautomated digestion method for isolating islets from the porcine pancreas. However, although the isolation technique was standardized and collagenase of controlled quality was used, we were unable to attain high islet yields with a satisfactory degree of reproducibility. One hypothesis was that varying degrees of interference by donor pancreatic enzymes were responsible for this failure. The aim of this study was to examine the kinetics of four types of enzymatic activity during the isolation procedure, as well as their effects on islet yield: collagenase, trypsin, neutral protease, and clostripain. Our results indicate that while exogenous collagenase activity decreases slightly during the isolation procedure, the activity of the pancreas enzymes neutral protease and trypsin increases. In some cases, trypsin activity increases very strongly. A strong increase in trypsin activity correlates with poor islet yield, whereas low trypsin activity always correlates with high islet yield. Addition of the protease inhibitor Pefabloc to the isolation medium results in low trypsin activity and reproducible high islet yields.

Animals↗

PubMed1996

Beta cells are important for islet innervation: evidence from purified rat islet-cell grafts.

Pancreatic islets receive an extensive and complex innervation that includes sympathetic, noradrenergic nerve fibres also storing neuropeptide Y. Islets transplanted to the kidney capsule become progressively reinnervated, mainly by sympathetic fibres and to a lesser extent by parasympathetic and sensory fibres. The density of nerve fibres in the islet grafts is often higher than in the graft-bearing organ, suggesting that the grafted islets contain factors that promote ingrowth of nerve fibres. To find out if beta cells are of any importance for attracting nerve fibres, purified preparations of rat islet beta and non-beta cells were transplanted to the kidneys of nude mice. Some of the mice were rendered diabetic by alloxan injection before transplantation. Immunocytochemical analysis revealed that the beta-cell grafts became richly reinnervated by noradrenergic (tyrosine hydroxylase-containing) nerve fibres, also storing neuropeptide Y. Non-beta islet-cell grafts were virtually devoid of demonstrable nerve fibres. There was no discernible difference in the reinnervation pattern between diabetic and non-diabetic mice. The findings indicate that factors mediating islet neurotrophism are produced by the beta cells.

Animals↗

PubMed1991

Islet amyloid polypeptide in insulinoma and in the islets of the pancreas of non-diabetic and diabetic subjects.

Amyloid deposition is a common pathological feature in insulinoma and in the islets of the pancreas in type-2 diabetic patients. The present immunohistochemical study revealed that normal B-cells, insulinoma, and amyloid deposits in insulinoma and diabetic pancreatic islets were commonly immunoreactive with antiserum to C-terminal synthetic tetradecapeptide of human islet amyloid polypeptide (IAPP) (24-37). Amyloid fibrils in insulinoma were also positive to IAPP by immunoelectron microscopy. A high level of IAPP was detected in the plasma and tissue of a insulinoma patient by radioimmunoassay suggesting that amyloid deposition in insulinoma is due to overproduction of IAPP. Amyloid deposits immunoreactive to IAPP were also seen in all diabetic pancreatic islets, but in no non-diabetic islets. There was much amyloid deposition in the islets of severe diabetics, whose B-cells demonstrated decreased immunoreactivities for IAPP and insulin. The IAPP content of the pancreas was 649.0 and 847.7 pg/mg wet weight in each of two diabetic patients, and 1034.6 and 1447.7 pg/mg wet weight in two non-diabetic patients. The present study revealed that IAPP is a bioactive peptide secreted from islet B-cells and are amyloidogenic peptide concerned in diabetogenensis and/or the progression of type-2 diabetes mellitus.

Adult↗

PubMedDate not supplied

Expression of human Fas ligand on mouse beta islet cells does not induce insulitis but is insufficient to confer immune privilege for islet grafts.

Fas (CD95) and Fas ligand (FasL/CD95L) are involved in programmed cell death and the regulation of host immune responses. FasL has been shown to provide immune privilege, thus prolonging the survival of unmatched grafts in a variety of tissues, such as eyes and testis. In murine FasL (mFasL) transgenic mice, FasL provoked granulocyte infiltration and insulitis in the pancreas. We intended to study whether the expression of human FasL, instead of mFasL, on mouse beta islet cells could avoid granulocyte infiltration, and whether islet cells transgenic for FasL could be used in islet transplantation. We produced transgenic mice in which the human FasL transgene was driven by rat insulin promoter and was expressed exclusively in the pancreas islet cells in ICR mice. In contrast to mFasL transgenic mice, histochemical staining showed that the pancreas was intact in human FasL transgenic ICR mice. However, when human FasL transgenic islet cells were transplanted into allogeneic mice with streptozotocin-induced diabetes, human FasL appeared not to prolong graft survival. Intensive granulocyte infiltration into the islet grafts was observed in recipients (Balb/c mice) which received islet grafts from human FasL transgenic mice, but not from nontransgenic, allogeneic ICR mice on day 31. Our observations suggest that FasL alone is insufficient to confer immune protection, and that other environmental factors might contribute to the formation of immune privilege sites in vivo

Animals↗