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PubMed1987

Survival of cryopreserved isolated adult human pancreatic islets of Langerhans.

Human islets of Langerhans were isolated from the pancreata of 13 adult organ donors, cultured for 24 h, cryopreserved, stored in liquid nitrogen at -196 degrees C for 6-88 days, thawed, and then cultured again. The number of islets recovered after this procedure was 80% of that present at the beginning. The viability of cultured/cryopreserved islets was then compared with that of islets from the same donor cultured for 24 hr, and was assessed by supravital staining, insulin response to glucose, and survival after implantation under the kidney capsule of nude rats. Supravital staining showed more nonviable cells in cryopreserved islets than in their cultured counterparts. Significant response to glucose was seen before and after cryopreservation in 2 of 4 sets of islets. Xenografts of 200 cultured islets (from 13 donors) were implanted in 15 nude rats under the kidney capsule, and a further 15 rats had cryopreserved islets (from the same 13 donors) similarly implanted beneath the kidney capsule. Two weeks later tissue was visible at the site of implantation in all 30 rats. Histological examination of both groups showed the tissue to have the morphology of islets, confirmed by immunohistochemical chemical localization of insulin. The insulin content of kidneys bearing 200 cultured islets was 7.88 +/- 1.6 mU (n = 13) versus 6.84 +/- 1.43 mU (n = 13) for kidneys bearing cryopreserved islets. Thus this technique for cryopreservation of isolated adult human islets enables a high recovery of endocrine tissue that survives after transplantation to nude rats, but some evidence of damage was apparent from insulin secretion studies and electron-microscopic studies.

Animals↗
PubMed1995

[Islet of Langerhans transplantation].

Islet of Langerhans transplantation is considered to be the ideal treatment for type I insulin-dependent diabetes. The permanent and adapted insulin secretion obtained by this method ensures prevention or even regression of the degenerative lesions which now constitute the severity of this frequent disease. Islets of Langerhans can be isolated from human pancreas and implanted freely in the liver or spleen. However, this source of grafts is limited and implantation of alloantigens requires the use of anti-rejection immunosuppressant therapy. The isolation of islets of Langerhans from porcine pancreas would represent an ideal solution to the shortage of human grafts, but the high immunoreactivity of xenoantigens prevents the possibility of free graft. For this reason, cell encapsulation systems in semipermeable and biocompatible membranes, at least theoretically able to ensure permanent tolerance of the cells, have been developed. The objective of this review is to inform general surgeons about the state of progress of studies in an area considered to be the first step of a promising therapeutic era in which they will be required to participate: that of cell therapy.

Humans↗
PubMedDate not supplied

Cell preservation in University of Wisconsin solution during isolation of canine islets of Langerhans.

Allogeneic islet transplantation in Type I diabetic patients is considerably hampered by the variable outcome of islet isolation and purification. After collagenase digestion of the pancreas, islet isolation is traditionally performed under hypothermic conditions in physiological solutions such as Hanks and RPMI. The University of Wisconsin solution (UWS) has been shown superior for hypothermic preservation of the pancreas. We, therefore, compared the UWS and RPMI for canine islet isolation and subsequent purification in either a conventional hyperosmotic density gradient of dextran in Hanks, or a novel normosmotic density gradient of Percoll in UWS. The isolation solution did not affect islet yield before purification (51% of the native islet mass). Loss of amylase (30%) and swelling of the acinar cells were observed in RPMI. In contrast, no loss of amylase and slight shrinkage of the acinar cells were observed in the UWS. Cell swelling affected the density separation and viability of the cells. Dextran density separation resulted in a 15% purity and 41% recovery of the islets isolated in RPMI, as compared to a 93% purity and 52% recovery of islets isolated in UWS. Percoll density separation improved the purity (99%) and recovery (74%) of islets isolated in UWS. Islets isolated in UWS demonstrated a superior basal and glucose stimulated insulin release during perifusion. Electron microscopy demonstrated a well-preserved islet ultrastructure after isolation in both solutions--except for slightly swollen mitochondria after isolation in RPMI. Autotransplantation of islets in pancreatectomised dogs was successful both after isolation in UWS and RPMI. We conclude that prevention of cell swelling during isolation and purification in the UWS resulted in an improved yield of viable and consistent virtually pure islets. Prevention of cell swelling during islet isolation should facilitate the analysis and control of other factors affecting outcome in man.

Animals↗
PubMed1987

Selective secretion of only the urokinase plasminogen activator from rat islets of Langerhans.

Rat islets of Langerhans produce plasminogen activators (PA). The islet level of PA and the enzyme secreted in the islet incubation medium, are regulated by agents which modulate insulin synthesis and release. The cellular PA activity is due to 2 molecular forms of the enzyme, a Mr 72,000 and a Mr 48,000 species found in almost equal proportions. But the enzyme activity in the medium is due to only the lower molecular weight form. It is shown that this enzyme activity in the medium is due to immunologically identifiable urokinase type PA (uPA) and the cellular enzyme activity is due to both, uPA and tissue-type PA (tPA).

Animals↗
PubMed1981

Effects of an enkephalin analogue (DAMME) on insulin release from cultured rat islets of Langerhans.

Rat islets of Langerhans were maintained for 2 days in tissue culture. Following the culture period, the insulin secretory responses of the islets on incubation in bicarbonate medium were measured. The enkephalin analogue D-ala2, MePhe4, Met(0)-ol (DAMME), 8.3 X 10(-8) mol/l, augmented insulin release stimulated by glucose (5 or 7 mmol/l) by 76% and 47% respectively; increased insulin release stimulated by alpha-ketoisocaproate (7.5 mmol/l) by 23%; and enhanced insulin release in the presence of glibenclamide (10 microgram/ml) plus glucose (3.3 mmol/l) by 38%. Insulin release in the presence of glucose at 2 or 12 mmol/l was not affected by DAMME (8.3 X 10(-8) mol/l). The potentiatory effect of DAMME on insulin release in the presence of glucose (5 mmol/l) was blocked by naloxone (11 mumol/l): naloxone alone did not affect glucose-stimulated insulin release. A high concentration (3.3 X 10(-6) mol/l) of DAMME did not modify glucose-stimulated insulin release. Inhibition of glucose-stimulated insulin release by trifluoperazine, an inhibitor of calmodulin, was not overcome by DAMME. Insulin secretory responses were not enhanced by exposure of the islets to DAMME (8.3 X 10(-8) mol/l) during the culture period. It is concluded that insulin release from isolated islets is capable of being influenced by an opioid peptide.

Animals↗
PubMed1985

Endogenous release of hepoxilin A3 from isolated perifused pancreatic islets of Langerhans.

Pancreatic islets of Langerhans were perifused with Krebs-bicarbonate solution containing glucose (5 and 10 mM). The perifusate was spiked with tetradeuterated hepoxilin A3 and was extracted and analysed by gas chromatography-mass spectrometry using NICI detection. Evidence is presented showing the presence of hepoxilin A3 as the hydrolysis product trioxilin A3. These results demonstrate for the first time that this pathway is active in intact cells; this finding, taken together with our previous evidence that hepoxilins possess insulin secretagogue properties further supports our hypothesis that these products could play a role as endogenous mediators of insulin release.

8,11,14-Eicosatrienoic Acid↗
PubMed2004

Metabotropic glutamate receptor type 4 is involved in autoinhibitory cascade for glucagon secretion by alpha-cells of islet of Langerhans.

In islets of Langerhans, L-glutamate is stored in glucagon-containing secretory granules of alpha-cells and cosecreted with glucagon under low-glucose conditions. The L-glutamate triggers secretion of gamma-aminobutyric acid (GABA) from beta-cells, which in turn inhibits glucagon secretion from alpha-cells through the GABAA receptor. In the present study, we tested the working hypothesis that L-glutamate functions as an autocrine/paracrine modulator and inhibits glucagon secretion through a glutamate receptor(s) on alpha-cells. The addition of L-glutamate at 1 mmol/l; (R,S)-phosphonophenylglycine (PPG) and (S)-3,4-dicarboxyphenylglycine (DCPG), specific agonists for class III metabotropic glutamate receptor (mGluR), at 100 micromol/l; and (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I) at 50 micromol/l inhibited the low-glucose-evoked glucagon secretion by 87, 81, 73, and 87%, respectively. This inhibition was dose dependent and was blocked by (R,S)-cyclopropyl-4-phosphonophenylglycine (CPPG), a specific antagonist of class III mGluR. Agonists of other glutamate receptors, including kainate and quisqualate, had little effectiveness. RT-PCR and immunological analyses indicated that mGluR4, a class III mGluR, was expressed and localized with alpha- and F cells, whereas no evidence for expression of other mGluRs, including mGluR8, was obtained. L-Glutamate, PPG, and ACPT-I decreased the cAMP content in isolated islets, which was blocked by CPPG. Dibutylyl-cAMP, a nonhydrolyzable cAMP analog, caused the recovery of secretion of glucagon. Pertussis toxin, which uncouples adenylate cyclase and inhibitory G-protein, caused the recovery of both the cAMP content and secretion of glucagon. These results indicate that alpha- and F cells express functional mGluR4, and its stimulation inhibits secretion of glucagon through an inhibitory cAMP cascade. Thus, L-glutamate may directly interact with alpha-cells and inhibit glucagon secretion.

Animals↗
PubMed1999

Activation and expression of ERK, JNK, and p38 MAP-kinases in isolated islets of Langerhans: implications for cultured islet survival.

Isolation and purification of islet cells exposes them to ischemic, osmotic and mechanical stresses. The objective of this study was to determine the roles of the MAP-kinases in islets immediately following isolation. During the first 48 h, activity of JNK1 and JNK2 declined markedly. Activity of p38 increased steadily with time in culture while extracellular signal regulated kinase (ERK) activity declined dramatically within 24 h post-isolation. High p38 activation relative to ERK activation immediately following isolation correlated with a decrease in islet survival after 36 h in culture. Absence and/or transiency of ERK signaling in conjunction with sustained activation of p38 pathway could be an important regulator of cell death in islets during and following their isolation by commonly employed procedures.

Adolescent↗
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↗
PubMed1992

Immunoprecipitation of a pertussis toxin substrate of the G(o) family from rat islets of Langerhans.

Rat islets express a pertussis toxin sensitive G-protein involved in receptor-mediated inhibition of insulin secretion. This has been assumed previously to represent "G(i)" which couples inhibitory receptors to adenylate cyclase. Incubation of islet G-proteins with 32P-NAD and pertussis toxin resulted in the labelling of a band of molecular weight 40,000. This band was very broad and did not allow resolution of individual components. Incubation of the radiolabelled proteins with an anti-G(o) antiserum resulted in specific immunoprecipitation of a 32P-labelled band. These results demonstrate that the complement of pertussis toxin sensitive G-proteins in rat islets includes G(o).

Adenylate Cyclase Toxin↗
PubMed1983

Identification and metabolism of polyphosphoinositides in isolated islets of Langerhans.

Isolated islets were incubated with [32P]P1 and radiolabelling of polyphosphoinositides were determined. Labelling equilibrium was approached after 45 min, with a half-time of 15 min. D-Glucose decreased the amount of [32P]PO4 in phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] and phosphatidylinositol 4-phosphate (PtdIns4P) within 0.5 min, and loss of radiolabel was still evident at 1 min. [32P]PO4 levels in polyphosphoinositides returned to basal levels within 5 min. Neither D-galactose nor D-glucose after pretreatment of islets with mannoheptulose elicited the polyphosphoinositide effect. The glucose-stimulated breakdown of polyphosphoinositides was inhibited by EGTA; re-addition of Ca2+ partially restored the glucose effect. Ionomycin and tolbutamide promoted the rapid breakdown of PtdIns(4,5)P2, whereas the breakdown of PtdIns4P was less rapid and of a lesser magnitude. The results suggest that the Ca2+-dependent breakdown of polyphosphoinositides in an early metabolic event during the initiation of insulin release.

Animals↗
PubMed1994

Murine pancreatic ductal adenocarcinoma produced by in vitro transduction of polyoma middle T oncogene into the islets of Langerhans.

Pancreatic islets isolated from juvenile but not aging adult mice, when infected with a retrovirus carrying polyomavirus middle T oncogene, produced cell lines, mPAC, with characteristics both of pancreatic ductal epithelium and neuroendocrine cells of the islets. Following three cycles of single cell cloning, mPAC cells consisted of two subtypes, a null cell, and a double-positive cell that co-expressed cytokeratin, a marker of ductal epithelium, and A2B5, a neuroendocrine ganglioside expressed in developing islet cells. Two islet cell genes, encoding somatostatin and pancreatic polypeptide, were transcribed at low levels in most mPAC clones, whereas the insulin and glucagon genes were not. Upon inoculation of mice, mPAC cells rapidly formed well-differentiated ductal adenocarcinomas that expressed cytokeratin but not the islet cell markers. The mPAC phenotype may result from a specific dedifferentiation of juvenile islet cells or ductal epithelium induced by middle T protein. Alternatively, mPAC cells may arise by transformation of a multipotential progenitor present within or in juxtaposition to juvenile islets. This cell type could therefore represent one of the targets in human cancers of the pancreatic duct. Moreover, signal transduction systems modulated by middle T, including src-related kinases, phosphatidylinositol kinase, and protein phosphatase 2A, may be involved in pancreatic carcinogenesis.

Animals↗
PubMed1979

[The effect of exocrine glandular tissue on the transplantation results of isolated islands of Langerhans].

Islet cells were transplanted into isologous rat strains with exocrine pancreatic tissue as contaminant. The relationship of transplant function to the degree of contamination was tested. No influence on transplant success was found despite a five fold amount of exocrine tissue in one group after transplantation into livers of diabetic animals. But a 12-fold contamination of the 2000 isolated islets of Langerhans did not allow a normalization of blood sugar content. The glucose assimilation coefficient was constantly below 1.0. Purification of islet cell transplants was estimated by determination of amylase activity per islet according to SUTHERLAND.

Animals↗
PubMed1996

Follow-up study of the revascularization process of cryopreserved islets of Langerhans.

Cryopreservation of islets of Langerhans is a necessary procedure since human pancreatic islet transplantation has become a reality for the clinical treatment of Type I, insulin-dependent diabetes mellitus. Although successful cryopreservation of rodent and human islets is a well-established technique for islet storage after isolation and purification, little is known about the influence of the freeze-thaw procedure on the islets' potential to induce angiogenesis and revascularization, a major process necessary for the viability of grafted cells. In this study, the revascularization process of cryopreserved islets transplanted in the liver and in the renal subcapsular space of diabetic and nondiabetic rats is analyzed by a double indirect immunofluorescence technique. Frozen-thawed pancreatic islets were cooled slowly to -40 degrees C, stored at -196 degrees C, and thawed rapidly. Lewis rat were grafted with either Lewis (isografts) or Wistar (allografts) overnight-cultured and frozen-thawed islets obtained by collagenase digestion. Rats were killed different days after implantation, and the livers and kidneys bearing the grafted islets were snap-frozen and immunohistochemically stained with a double immunofluorescence technique using a rabbit anti-factor VIII antiserum (which labels endothelial cells) and a guinea pig anti-insulin antibody. Overnight-cultured islet grafts completed revascularization by Days 4-7 after transplantation, as shown by the detection of endothelial cells within and surrounding the islets. The identical staining pattern of revascularization was observed in islets frozen-thawed before transplantation. It is concluded that islet cryopreservation is a suitable technique for long-term storage prior to transplantation since it does not interfere with the neovascularization process of islet grafts.

Animals↗
PubMed1976

Tumors of the islets of Langerhans.

The islet cell tumors of the pancreas are now known to produce a variety of polypeptides in addition to insulin. These include glucagon, serotonin, corticotropin, melanocyte-stimulating hormone, gastrin and a secretinlike hormone that may be VIP or a combination of such polypeptides. The development and wide availability of the newer immunoassays for the various recognized hormones as well as candidate hormones of the gut will simplify the diagnosis of these challenging tumors, which up until this time have produced symptoms that were bizarre and often fatal to the patient.

Achlorhydria↗