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PubMed1994

Intraportal transplantation of pancreatic islets into livers of diabetic rats. Reinnervation of islets and regulation of insulin secretion by the hepatic sympathetic nerves.

Two weeks after intraportal transplantation of 2,000 neonatal pancreatic islets, recipient rats completely recovered from streptozotocin-induced diabetes. The reversal of diabetes could be documented by the normalization of blood glucose levels, by a restored weight gain, by normal glucagon and insulin levels in blood, and by a disappearance of polyuria and polydipsia. The reversal remained stable for at least 9 months. This study determined whether intraportally transplanted pancreatic islets were reinnervated after transplantation and whether the secretion of insulin and glucagon from pancreatic islets might be modulated by the vegetative innervation of recipient livers. Predominantly catecholaminergic but also cholinergic nerve fibers were detected not only within the portal tracts around hepatic arteries, portal veins, and bile ducts, but also at the borderline of hepatocytes and beta-cells and in islet cell complexes between beta-cells. Corresponding electron micrographs showed beta-cells in close contact with axons of nonmyelinated nerve fibers. Isolated livers were single pass perfused via both the hepatic artery and the portal vein. An increase in glucose level from 5 to 14 mmol/l enhanced hepatic glucose uptake and increased insulin secretion from transplanted islets with a biphasic secretion profile but had no effect on glucagon output. Stimulation of the nerve plexus around the hepatic artery and the portal vein (7.5 Hz, 2 min), which activates primarily the sympathetic system, not only reduced glucose uptake and perfusion flow but also completely reversed the glucose-stimulated increase in insulin secretion. Nerve stimulation did not influence glucagon secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Human islet amyloid polypeptide accumulates at similar sites in islets of transgenic mice and humans.

The cellular mechanisms responsible for conversion of islet amyloid polypeptide (IAPP) into insoluble amyloid deposits in non-insulin-dependent diabetes mellitus (NIDDM) are not clear. Overexpression of IAPP and the amino acid sequence of human IAPP (hIAPP) have both been implicated. To examine factors involved in amyloid formation, transgenic mice expressing the hIAPP or rat IAPP (rIAPP) gene were generated. These mice had elevated plasma IAPP concentrations, and they were normoglycemic and normoinsulinemic. No amyloid deposits were detected by light microscopy. To examine the ultrastructure of islets, pancreatic tissue was studied from hIAPP and rIAPP transgenic mice and from age-matched control mice by immunoelectron microscopy. IAPP was immunolocalized in beta-cell secretory granules of all mice, and the COOH- and NH2-terminal flanking peptides of hIAPP were localized in beta-cell granules of hIAPP mice. Accumulations of nonfibrillar perivascular IAPP-immunoreactive material were found between capillaries and beta-cells in hIAPP transgenic mice but not in rIAPP transgenic or control mice. Similar nonfibrillar masses were identified in islets of an NIDDM patient. Secondary lysosomes in beta-cells and macrophages of hIAPP transgenic mice showed dense labeling for IAPP. We suggest that hIAPP is degraded more slowly than rIAPP or mouse IAPP by beta-cell lysosomes. Accumulations of IAPP in islet perivascular spaces may represent the early stages of islet amyloid formation.

Aged↗

PubMedDate not supplied

Neonatal islet cell adenoma: a distinct type of islet cell tumor?

An encapsulated, compact-type islet cell adenoma of the pancreas, found in a newborn infant with hyperinsulinemic hypoglycemia, was investigated by conventional histology and immunofluorescence. Although the histologic structure of the tumor was indistinguishable from that of most islet cell tumors of adults, immunofluorescence revealed that the four islet cell hormones (insulin, glucagon, somatostatin, and pancreatic polypeptide) were all present in the tumor. They were stored in different cells that showed the same spatial distribution usually seen in normal islets. We conclude that neonatal islet cell adenoma can be distinguished from those of adults on the basis of the content and topographic distribution of their constituent endocrine cells.

Adenoma, Islet Cell↗

PubMed1992

High efficiency presentation of TNP-conjugated islet antigen to islet-specific T cells by a hybrid B cell line expressing TNP-specific surface Ig.

There is compelling evidence from animal models that type I diabetes is a consequence of T cell-mediated destruction of islet beta-cells. The recent isolation of islet-specific T cell clones from nonobese diabetic mice provides a means of identification of the Ag on islet cells that are responsible for stimulation of autoreactive T cells. We describe an APC line constructed by fusion of spleen B cells obtained from nonobese diabetic mice to a B lymphoma that was transfected with the H and L chains of an IgM specific to the hapten TNP. Using this hybrid APC we have observed a dramatic increase in the efficiency of presentation of TNP-conjugated islet cell protein preparations compared to that seen with conventional APC. Our results illustrate the potential use of this APC line for isolation and characterization of islet Ag relevant to the T cell response.

Adenoma, Islet Cell↗

PubMed1988

Weight-corrected islet counts are predictive of outcome in the canine intrahepatic islet autograft model.

A combination of high-concentration collagenase digestion and density-gradient purification of canine pancreatic tissue made it possible to obtain relatively pure islets which could be quantified and the outcome of intrahepatic autotransplantation correlated with weight-corrected islet counts in the transplanted tissue. Of eleven dogs, seven achieved durable euglycaemia within 24 hours. All of these animals received islet doses of greater than 4,380 per kilogram of body weight. The remaining four animals became progressively hyperglycaemic necessitating sacrifice within one week; they all received islet doses of less than 4,380 per kilogram (p = 0.042). This model is therefore satisfactory for the investigation of preservation injury to islets and of allotransplantation because it identifies prospectively the transplants which ought to succeed, giving evidence for or against additional immune or ischaemic resistance to graft function.

Animals↗

PubMed1995

Antioxidant, probucol, can inhibit the generation of hydrogen peroxide in islet cells induced by macrophages and prevent islet cell destruction in NOD mice.

The preventive effect of antioxidant on the islet cell destruction in NOD mice was studied. Oral administration of probucol prevented the development of cyclophosphamide induced diabetes in NOD mice (incidence of diabetes; probucol: 0/10 vs. control: 9/15) As in vitro studies, the effects of probucol on the generation of H2O2 in the content of H2O2 in islet cells co-cultured with M phi were measured. Intracellular oxidation of 2'7'-dichlorofluorescin by H2O2 was analyzed by flow cytometry. The probucol-treated M phi induced less marked increase of H2O2 in islet cells in comparison with control M phi. The generation of H2O2 by M phi in islet cells from treated mice was less marked than that in controls. These results suggest that the preventive effect of probucol may be mediated by protection of islet cells from oxidative stress induced by M phi.

Animals↗

PubMed2006

Assessment of islet function following islet and pancreas transplantation.

Pancreas and islet transplant recipients are monitored using various metabolic and imaging methods. The inaccessibility of the transplanted whole pancreas and of the isolated islets poses specific problems (eg, all assessment techniques are indirect). Although successful pancreas transplantation typically restores normal glucose homeostasis, islet transplantation into the liver does not completely normalize islet hormone secretion and glucose metabolism. Development of better testing strategies, such as direct islet imaging, will significantly advance the field.

Diabetes Mellitus, Type 1↗

PubMed1989

Detection of islet cell specificity of monoclonal islet cell surface antibodies by means of double-staining immunofluorescence.

We have generated monoclonal antibodies (mcab) reactive with islet cell surface antigens. 10 different mcab were characterized regarding their islet cell binding specificity by means of a modified double immunofluorescence test. At this assay, the monoclonal islet cell surface antibodies were visualized on rat islet cells by indirect immunofluorescence with fluorescein isothiocyanate-labelled antibodies against mouse immunoglobulin. The alpha and beta cell specificity was determined by indirect immunofluorescence using anti-glucagon or anti-insulin serum and a tetramethyl rhodamine isothiocyanate-labelled second antibody. The target islet cell suspension used contained 61% beta and 23% alpha cells. The monoclonal antibody K28D6 preferentially reacted with alpha cells. The binding of K29aC6 and K56aF3 indicates a high specificity against beta cells. The remaining 7 antibodies were reactive with alpha as well as with beta cells.

Animals↗

PubMedDate not supplied

IgG subclasses of islet cell surface antibodies and their cytotoxic activity against pancreatic islet cells.

IgG subclasses of islet cell surface antibodies (ICSA) and their cytotoxic activities against pancreatic islet cells in the presence of complements were simultaneously investigated in ICSA-positive patients with insulin-dependent diabetes mellitus (n = 15). ICSA (IgG class) and ICSA-IgG subclasses were determined by flow cytometry using a fluorescence-activated cell sorter (FACS). Complement-dependent antibody-mediated cytotoxicity (CAMC) was measured by release of 51Cr from target cells. For these assays, rat insulinoma (RINr) cells were used as antigenic or target cells. Sera from 11 out of 15 patients who were positive for ICSA possessed at least one positive ICSA-IgG subclass, though these sera did not always exert positive CAMC activities. When the relationship between ICSA-IgG subclasses and CAMC was tested by chi-square analysis, a significant relationship (P less than 0.01) was observed between ICSA-IgG3 and CAMC. In sera from the other four patients, not any positive ICSA-IgG subclass or CAMC activity was found. The data suggest that (1) ICSA (IgG class) found in diabetics are not always cytotoxic to pancreatic islet cells, (2) the IgG subclass of ICSA varies with the patients, and (3) ICSA-IgG3 have a significantly higher association with CAMC to pancreatic islet cells. Thus, ICSA (IgG class) might not always be responsible for the impairment of pancreatic islet cells, at least in part, because of the heterogenous ICSA-IgG subclass.

Adolescent↗

PubMed1972

The mode of action of adenosine 3':5'-cyclic monophosphate in mammalian islets of Langerhans. Preparation and properties of islet-cell protein phosphokinase.

1. A protein was demonstrated in mammalian islets of Langerhans that after purification appeared as a single component possessing both cyclic-AMP (adenosine 3':5'-cyclic monophosphate)-binding and cyclic-AMP-dependent protein phosphokinase activities. 2. The protein had an intrinsic association constant for cyclic AMP of 1.15x10(-8)m, which was similar to the K(m) for cyclic AMP (1.11x10(-8)m) of the protein phosphokinase activity. 3. Incubation of the protein in the presence of cyclic AMP resulted in its dissociation into cyclic-AMP-independent protein phosphokinase (catalytic) and cyclic-AMP-binding (receptor) subunits, which could be separated on Sephadex G-200. 4. The cyclic-AMP-dependent protein phosphokinase was capable of phosphorylating a variety of proteins, the most readily phosphorylated being histone, casein and protein components of sub-cellular fractions prepared from islets of Langerhans. 5. The cyclic-AMP-dependent phosphorylation of histone had a K(m) for ATP of 1.1x10(-5)m. 6. The endogenous protein phosphokinase activity in rat islets incubated with agents that are known to alter the intracellular concentration of cyclic AMP was investigated. Theophylline and 3-isobutyl-1-methylxanthine, agents that raise cyclic AMP concentrations in islets, increased the activity of the protein phosphokinase, whereas adrenaline, which lowers islet cyclic AMP concentrations, decreased its activity. 7. It is suggested that cyclic AMP may exert its effects on insulin release by increasing the activity of a protein phosphokinase and may thereby promote the phosphorylation and activity of a rate-determining component of the secretory mechanism.

Animals↗

PubMed1989

The conditions under which rat islets are labelled with [3H]inositol alter the subsequent responses of these islets to a high glucose concentration.

Isolated rat islets were incubated with myo-[2-3H]inositol for 2 h to label their phosphoinositide (PI) pools. Labelling was carried out under three separate conditions: in media containing low (2.75 mM) glucose, high (13.75 mM) glucose, or low (2.75 mM) glucose plus sulphated cholecystokinin (CCK-8S; 200 nM). After labelling, the islets were perifused and the insulin-secretory response to 20 mM-glucose was measured. PI hydrolysis in these same islets was assessed by measurements of both [3H]inositol efflux and the accumulation of labelled inositol phosphates. The following major observations were made. After prelabelling for 2 h in low glucose, perifusion with 20 mM-glucose resulted in a biphasic insulin-secretory response, an increase in [3H]inositol efflux and a parallel increase in the accumulation of labelled inositol phosphates. After prelabelling in high (13.75 mM) glucose, peak first-phase insulin secretion induced by 20 mM-glucose increased 2-2.5-fold, whereas the second phase of insulin release, as well as [3H]inositol efflux and inositol phosphate accumulation, were significantly decreased. The simultaneous infusion of the diacylglycerol kinase inhibitor 1-mono-oleoylglycerol (50 microM), along with 20 mM-glucose, restored the second-phase insulin-secretory response from these islets. After labelling in low (2.75 mM) glucose plus CCK-8S, the initial phases of the insulin-secretory and [3H]inositol-efflux responses to 20 mM-glucose were blunted and the sustained phases of both responses were markedly decreased. Inositol phosphate accumulation was also impaired. Labelling islets in high (13.75 mM) glucose or low (2.75 mM) glucose plus CCK-8S suppresses, in a parallel fashion, glucose-induced increases in PI hydrolysis and in second-phase insulin release. These findings suggest that desensitization of the insulin-secretory response is a consequence of impaired information flow in the inositol lipid cycle.

Animals↗

PubMed2006

Insulin protects islets from apoptosis via Pdx1 and specific changes in the human islet proteome.

Insulin is both a hormone regulating energy metabolism and a growth factor. We and others have shown that physiological doses of insulin initiate complex signals in primary human and mouse beta-cells, but the functional significance of insulin's effects on this cell type remains unclear. In the present study, the role of insulin in beta-cell apoptosis was examined. Exogenous insulin completely prevented apoptosis induced by serum withdrawal when given at picomolar or low nanomolar concentrations but not at higher concentrations, indicating that physiological concentrations of insulin are antiapoptotic and that insulin signaling is self-limiting in islets. Insulin treatment was associated with the nuclear localization of Pdx1 and the prosurvival effects of insulin were largely absent in islets 50% deficient in Pdx1, providing direct evidence that Pdx1 is a signaling target of insulin. Physiological levels of insulin did not increase Akt phosphorylation, and the protective effects of insulin were only partially altered in islets lacking 80% of normal Akt activity, suggesting the presence of additional insulin-regulated antiapoptotic pathways. Proteomic analysis of insulin-treated human islets revealed significant changes in multiple proteins. Bridge-1, a Pdx1-binding partner and regulator of beta-cell survival, was increased significantly at low insulin doses. Together, these data suggest that insulin can act as a master regulator of islet survival by regulating Pdx1.

Analysis of Variance↗

PubMed2001

Prevention of early islet graft failure by selective inducible nitric oxide synthase inhibitors after pig to nude rat intraportal islet transplantation.

BACKGROUND: Clinical and experimental data indicate that early failure of intraportally grafted islets is caused by inflammation including secretion of cytokines and nitric oxide. Direct inducible nitric oxide synthase suppression may avoid detrimental effects associated with steroid administration. We compared the efficiency of selective and unselective inducible nitric oxide synthase inhibitors with dexamethasone to suppress nitric oxide generation after intraportal islet xenotransplantation into nude rats. METHODS: Nonfasting serum glucose levels were daily evaluated after intraportal transplantation of 4000 freshly isolated pig islets into diabetic nude rats (85 mg/kg streptozotocin) either sham-treated with saline (n=21) or continuously infused for 7 days with L-NG-monomethyl-arginine (n=7), S-methyl-isothiourea (n=15), or S-(2-aminoethyl)-isothiourea (n=19) in a dosage of 240, 100, or 50 mg/kg/day, respectively. Dexamethasone was injected i.p. twice as a daily bolus of 20 mg/kg (n=10) starting 1 day pretransplant. The nitrate/nitrite serum level was quantified colorimetrically 0, 24, and 48 hr posttransplant. RESULTS: Saline treatment partially resulted in graft function (4/21) throughout the observation period (21 days). L-NG-monomethyl-arginine-treated rats showed sustained hyperglycemia (0/7) not different from diabetic controls. Normoglycemia was observed after treatment with dexamethasone (6/10, P<0.05 versus saline and L-NG-monomethyl-arginine), S-methyl-isothiourea (10/15, P<0.01), or S-(2-aminoethyl)-isothiourea (15/19, P<0.001). Graft function was associated with complete suppression of nitric oxide generation after S-methyl-isothiourea and S-(2-aminoethyl)-isothiourea treatment (P<0.001 versus saline) and partial suppression after dexamethasone treatment (P<0.05). CONCLUSIONS: Our observation of long-term function of xenogeneic islets in an inflammatory environment without interference of reactive T cells revealed the potency of highly selective isothioureas to completely suppress inducible nitric oxide synthase making reduction of islet-toxic immunosuppression feasible.

Animals↗

PubMed1986

Mechanisms of pancreatic islet cell destruction. Dose-dependent cytotoxic effect of soluble blood mononuclear cell mediators on isolated islets of Langerhans.

Supernatants of peripheral blood mononuclear cells from healthy human donors stimulated with recall antigen (purified protein derivative of tuberculin) or lectin (phytohaemagglutinin) markedly inhibited the insulin release from isolated human and rat islets of Langerhans, and decreased rat islet contents of insulin and glucagon in a dose-dependent manner. A maximal effect on islet function was obtained with supernatant concentrations down to 5%. Supernatants of mononuclear cells stimulated with tuberculin were more potent than supernatants produced by lectin stimulation. Culture medium reconstituted with tuberculin or phytohaemagglutinin did not impair islet function. Electron microscopy demonstrated that supernatants were cytotoxic to islet cells. The cytotoxic mononuclear cell mediator(s) was non-dialysable, sensitive to heating to 56 degrees C, labile even when stored at -70 degrees C, but stable when lyophilised.

Animals↗

PubMed2004

Overexpression of pituitary adenylate cyclase-activating polypeptide in islets inhibits hyperinsulinemia and islet hyperplasia in agouti yellow mice.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an intraislet neuropeptide and shares insulinotropic and insulin-sensitizing properties with glucagon-like peptide-1 (GLP-1); however, the pathophysiological significance of PACAP in diabetes remains largely unknown. To assess this, we crossed our recently developed transgenic mice overexpressing PACAP in pancreatic beta-cells (Tg/+), with lethal yellow agouti (KKA(y)) mice (A(y)/+), a genetic model for obesity-diabetes, and examined the metabolic and morphological phenotypes of F(1) animals. Tg/+ mice with the A(y) allele (Tg/+:A(y)/+) developed maturity-onset obesity and diabetes associated with hyperglycemia, hyperlipidemia, and hyperphagia, similar to those of A(y)/+ mice, but hyperinsulinemia was significantly ameliorated in Tg/+:A(y)/+ mice. Although A(y)/+ mice exhibited a marked increase in islet mass resulting from hyperplasia and hypertrophy, this increase was significantly attenuated in Tg/+:A(y)/+ mice. Size frequency distribution analysis revealed that the very large islets comprising one-fourth of islets of A(y)/+ mice were selectively reduced in Tg/+:A(y)/+ mice. Because functional defects have been demonstrated in the large islets of obese animal models, together these findings suggest that PACAP regulates hyperinsulinemia and the abnormal increase in islet mass that occurs during the diabetic process.

Animals↗

PubMed2005

Cocarcinogenic effects of islet hormones and N-nitrosomorpholine in hepatocarcinogenesis after intrahepatic transplantation of pancreatic islets in streptozotocin-diabetic rats.

In contrast to high local insulin levels obtained after low-number transplantation (n = 350) of islets of Langerhans into the livers of diabetic rats, low insulin levels after high-number transplantation (n = 1,000) do not suffice to induce hepatocarcinogenesis. Herein, we investigated the possible cocarcinogenic potential of high and, in particular, low insulin levels, combining this in vivo model with a chemical model of hepatocarcinogenesis after administration of N-nitrosomorpholine (NNM). In three main experiments, different schemes of single or continuous NNM administration were combined with different transplantation procedures in diabetic or nondiabetic animals, i.e., low-number and high-number islet transplantation, transplantation of polystyrene particles, and sham transplantation. Animals were sacrificed between 3 and 53 weeks after transplantation procedures. Evidence for the cocarcinogenic effects of NNM and insulin was provided in each main experiment. NNM treatment after low-number islet transplantation resulted in an increase in the number of preneoplastic hepatocellular foci, and a significant increase in the number and an earlier appearance of hepatocellular adenomas and carcinomas compared with controls. Most intriguing was the increase in preneoplastic foci after combined NNM treatment and high-number islet transplantation, proving that insulin, even in lower doses, has at least cocarcinogenic effects on the downstream hepatocytes and thus promotes an otherwise initiated hepatocarcinogenic process. Conclusively, intrahepatic transplantation of pancreatic islets acts as a strong cocarcinogenic factor together with NNM in streptozotocin-diabetic rats.

Animals↗

PubMed1986

Characteristics of insulin and glucagon release from the perfused pancreas, intact isolated islets, and dispersed islet cells.

There are a variety of different tissue preparations which have been used to study secretion from the endocrine pancreas and there are considerable differences in the results obtained from these. The purpose of this study was to compare several preparations in one laboratory using the same rats, buffers, and radioimmunoassays. The preparations included the isolated perfused rat pancreas, fresh isolated intact islets and dispersed cells, and cultured islets and cells. Insulin release from the perfused rat pancreas at 2.8 mM glucose was so low that it could not be measured, such that over a 90-min time period the amount of insulin released was less than 0.004% of pancreatic insulin content. In contrast, islets in static incubation appear to release 2.0% of their stored content and dispersed cells appear to release 2.6% of their content. Samples were taken at early time points during incubations of fresh islets and dispersed cells, and it was found that almost all of the insulin found at the end of a 90-min incubation period was present during the first 5 min. It is therefore suspected that the true secretory rate of insulin at a low glucose concentration is far lower than had been generally appreciated. Glucagon release patterns showed similarities in that with isolated islets and dispersed cells a disproportionate amount of glucagon release was found during a 0- to 30-min incubation period when compared with the 30- to 90-min period. In summary, artifacts have been identified in some of the in vitro systems used for the study of endocrine pancreatic secretion and these deserve greater recognition.

Animals↗

PubMedDate not supplied

Immunocytochemical detection and characterization of intrahepatic human pancreatic islets after combined liver-islet allotransplantation.

The unique availability of an explanted liver-islet allograft, removed for primary nonfunction of the liver, led us to evaluate distribution and phenotype of exocrine and endocrine components of the pancreatic graft. Immunocytochemistry was used to map patterns of gene products for islet hormones, proprotein processing enzymes, panneuroendocrine markers, and pancreatic exocrine markers. When compared with age-matched control pancreases, insulin-, glucagon-, somatostatin-, and pancreatic polypeptide-producing cells were similarly represented and distributed within the grafted islet. We also demonstrate that the intrahepatic transplanted islets retained the enzyme machinery able to process the hormone precursors into bioactive fragments. In the clinical setting, this resulted in an immediate functioning of the graft and insulin-independence of the patient one month after transplantation. The purity in islets, as assessed by immunocytochemistry with antibodies to tissue constituents of endocrine and exocrine lineages, was around 40%. Despite the massive intraportal presence of pancreatic acinar tissue, no signs or symptoms attributable to ectopic hypersecretion of exocrine enzymes occurred. In fact, when tested with antibodies to such enzymes, low levels of immunoreactivity were observed in the grafted acinar cells.

Biomarkers↗