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PubMed1995

Distribution of the Kexin family proteases in pancreatic islets: PACE4C is specifically expressed in B cells of pancreatic islets.

The distribution of Kexin family proteases in adult rat pancreatic islets was investigated by immunohistochemical means using a series of specific antibodies specific for PC1, PC2, PC6, Furin, PACE4A and a recently identified member of the Kexin family, PACE4C. PACE4C expression was limited to B cells of the pancreatic islets. PC2 was found in A and in some D cells more than in B cells and PC1 was evident only in B cells. Furin and PC6 were weakly and evenly expressed in the entire islet. PACE4A was hardly found in the islets. These findings indicated that individual Kexin family proteases are uniquely distributed in the islets and suggested that these proteases share roles in these cells as follows: PC2 is involved in the peptide hormone precursor processing in A cells and in D cells, and PACE4C, PC1 and PC2 (mainly PACE4C and PC1) are responsible for the processing event(s) specific to B cells.

Animals↗

PubMed2001

Morphological changes in pancreatic islets of KATP channel-deficient mice: the involvement of KATP channels in the survival of insulin cells and the maintenance of islet architecture.

The ATP-sensitive potassium channel (KATP channel) is an essential ion channel involved in glucose-induced insulin secretion. The KATP channel is composed of an inwardly rectifying potassium channel, Kir6.2, and the sulfonylurea receptor (SUR 1); in the pancreas it is reported to be shared by all endocrine cell types. A previous study by our research group showed that Kir 6.2-knockout mice lacked KATP channel activities and failed to secrete insulin in response to glucose, but displayed normal blood glucose levels and only mild impairment in glucose tolerance at younger ages. In some aged knockout mice, however, obesity and hyperglycemia were recognizable. The present study aimed to reveal morphological changes in pancreatic islets of Kir 6.2-knockout mice throughout life. At birth, there were no significant differences in the islet cell arrangement between the knockout mice and controls. At 14 postnatal weeks glucagon cells appeared in the central parts of islets, and this image became more pronounced with aging. In animals older than 50 weeks insulin cells decreased in numbers and intensity of insulin immunoreactivity; most islets in 70- and 80-week-old mice were predominantly composed of glucagon cells and peptide YY (PYY)-containing cells. Staining of serial sections and double staining of single sections from these old mice demonstrated the frequent coexpression of glucagon and PYY, which is a phenotype for the earliest progenitor cells of pancreatic endocrine cells. These findings suggest that the KATP channel is important for insulin cell survival and also regulates the differentiation of islet cells.

Adenosine Triphosphate↗

PubMed2004

Is presence of islet autoantibodies at birth associated with development of persistent islet autoimmunity? The Diabetes Autoimmunity Study in the Young (DAISY).

OBJECTIVE: To determine whether the presence of islet autoantibodies in the umbilical cord blood is predictive of subsequent development of islet autoimmunity. RESEARCH DESIGN AND METHODS: Cord blood sera from 1,118 subjects from the Diabetes Autoimmunity Study in the Young (DAISY) cohort, as well as their venous blood samples taken at follow-up clinic visits, were tested for GAD65 autoantibodies (GAAs), insulin autoantibodies (IAAs), and IA-2 autoantibodies (IA-2As). Venous blood samples taken from mothers of cord blood autoantibody-positive children were analyzed for the same autoantibodies. RESULTS: At least one of three islet autoantibodies was present in 42 (3.7%) of the cord blood samples tested. The presence of cord blood autoantibodies did not predict the subsequent development of islet autoimmunity (adjusted hazard ratio = 0.73 [0.09, 5.88]). Discordance between cord blood and corresponding maternal autoantibodies was seen in 3 of 36 infants. A strong correlation between levels of autoantibody in cord blood and maternal circulation was found for GAA (r(2) = 0.93, P < 0.001) and IAA (r(2) = 0.89, P < 0.001) but not IA-2A (r(2) = 0.05, P = 0.19). Cord blood autoantibodies in all but one subject disappeared by 9 months of age. CONCLUSIONS: The presence of cord blood autoantibodies is not predictive of subsequent development of islet autoimmunity. The majority of cord blood autoantibodies appear to result from maternal transmission.

Autoantibodies↗

PubMed2006

Increased expression of SNARE proteins and synaptotagmin IV in islets from pregnant rats and in vitro prolactin-treated neonatal islets.

During pregnancy and the perinatal period of life, prolactin (PRL) and other lactogenic substances induce adaptation and maturation of the stimulus-secretion coupling system in pancreatic beta-cells. Since the SNARE molecules, SNAP-25, syntaxin 1, VAMP-2, and synaptotagmins participate in insulin secretion, we investigated whether the improved secretory response to glucose during these periods involves alteration in the expression of these proteins. mRNA was extracted from neonatal rat islets cultured for 5 days in the presence of PRL and from pregnant rats (17th-18th days of pregnancy) and reverse transcribed. The expression of genes was analyzed by semi-quantitative RT-PCR assay. The expression of proteins was analyzed by Western blotting and confocal microscopy. Transcription and expression of all SNARE genes and proteins were increased in islets from pregnant and PRL-treated neonatal rats when compared with controls. The only exception was VAMP-2 production in islets from pregnant rats. Increased mRNA and protein expression of synaptotagmin IV, but not the isoform I, also was observed in islets from pregnant and PRL-treated rats. This effect was not inhibited by wortmannin or PD098059, inhibitors of the PI3-kinase and MAPK pathways, respectively. As revealed by confocal laser microscopy, both syntaxin 1A and synaptotagmin IV were immunolocated in islet cells, including the insulin-containing cells. These results indicate that PRL modulates the final steps of insulin secretion by increasing the expression of proteins involved in membrane fusion.

Animals↗

PubMed1998

The role of adhesion molecules in allotransplanted islet cells rejection. Prolongation of islet cells allograft survival by antiadhesion treatment.

Insulin-dependent diabetes mellitus is an autoimmune disease caused by the selective destruction of islet beta cells. Allo or xeno transplantation of islet cells may establish a novel promising method of IDDM therapy. Understanding how lymphocytes recognize beta cell antigens is essential for the elucidation of the pathogenesis of islet dysfunction. Leukocyte adhesion to the target cells (endothelium, islets) via adhesion molecule pathways plays an important role in auto and allo/xeno antigen recognition and effector cytodestruction of target cells. However, the expression of these molecules on the endothelium and islet cells during the rejection process still remains unclear. There are some publications describing possible roles of these antigens in the response to the graft. The expression of some of adhesion molecules may contribute to a new method for the diagnosis of graft rejection and its therapy when adhesion blocking substances are used for the treatment.

Animals↗

PubMed1992

Experimental hybrid islet transplantation: application of polyvinyl alcohol membrane for entrapment of islets.

In this study, we first examined in vitro a polyvinyl alcohol membrane to be used to contain hybrid islet cells, and second we tested a bioartificial pancreas with entrapment of pancreatic islets in polyvinyl alcohol membrane in rats with experimentally induced diabetes. The permeability of the polyvinyl alcohol membrane to different substances was studied in a two-cell chamber system. Glucose, insulin, and nutrients passed through the membrane easily, whereas the passage of immunoglobulin G was completely prevented, indicating that this membrane could be effective in protecting the bioartificial pancreas from immunorejection. Approximately 2,000 islets collected from three Sprague-Dawley rats were enclosed in a mesh-reinforced polyvinyl alcohol tube and transplanted into the peritoneal cavity of six Wistar rats with streptozotocin-induced diabetes. Their nonfasting serum glucose levels were significantly decreased for at least 12 days. Six diabetic rats receiving intraperitoneal transplantation of free islets without the tube showed a slight but significant decrease in nonfasting serum glucose levels for only 3 days. One diabetic rat with transplantation of the bioartificial pancreas had a significant and sustained decrease in nonfasting glucose levels from pretransplanted levels of 440-500 mg/dl to a mean value of 162 +/- 13 mg/dl for over 3 months without immunosuppression. The bioartificial pancreas was then removed, and glucose levels gradually increased to over 500 mg/dl. The results of the present study suggest that a bioartificial pancreas with entrapment of islets in a polyvinyl alcohol membrane could be a promising therapeutic approach to diabetes mellitus.

Animals↗

PubMed1991

[The pig--an experimental model for transplantation of isolated islets pancreatic islets].

The authors present results of autotransplantation of the islets of Langerhans of the pancreas in pigs and miniature pigs ("Troll"). Diabetes was induced by total pancreatomy. From the removed pancreas the islets of Langerhans were separated by the method of intraductal perfusion with collagenase and implanted into the spleen or liver via the portal vein. The mortality on operation in pigs was 33%, in miniature pigs 20%. In domestic pigs normal blood sugar levels were achieved in 25% after implantation of the islets of Langerhans into the liver (in 2 of 8 animals) and in 50% after implantation into the spleen (in 4 of 8 animals). In miniature pigs autotransplantation of the islets of Langerhans was equally successful when transplanted into the liver or the spleen -50%. The 50% success of autotransplantations justifies the use of pigs as a model for further investigations of allo- or xenotransplantations of the islets of Langerhans.

Animals↗

PubMed1986

Effect of vitamin E deficiency and selenium deficiency on insulin secretory reserve and free radical scavenging systems in islets: decrease of islet manganosuperoxide dismutase.

There is increasing evidence that islet beta cells may be susceptible to redox insult, and that this susceptibility may contribute to the pathogenesis of experimental models of diabetes mellitus. We investigated the effect of vitamin E deficiency, selenium deficiency, and combined deficiency on islet function and free radical scavenging systems. The tissue levels of glutathione peroxidase, catalase, and immunoreactive superoxide dismutases were measured in four groups of rats (i.e., controls and those with vitamin E, selenium, and combined deficiency). Glucose tolerance tests were performed for each animal before sacrifice. Superoxide dismutase concentrations in liver, heart, and skeletal muscle were within 20% of the control levels in all groups. However, the manganosuperoxide dismutase concentrations in islets were significantly lower than control levels in response to vitamin E, selenium, and combined deficiency. Combined deficiency appeared to have an additive effect. In contrast, cuprozinc superoxide dismutase concentration in islets was higher in the deficient groups than in controls. Insulin secretory reserve was decreased in each of the three deficient groups. This decrease was reflected as glucose intolerance only in the group with combined deficiency. Glutathione peroxidase activity was markedly decreased in selenium-deficient animals in all tissues studied. Catalase activity did not change significantly among groups in any tissue studied. Islets had the lowest glutathione peroxidase and cuprozinc and total superoxide dismutase levels among tissues studied.

Animals↗

PubMed1982

Pancreatic islet cell suspensions of newborn rats and the formation of pseudo-islets in culture.

Well preserved pancreatic islet cell suspensions were isolated by trypsin treatment from islets of Langerhans of newborn rats. (Pro)insulin biosynthesis of freshly isolated islet cells can be stimulated by increasing glucose concentrations. In contrast insulin secretion on glucose as the only stimulus is drastically reduced but can be potentiated by 3-isobutyl-1-methylxanthine (IBMX). Within a period of 4-6 days in tissue culture pancreatic islet cells of newborn rats show the tendency to aggregate and form pseudo-islets of different size.

1-Methyl-3-isobutylxanthine↗

PubMed1980

Slow interaction of islet-activating protein with pancreatic islets during primary culture to cause reversal of alpha-adrenergic inhibition of insulin secretion.

The manner in which islet-activating protein (IAP), a protein purified from the culture medium of Bordetella pertussis, interacts with the islet B-cell was studied by following the progressive development of IAP-induced reversal of alpha-adrenergic inhibition of insulin release during maintenance of islets in culture with glucose and epinephrine. This action of IAP developed in an exponential manner dependent on its concentration after a true lag period of about 1 h. The lag period was not grossly dependent on the concentration of IAP added but highly dependent on temperature of culture, and was still seen upon adding a second dose of IAP to partially stimulated cells. After 24-h culture significantly more insulin was secreted with IAP at a concentration as low as 1 pg/ml and the half-maximal effect was observed at 0.1 ng/ml. The development of IAP action occurred even in the islets that had been exposed to IAP for only 30 s, but was significantly prevented by anti-IAP serum added before the end of the lag period. IAP was effective in the presence of cycloheximide, an inhibitor of protein synthesis, or of vinblastine or cytochalasin B, microtubular-microfilamentous modifiers. It is suggested that the IAP molecule is rapidly bound to the receptor area of the islet B-cell and then is gradually inserted into the cell membrane before appearance of its action to activate native calcium ionophores. This slow interaction of IAP with the membrane may be responsible for potentiation of insulin secretory and cAMP responses of the cell to various stimuli as well as for reversal of alpha-adrenergic inhibition.

Animals↗

PubMed1981

Islet-activating protein. A modifier of receptor-mediated regulation of rat islet adenylate cyclase.

Adenylate cyclase of the membrane-rich fraction of 24-h cultured islets was inhibited by epinephrine via alpha-adrenergic receptors. Epinephrine was inhibitory only when the enzyme was activated by GTP; the degree of inhibition was highly proportional to the degree of GTP activation. Adenylate cyclase of islets cultured with islet-activating protein (IAP), one of the pertussis toxins, was less susceptible to epinephrine inhibition. The degree of the inhibition was markedly reduced without changes in potency of the catecholamine and in GTP dependence after IAP treatment. None of the other kinetic properties of the enzyme including the affinity for substrate, sensitivity to guanine nucleotide and fluoride activation, and cholera toxin-induced modification of enzymic activity were affected by treatment of islets with IAP, suggesting that neither the catalytic nor the GTP-regulatory component of the membrane adenylate cyclase complex is the site of IAP action. Slight activation of the enzyme by glucagon or adenosine tended to be enhanced by IAP treatment. Thus, a mechanism whereby membrane receptors are linked to adenylate cyclase appears to be modified by exposure of islet cells to IAP.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗

PubMed1976

[Pancreatic polypeptide islets and glucagon islets : distinct topographic distribution in rat pancreas].

The immunocytochemical technique for the cellular localization of hormones allows a precise identification of islet cell types responsible for the production of insulin, glucagon, somatostatin and pancreatic polypeptide. A systematic study of Rat pancreas has revealed a hitherto undescribed morphological heterogeneity of islets. In fact, the cellular composition of islets differs according to their anatomical distribution. The "PP islets" are preferentially located in the inferior 2/3 of the head of the pancreas, whilst "glucagon islets" populate the remainder of the gland.

Animals↗

PubMedDate not supplied

[Islet of Langerhans transplantation. A comparative study of two different methods for isolating islet cells from rat pancreas].

Two different methods for isolation of islet of Langerhans on control of metabolic abnormalities of alloxan-induced diabetic rat were tested. Sixty rats were randomly assigned to four experimental groups: GI included 10 non-diabetic control rats, GII included 10 diabetic control rats, without treatment, GIII included 20 diabetic rats (10 inbred and 10 outbred rats) that received islet of Langerhans transplantation (ILT) using islet cells prepared by collagenase, and GIV included 20 diabetic rats (10 inbred and 10 outbred rats) submitted to ILT using islet cells prepared by nonenzymatic method. Clinical and laboratory parameters at beginning and 4, 7, 14, 21 and 30 days of follow-up were recorded. Outbred rats were immunosuppressed with cyclosporin A, diabetes was induced by e.v. alloxan administration, and islet cells were isolated from normal donor Lewis rats and injected into the portal vein. ILT corrected the body weight gain, polyuria, polydipsia, polyphagia, and the high levels of blood and urine glucose in 73.7% of rats treated by enzymatic method and in 64.7% of those ones treated by nonenzymatic method. However, there was no significantly difference between the two methods (P > 0.50). We did not also observe significantly difference between the two methods when ILT was performed either in inbred or outbred rats. We concluded that ILT performed by nonenzymatic method may be an alternative treatment for diabetes due to be less expensive and to have possible advantages in the isolation process.

Animals↗

PubMed1993

Cyclosporine and islet mass--implications for islet transplantation.

Cyclosporine (CsA) is an inhibitor of ornithine decarboxylase (ODC), a key enzymatic step in cell proliferation. The purpose of this study was to determine the effect of CsA on islet cell mass. Partial obstruction (PDO) of the hamster pancreas is an established model of islet cell differentiation and proliferation in which regeneration is mediated by the induction of trophic activity (TA) that can be extracted from the pancreas. In Part 1 of these studies, hamsters were randomized to (i) Control (n = 5); (ii) PDO alone (n = 5); (iii) PDO + CsA (20 mg/kg ip daily) (n = 5); (iv) CsA alone (n = 5). On Day 21, 1 hr prior to sacrifice, animals received tritiated thymidine, 2 microCi/g body wt ip. Pancreata were excised for analysis of islet cell mass (No. islets/mm2) by morphometry and of cell proliferation (islet cell labeling index) by autoradiography. In Part 2 of these studies, hamsters were randomized to receive CsA (n = 34), as in Part 1, or saline (n = 30). After 7 days, animals received 1 ml of TA ip and were sacrificed after 0, 6, 8, and 10 hr. The pancreata were excised and determinations made of organ weight, DNA content, and ODC bioactivity (pmole/CO2/hr/mg DNA). Data (mean +/- SEM) were analyzed by ANOVA. In Part 1, the number of islets/mm2 in the PDO group was increased two-fold compared to control animals, those receiving CsA, and those undergoing PDO with CsA (2.4 +/- 0.1 vs 1.1 +/- 0.0, 1.4 +/- 0.2, 1.2 +/- 0.1, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Islet amyloid polypeptide (IAPP) and pro-IAPP immunoreactivity in human islets of Langerhans.

Islet amyloid polypeptide (IAPP) is a 37-amino-acid putative hormone which is expressed by islet B-cells and most probably is co-released with insulin. IAPP is synthesized as an 89-amino-acid prepropeptide in which IAPP is flanked by two short peptides. The two short peptides are ultimately cleaved off at basic residues. In the present study, we used antisera to three different synthetic peptides corresponding to positions 18-30, 40-50 and 53-62 of prepro-IAPP. The two latter peptides fall within the mature IAPP molecule while the first peptide corresponds to the N-terminal flanking peptide. We demonstrate that normal B-cells and islet amyloid both react immunohistochemically with all of these antisera. Using the immunogold labelling technique, we also demonstrate electron microscopically that both the IAPP immunoreactivity and the pro1-IAPP immunoreactivity in amyloid deposits are confined to the amyloid fibrils per se. These data indicate that not only mature IAPP but also the N-terminal flanking peptide is present in islet amyloid deposits. It remains to be shown if the propeptide segments are involved in the pathogenesis of these amyloid depositions.

Aged↗

PubMed1990

Heterogeneity of islet cell autoantibodies in terms of insulin release from rat islets and insulinoma cells.

The clinical significance of cytoplasmic islet cell autoantibodies (ICA) has been studied since their discovery by Bottazzo et al. in 1974. Some ICAs destroy pancreatic B cells in the presence of complement, whereas others take no part in this destruction. This suggests that islet function varies with the amount of ICA produced. In the present investigation we report the heterogeneity of monoclonal islet cell antibodies produced by one of us in terms of insulin release from isolated rat islets as well as from rat insulinoma cells (RINr).

Adenoma, Islet Cell↗

PubMed1992

Islet amyloid polypeptide (IAPP) gene analysis in a Japanese diabetic with marked islet amyloid deposition.

Islet amyloid polypeptide (IAPP) is a major constituent of pancreatic amyloid deposits in many patients with non-insulin-dependent diabetes mellitus (NIDDM). We analyzed the IAPP gene in a Japanese diabetic with marked islet amyloid deposition. Pancreatic specimens were obtained from an 87-year-old NIDDM patient who had had diabetes for 37 years. All islets (100/100) in his pancreas had IAPP-positive amyloid deposition, and 70% of the area of the islet was replaced by amyloid. We amplified the coding regions as well as the upstream region of the IAPP gene by polymerase chain reaction (PCR). The products of PCR were sequenced, and the sequences of the coding regions were identical to the Caucasian ones. However, the nucleotides of two positions of 5'-upstream and one position of intron 2 were different from the Caucasian data: the upstream region of the IAPP gene in the patient had cytosine substituted for thymine at -259, and had two alleles including cytosine and adenine at -229, respectively. The nucleotide of position 539, that is guanine, was deleted. A possible difference in the IAPP promoting region between the Japanese and Caucasian population was suggested.

Aged↗

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↗