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PubMed2005

Activation of peroxisome proliferator-activated receptor-gamma by rosiglitazone protects human islet cells against human islet amyloid polypeptide toxicity by a phosphatidylinositol 3'-kinase-dependent pathway.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by a deficit in beta-cell mass, increased beta-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). Human IAPP (h-IAPP) applied to beta-cells forms toxic oligomers that induce apoptosis. Thiazolidinediones, ligands of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), can delay the onset of T2DM. OBJECTIVE: We questioned whether activation of endogenous PPAR-gamma in human islets by rosiglitazone (RSG) inhibits h-IAPP-induced islet cell death and, if so, by which mechanism. METHODS AND RESULTS: Vehicle or h-IAPP was applied to human islets with or without RSG (10 and 50 microM) for 48 h. A 2-fold increase in the number of terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling-positive nuclei was detected in h-IAPP-treated human islets (P < 0.001). RSG (10 and 50 microM) prevented h-IAPP-induced apoptosis in human islets (P < 0.001). Thioflavin T binding assays confirmed that this effect was not mediated by interference with h-IAPP oligomerization. Expression of dominant negative PPAR-gamma in human islets prevented the protective effect of RSG. RSG activation of PPAR-gamma resulted in downstream activation of the serine/threonine protein kinase Akt, an outcome that was inhibited by a specific phosphatidylinositol 3-kinase inhibitor, which ablated RSG protection against h-IAPP-induced islet cell apoptosis. CONCLUSION: We conclude that in human islets, activation of PPAR-gamma inhibits h-IAPP-induced islet cell apoptosis, and this action is at least in part mediated through activation of the phosphatidylinositol 3'-kinase-Akt cascade. If this action is present in vivo, then thiazolidinediones have the potential to decrease beta-cell apoptosis in T2DM and reduce loss of beta-cell mass.

Amyloid↗

PubMed1985

Effect of islet transplantation on diabetes mellitus after subtotal pancreatectomy in rat: a quantitative analysis of islet tissue.

A reproducible model of diabetic state was produced by resecting more than 90% of the pancreatic tissue in Wistar strain male rats. Five rats with diabetic state after the resection received islet transplantation into the liver through the portal vein. All these five rats showed normoglycemia one week after the injection and it lasted about six months. A morphometric analysis using 1190 serial sections of the control rat pancreas showed that the islet distribution accorded satisfactorily with Weibull and gamma distribution, when an islet was regarded as a sphere in the three dimensional space. The estimated value of radius and number of the islets was 0.0155 mm and 131.2/mm3, respectively, whereas volume fractions of the islet tissue in the splenic and gastric segments, and parabiliary and duodenal segments were estimated at 1.45 and 0.98%, respectively. The mean half of the largest diameter of the isolated islets under dissecting microscope reached to 0.080 mm and 500 isolated islets account for about 14% of volume fraction in a whole pancreas. As the remnant pancreas possibly had approximately five percent of islet volume, the transplanted animal contained about 19% of islet volume as compared to the control animal. It could be concluded that transplantation of 500 islets controlled diabetes in the rat with subtotal pancreatectomy. But the transplanted rats eventually became diabetic about six months after the transplantation possibly because of insufficient volume of implanted islets.

Animals↗

PubMed1996

Treatment with growth hormone and dexamethasone in mice transgenic for human islet amyloid polypeptide causes islet amyloidosis and beta-cell dysfunction.

Islet amyloid derived from islet amyloid polypeptide (IAPP) is a well-recognized feature of type II diabetes. However, the mechanism of islet amyloidogenesis is unknown. In vitro studies suggest that amino acid residues 20-29 in human, but not mouse, IAPP confer amyloidogenicity consistent with the absence of spontaneous islet amyloidosis in mice. Several clinical and in vitro studies suggest that increased synthetic rates of IAPP predispose to IAPP-amyloidosis. In the present study, we sought to test the hypothesis that pharmacological induction of insulin resistance in a mouse transgenic (TG) for human IAPP would induce islet amyloid and beta-cell dysfunction. TG and non-transgenic (N-TG) control mice were treated with both rat growth hormone (12 micrograms/day) and dexamethasone (0.24 mg/day) (dex/GH) or received no treatment for 4 weeks, after which animals were killed to examine islet morphology. Treatment with dex/GH caused hyperglycemia (7.3 +/- 0.4 vs. 5.2 +/- 0.1 mmol/l, TG vs. N-TG, P < 0.001) associated with a decreased plasma insulin concentration (595 +/- 51 vs. 996 +/- 100 pmol/l, TG vs. N-TG, P < 0.05) in TG versus control mice. Islet amyloid was induced in treated TG mice but not in control mice. Islet amyloid was identified in both intra- and extracellular deposits, the former being associated with evidence of beta-cell degeneration. We conclude that dex/GH treatment in mice TG for human IAPP induces IAPP-derived islet amyloid, hyperglycemia, and islet dysfunction. The present model recapitulates the islet morphology and phenotype of type II diabetes.

Amyloid↗

PubMed2003

Islet cell transplantation as a cure for insulin dependent diabetes: current improvements in preserving islet cell mass and function.

OBJECTIVE: To review the current progress of islet cell transplantation in patients with insulin-dependent diabetes, emphasizing on the difficulties with recovering and preserving islet cell mass and function, 30% of which is lost during the peri-transplantation period. RESULTS: The islet-cell isolation technique is perfected, but improvements are still progressing in two major directions: preservation of islet cells and tolerance induction. Optimum islet cell viability and function depends on appropriate revascularization of the islet graft and blockade of thrombus formation as well as cytokine and free radical release. Conditioning the islet cells in-vitro prior to transplantation to either upregulate VEGF expression or downregulate NF-kappa B transcription factor has proven to improve revascularization and to prevent islet cell apoptosis and cytokine-mediated damage. Tolerance induction is currently being best achieved by selecting and combining immunosuppressive agents such as monoclonal antibodies which target the major signaling molecules during immune activation, but which are least toxic to islet cells. CONCLUSIONS: Patients with insulin-dependent diabetes will greatly benefit from current developments in effective approaches to protect islets during the peritransplant period. Emerging interest in stem cell biology and differentiation may provide the ultimate solution to the problem of organ scarcity and islet cell protection from the peritransplant induced damage.

Animals↗

PubMed1993

Reinnervation of transplanted pancreatic islets. A comparison among islets implanted into the kidney, spleen, and liver.

Islets transplanted beneath the kidney capsule become reinnervated during the first 3-4 months after implantation by both afferent and efferent nerve fibers. To evaluate the importance of the implantation organ for this process, the present study compared both the degree and the types of nerve fibers reinnervating islets transplanted into the liver, kidney, and spleen. For this purpose, 150 syngeneic islets were grafted under the kidney capsule of C57BL/6 mice. In addition, the same animals were injected with 150 islets into the spleen or liver. All animals were killed 14 weeks after transplantation, after which the graft-bearing organs were processed for indirect immunofluorescence for neuropeptides and tyrosine hydroxylase (TH), and with acetyl cholinesterase (AchE) staining to visualize nerve fibers. Both afferent (containing substance P and/or calcitonin gene-related peptide) and parasympathetic (containing vasoactive intestinal peptide or AchE) nerve fibers were absent from islets implanted into the spleen; an occasional CGRP fiber was seen in islets implanted into the liver; and all these fibers were regularly seen in islets implanted beneath the renal capsule. The islets implanted into the liver or spleen contained a dense network of sympathetic (containing neuropeptide Y and TH) nerve fibers that was often more dense than in the islet grafts under the kidney capsule. One-fifth of islets implanted into the liver were, however, completely devoid of demonstrable nerve fibers. In conclusion, there are marked differences with regard to the pattern of reinnervation of islets transplanted to different implantation sites.

Acetylcholinesterase↗

PubMed1993

Intercellular communication and maintenance of islet cell mass--implications for islet transplantation.

BACKGROUND: The major emphasis in islet transplantation has been the development of methods to enhance islet purity. This focus assumes that islets do not require support from other cellular elements of the pancreas. We chose to examine a possible duct-islet interaction because of the embryologic origin of islets from ductal epithelium. METHODS: Duct and islet cells were prepared by collagenization of hamster pancreas and purified on a bovine serum albumin gradient. Primary duct cultures were passaged twice. Duct-conditioned medium was collected from the tertiary cultures. Three groups of cultures were established: group 1, 100 islets/plate in minimal medium (Dulbecco's modified Eagle medium/F12); group 2, 100 islets + 40 duct fragments/plate in Dulbecco's modified Eagle medium/F12; and group 3, 100 islets/plate+duct-conditioned medium. After a 3-day incubation, tritiated thymidine (1 microCi/ml) was added for 24 hours. The islets were separated from the ducts by handpicking and then sonicated. DNA was measured (microgram) fluorometrically and tritiated thymidine incorporation, a measure of cell proliferation, was determined in trichloroacetic acid-precipitated material by liquid scintillation. Data (mean +/- SEM) were compared by two-tailed Student's t test. RESULTS: Tritiated thymidine incorporation into islet cells in minimal medium (81.1 +/- 24.6 disintegrations per minute [dpm]/microgram DNA [n = 8 plates]) was less than 25% (p < 0.001) of that of islet cells cocultured with ducts (323.2 +/- 54.5 dpm/micrograms DNA [n = 6]) or with duct-conditioned medium (389.7 +/- 27.6 dpm/micrograms DNA [n = 5]). CONCLUSIONS: Pancreatic duct epithelium can stimulate islet cell proliferation in a paracrine manner.

Animals↗

PubMed1983

Immune islet killing mechanisms associated with insulin-dependent diabetes: three rabbit antibody-mediated islet cell cytotoxicity models.

Antibody-mediated islet cell killing mechanisms have been associated with human insulin-dependent diabetes. Several types of antibody-mediated cytotoxic mechanisms exist, but only complement-dependent antibody-mediated cytotoxicity is reported for islet killing. To evaluate further islet cytotoxic antibody mechanisms, we have studied antibody-dependent cellular cytotoxicity and complement augmented antibody-dependent cellular cytotoxicity using polyclonal rabbit anti-rat islet cell immune serum and 51Cr-labelled dispersed normal rat islet target cells. Maximal immune serum-mediated islet cell specific cytotoxicity was 80% for complement-dependent antibody-mediated cytotoxicity, 40% for antibody-dependent cellular cytotoxicity and 20% for complement-augmented antibody-dependent cellular cytotoxicity. The minimum serum dilution for maximal islet cell cytotoxicity was 1:100 for complement-dependent antibody-mediated cytotoxicity, 1:10 for complement-augmented antibody-dependent cellular cytotoxicity. These data indicate a unique optimal serum dilution for each of the three antibody killing mechanisms. Immune serum-mediated cytotoxicity was more specific for rat islet target cells than macrophage target cells. That antibody mediated these cytotoxic events was documented using immune serum-derived, DEAE purified immunoglobulin G which induced killing in all three antibody assays. Both antibody-dependent cellular cytotoxicity assays appear useful for studies of human diabetes, since human non-T mononuclear cells are cytotoxic to islet cells. These results suggest that for studies of potential islet cell killing mechanisms in insulin-dependent diabetes, specific xenogeneic assays exist not only for complement-dependent antibody-mediated islet cytotoxicity, but also for antibody-dependent cellular cytotoxicity and complement augmented antibody-dependent cellular cytotoxicity.

Adolescent↗

PubMed1995

The effects of islet cell surface antibodies on the metabolic function of mouse islet B cells in vitro.

Immunoglobulin (Ig) fractions from the plasma of a group of newly diagnosed insulin-dependent diabetes mellitus (type 1) patients and set of control subjects were assessed for their effects on isolated mouse islet function. It was found that Igs from type 1 patients caused a significant inhibitory effect on insulin secretion when incubated with mouse islets as compared with controls (25.6 +/- 2.9 pg islet-1 h-1 vs 44.7 +/- 7.7 pg islet-1 h-1, P < 0.05). The plasma samples from which the Igs were obtained were then tested for the presence of antibodies to the mouse islet cell surface (ICSA). Four of the nine patients were positive for ICSA, and plasma samples from eight control subjects were all negative. ICSA-positive samples appeared to have the greatest inhibitory effect on insulin secretion when compared with their respective controls (53.3 +/- 7.0 pg insulin islet -1 min-1 vs 30.9 +/- 3.7 pg insulin islet -1 min-1, (P < 0.05). In contrast, it was also found that ICSA-positive Ig fractions had no significant effect on glucose oxidation when co-incubated with mouse islets as compared with the controls (11.3 +/- 2.3 pmol islet-1 h-1 vs 11.2 +/- 2.9 pmol islet-1 h-1). These studies suggest that Igs from newly diagnosed type 1 patients containing ICSA may impair insulin secretion from isolated mouse islets by mechanisms which do not involve the inhibition of B-cell glucose metabolism.

Adolescent↗

PubMed1996

Characterization of the sphingomyelin content of isolated pancreatic islets. Evaluation of the role of sphingomyelin hydrolysis in the action of interleukin-1 to induce islet overproduction of nitric oxide.

Inflammatory cytokines may participate in the destruction of pancreatic islets during the pathogenesis of insulin-dependent diabetes mellitus, and the cytokine interleukin-1 (IL-1) strongly inhibits insulin secretion from rat pancreatic islets by a process which involves induction of expression of the inducible isoform of nitric oxide synthase and the overproduction of nitric oxide. The signaling events between IL-1 receptor occupancy and induction of nitric oxide synthase in rat islets involve activation of the transcriptional activator NFkappa B. Because sphingomyelin hydrolysis has been implicated as a signaling process both in NFkappa B activation and in IL-1 action in some cells, we have examined the potential involvement of sphingomyelin hydrolysis in the induction of islet nitric oxide overproduction by IL-1. Rat islet sphingomyelin pools were radiolabeled with [3H]choline, and sphingomyelin was then isolated by normal phase HPLC. Electrospray ionization-mass spectrometric analysis revealed islet sphingomyelin consists of at least 4 distinct molecular species, and the most abundant of them contained sphingosine as the long chain base and a residue of palmitic acid as the fatty acid substituent. Molecular species containing residues of stearic acid and arachidic acid were also observed. Neither interleukin-1 nor tumor necrosis factor-alpha was found to induce hydrolysis of islet sphingomyelin species, and neither an exogenous, cell-permeant ceramide species (N-acetyl-D-sphingosine) nor exogenous sphingomyelinase mimicked or potentiated the effect of IL-1 to increase rat islet nitric oxide generation, as reflected by nitrite production. Similar findings were obtained with RINm5F insulinoma cells and with mouse pancreatic islets. These findings provide the first information on the molecular species of sphingomyelin in pancreatic islets and suggest that sphingomyelin hydrolysis is not involved in the signaling pathway whereby IL-1 induces the overproduction of nitric oxide by pancreatic islets.

Animals↗

PubMed2004

Insulin secretory characteristics of monkey pancreatic islets: a simple method of islet isolation and the effect of various density gradients on separation.

We describe a simple stationary digestion method of islet isolation and separation by various density gradients from monkey pancreas (Macaca radiata radiata). Effective method, different types and concentrations of collagenase were standardized. Sigma type XI collagenase yielded >1000 islets/gram pancreas at the concentration of 4 mg/ml and 3 ml Hank's/gram pancreas. Slow digestion with less concentration of collagenase was suitable for monkey islet isolation. Discontinuous density gradients of bovine serum albumin (BSA) and dextran were compared with standard Ficoll for separation of islets. Islet yield (1038 +/- 81), insulin secretory response (stimulation index, S.I.11) and histological examination revealed dextran gradients were more appropriate for monkey islets when compared to BSA and Ficoll. Insulin secretory characteristics of monkey islets were studied by exposing them to low and high concentrations glucose (S.I.11.5), arginine (S.I.4.2), leucine (S.I.2.3) and tolbutamide (S.I.1.7). The results indicated that the magnitude of glucose induced insulin secretion of monkey islet is about half as that of rat and mouse islets. However, it is higher than that of porcine and bovine islets. In conclusion, the knowledge of insulin secretory ability of Indian bonnet monkey islets together with the techniques of isolation and separation are useful tool for diabetic research especially islet transplantation.

Amino Acids↗

PubMed2004

The rat pancreatic islets: a reliable tool to study islet responses to cholecystokinin receptor occupation.

This study was undertaken to show that rat purified islets can be used as a reliable tool to study some aspects of human islet's physiology related to CCKR occupation. Therefore, isolated foetal, adult human and rat islets were compared for (1) CCKR subtypes mRNA and protein expression and somatostatin (SS) mRNA and (2) co-localization of these receptors with insulin, glucagon and SS. Finally, rat islets were tested for their responsiveness to stimulation. Purified human and rat islets were used for CCKR subtypes and SS mRNA estimation by RT-PCR and protein by Western blots. Receptors and hormones co-localizations were evaluated by confocal microscopy. Hormones secretion served to determine rat islets responsiveness. Islets of both species express CCKA and CCKBR mRNA and proteins and SS mRNA. The CCKAR co-localizes with insulin and glucagon and the CCKBR with SS. Insulin release was increased 5-fold in response to 16 mM glucose and SS secretion reached 1.3- and 1.7-fold increments above basal in response to forskolin and IBMX. In conclusions, human and rat islets have comparable CCKR subtypes localized on the same cells; they also express SS mRNA. The rat islets are functional as they secrete but their response to hormonal stimulation remains to be clarified. These rat islets can thus serve as tools to study islets physiology.

1-Methyl-3-isobutylxanthine↗

PubMed2005

Inhibition of p38 mitogen-activated protein kinase protects human islets from cryoinjury and improves the yield, viability, and quality of frozen-thawed islets.

The development of an optimal islet cryopreservation method will permit transplantation of islets from multiple donors in a single procedure and contribute to alleviation of the islet shortage. In this study, we have improved human islet cryopreservation methods under serum-free conditions using an intracellular-based islet cryopreservation solution (ICS), especially supplemented with a p38 pathway inhibitor (p38IH) to suppress p38 mitogen-activated protein kinase (MAPK) activation. Three different solutions were compared for freezing and thawing of human islets (1) conventional RPMI1640 medium, (2) ICS, and (3) ICS supplemented with a p38IH, SD-282 (ICS-p38IH). Islet cryopreservation with ICS-p38IH significantly improved islet recovery, viability, and quality after thawing of cryopreserved islets. This improvement may allow the use of cryopreserved islets in clinical islet transplantation.

Cell Culture Techniques↗

PubMed1992

Lack of glyconeogenesis in pancreatic islets: expression of gluconeogenic enzyme genes in islets.

Studies were performed to obtain evidence for glyconeogenesis from pyruvate to the triose phosphates in pancreatic islets. Inability to show this evidence would be consistent with the fact that glyceraldehyde, but not pyruvate, is a potent insulin secretagogue. Synthesis of 14C-labelled glucose from 14C-labelled pyruvate could not be detected. Since this might have been due to lack of sensitivity required to measure 14C-glucose production in such a scarce tissue as islets, cDNA probes were used to estimate the relative expression of genes coding for gluconeogenic enzymes. Islets expressed pyruvate carboxylase mRNA, but even islets from rats which had been starved (a condition which induces phosphoenolpyruvate carboxykinase (PEPCK) in liver, kidney and adipose tissue) showed no PEPCK mRNA. This is consistent with our previous work showing the absence of PEPCK enzyme activity in islets. Therefore, islets can convert pyruvate to oxalacetate, but since they lack PEPCK, neither the beta nor alpha cell can convert oxalacetate to phosphoenolpyruvate and carry out glyconeogenesis. Pyruvate carboxylase mRNA was increased in islets that possessed the capacity for glucose-induced insulin release versus islets that lacked the capacity to respond to glucose, such as islets from fed rats (versus starved rats) and in islets cultured at a high concentration of glucose (versus at low glucose). Pyruvate carboxylase, therefore, must be involved in pyruvate metabolism and not glyconeogenesis in the pancreatic islet.

Animals↗

PubMed1996

Overexpression of parathyroid hormone-related protein in the pancreatic islets of transgenic mice causes islet hyperplasia, hyperinsulinemia, and hypoglycemia.

Parathyroid hormone-related protein (PTHrP) is produced by the pancreatic islet. It also has receptors on islet cells, suggesting that it may serve a paracrine or autocrine role within the islet. We have developed transgenic mice, which overexpress PTHrP in the islet through the use of the rat insulin II promoter (RIP). Glucose homeostasis in these mice is markedly abnormal; RIP-PTHrP mice are hypoglycemic in the postprandial and fasting states and display inappropriate hyperinsulinemia. At the end of a 24-hour fast, blood glucose values are 49 mg/dl in RIP-PTHrP mice, as compared to 77 mg/dl in normal littermates; insulin concentrations at this time are 6.3 and 3.9 ng/ml, respectively. Islet perifusion studies failed to demonstrate abnormalities in insulin secretion. In contrast, quantitative islet histomorphometry demonstrates that the total islet number and total islet mass are 2-fold higher in RIP-PTHrP mice than in their normal littermates. PTHrP very likely plays a normal physiologic role within the pancreatic islet. This role is most likely paracrine or autocrine. PTHrP appears to regulate insulin secretion either directly or indirectly, through developmental or growth effects on islet mass. PTHrP may have a role as an agent that enhances islet mass and/or enhances insulin secretion.

Animals↗

PubMed2001

Serine-protease inhibition during islet isolation increases islet yield from human pancreases with prolonged ischemia.

BACKGROUND: Islet isolation from the pancreatic tissue matrix remains highly variable. Recent evidence suggests that intrinsic human pancreatic proteases, including trypsin, may inhibit effective collagenase enzymatic activity during islet isolation, thereby impairing the isolation success. In this study we have hypothesized that serine protease inhibition applied during pancreatic digestion, could improve yield and/or functional viability of islets isolated from human pancreases. METHODS: Twelve organ donor pancreases with 12.9+/-0.6 hr cold storage (mean+/-SEM) were perfused via their ducts with Liberase-HI enzyme in the presence (n=6) or absence (n=6) of 0.4 mM Pefabloc. All were then gently dissociated and their purified islets separated with Ficoll density gradient centrifugation. RESULTS: Donor-related factors (age, gender, cold storage time, body mass index, and pancreas weight) did not differ significantly between the two experimental groups. Pefabloc supplementation did not affect the digestion time, islets remaining trapped in exocrine tissue, or final islet purity. Islet recovery was increased in the Pefabloc-treated group (mean+/-SEM yield 323.8+/-80.8 x 10(3) islet equivalents vs. 130.8+/-13.6 x 10(3) islet equivalents, P<0.05). Cellular composition, DNA and insulin content, and insulin secretory activity of the isolated islets was similar. CONCLUSIONS: Inhibition of intrinsic protease activity within pancreases after prolonged cold storage improves isolation of viable islets.

Adolescent↗

PubMed1999

Human islets in mixed islet grafts protect mouse pancreatic beta-cells from alloxan toxicity.

We have previously shown that human beta-cells are resistant to the toxic effects of alloxan. In order to further clarify this characteristic of human islets, we investigated whether these cells might transfer their alloxan resistance to alloxan-sensitive rat or mouse islets. Islets from two species (human-mouse or rat-mouse) were mixed into one graft, which was implanted into the subcapsular kidney space of nude mice. Alloxan or saline was injected intravenously two weeks after implantation and one week thereafter the mice were killed. The number of grafted and endogenous beta-cells were evaluated by a semi-quantitative method after immunohistochemistry. Human islet production of the scavenging enzymes extracellular superoxide dismutase and plasma glutathione peroxidase were analyzed with ELISA-techniques, and mouse and human islet hydrogen peroxide breakdown activity were monitored with a horseradish peroxidase-dependent assay. Mouse beta-cells transplanted together with human islets were protected against alloxan cytotoxicity. Rat islets did not protect mouse beta-cells against alloxan, suggesting that the mixing procedure as such did not impose the protection. Production of extracellular superoxide dismutase and plasma glutathione peroxidase by human islets was very low. Moreover, H2O2 breakdown in vitro, did not differ between human and mouse islets. Alloxan-insensitive human islets protect mouse beta-cells against alloxan-induced lesions, suggesting that yet to be identified extracellular factors are involved in human islet resistance to alloxan toxicity.

Alloxan↗

PubMed1990

Mechanism of action of growth-hormone-releasing hormone in stimulating insulin secretion in vitro from isolated rat islets and dispersed islet cells.

Human growth-hormone-releasing hormone [(1-44)NH2] (hGHRH) was a potent stimulus for insulin release from rat islets of Langerhans in vitro; the optimum concentration used was 10(-11) M. The dose response curves for hGHRH effects on insulin secretion were notably different in intact islets of Langerhans compared to cultured dispersed islet cells. Pancreatic islets responded to a very low hGHRH concentration (10(-12) M), but at a higher hGHRH concentration (10(-9) M) no stimulation of insulin release was observed. When somatostatin antiserum was included in the incubation medium, hGHRH (10(-9) M) stimulated insulin release from intact islets. In cultured dispersed islet cells, which are principally insulin-secreting B cells, hGHRH directly and potently stimulated insulin release even at a concentration of 10(-9) M. Addition of somatostatin (10(-7), 10(-8) M) significantly reduced the hGHRH-induced insulin-secretory responses of dispersed islet cells. hGHRH (10(-11)-10(-9) M) raised islet cAMP levels; individually, hGHRH and theophylline exerted positive effects on insulin release, their combined effect was greater than that caused by either one. We conclude that hGHRH directly affects insulin secretion in vitro by a cAMP-dependent mechanism, and that the difference in responses of intact islets versus islet cells to increasing concentrations of hGHRH may be related to hGHRH-induced release of somatostatin in intact rat islets.

Animals↗

PubMedDate not supplied

Islet cell mass and the longevity of islet grafts in diabetic rats.

In an attempt to demonstrate that a limited beta-cell mass is able to maintain normoglycemia in streptozocin-diabetic rats, two groups of inbred rats received transplants of 500 or 1000 neonatal islets (corresponding to 10 and 20% of total islet cell mass, respectively) into the spleen. A close correlation was found between the functional longevity of the islet graft, and the total beta-cell mass transplanted into the diabetic animals. Although euglycemia was maintained for 4-12 mo, the islet transplants were insufficient to produce glucose tolerance tests equal to those observed in normal rats. Relapse of diabetes correlated with histological findings of distorted islet architecture containing vacuolated beta-cells in the grafts. This condition was not reversed after a month of normoglycemia. Spontaneous recovery of beta-cell function in native islets was documented in 50% of the diabetic rats with prolonged normoglycemia following islet transplantation. This report shows that transplantation of as few as 500 neonatal islets, the equivalent of 10% of total islet cell mass, is sufficient to maintain normoglycemia in diabetic rats, albeit temporarily. A close correlation was found between the transplanted islet cell mass and the functional longevity of the islet graft.

Animals↗