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Lise Wogensen, Jesper Reimers, Thomas Mandrup-Poulsen and Jørn Nerup

Abstract.

Previous in vitro findings suggest the involvement of interleukin 1 (IL-1) in the pathogenesis of insulin-dependent diabetes mellitus. The aims of the present study were to investigate the effects of single or repeated ip injections of recombinant IL-1β on blood glucose and glucose tolerance in vivo. Normal Wistar Kyoto rats were injected ip with a single injection of 4 μg/kg of the mature form of recombinant IL-1β (amino acids 117-269) or once daily on 5 consecutive days. Control rats were given vehicle and were fed ad libitum or pair-fed together with the rIL-1β treated rats. An ip glucose tolerance test (0.2 g D-glucose/100 g) was performed 2 h after injection of rIL-1β. A single injection of rIL-1β caused a mild depression in blood glucose and an improved glucose tolerance. Multiple injections of rIL-1 β induced a diminished weight gain, a 24-28% reduction in food intake, a lasting mild depression of blood glucose (7 days) and a transiently impaired glucose tolerance on day 5. We conclude that systemic IL-1 should be considered an important regulator of glucose homeostasis in vivo.

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Henrik Ullits Andersen, Thomas Mandrup-Poulsen, Jørn Egeberg, Steffen Helqvist and Jørn Nerup

Abstract. This study was designed to investigate whether the genetic predisposition to insulin-dependent diabetes mellitus (IDDM) might be caused by an inherited increased sensitivity of the pancreatic B-cells to immune effector molecules e.g. the monokine interleukin 1 (IL-1), which is selectively cytotoxic to B-cells in vitro. Islets of Langerhans isolated from newborn diabetes prone and diabetes resistant Bio-Breeding rats, as well as from the inbred non-diabetic rat strains Wistar Furth, Brown-Norway and Lewis-Scripps were exposed to 0–1000 fg/1 of recombinant human IL-1 β for 7 days. Strain-related differences in the sensitivity to IL-1 were studied by comparing the dose-responses of insulin release at 11 mmol/l glucose and islet light microscopic morphology to varying concentrations of IL-1. Statistical analyses showed a significant impact of strain on B-cell sensitivity to IL-1, Brown-Norway islets being relatively resistant to the action of IL-1. However, the the diabetes prone islets were not more sensitive to the cytotoxic effect of IL-1 than the non-diabetic control strain islets. We conclude that genetic differences in the response to IL-1 exist in vitro, but that this phenomenon is unrelated to the propensity to develop IDDM.

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Giatgen A. Spinas, Jerry P. Palmer, Thomas Mandrup-Poulsen, Henrik Andersen, Jens Høiriis Nielsen and Jørn Nerup

Abstract. To investigate the hypothesis that interleukin 1 initially stimulates and then suppresses beta-cell function and that this sequential effect is directly related to interleukin 1 dose, duration of exposure, and ambient glucose concentration, insulin release was measured from cultured newborn rat islets exposed for 6 h to 6 days to interleukin 1 at doses ranging from 20 to 2000 ng/l at glucose concentrations of 3.3, 5.5 and 11 mmol/l. After 6 h of exposure and at all three glucose levels, all doses of interleukin 1 stimulated insulin release, maximal stimulation (370% of control) being observed at 5.5 mmol/l glucose and 100 ng/l interleukin 1. In contrast, after 6 days, all doses of interleukin 1 were inhibitory irrespective of glucose level, maximal inhibition (90%) being observed at 11 mmol/l glucose and 2000 ng/l interleukin 1. At 24 and 48 h of exposure, the biphasic effect of interleukin 1 was observed: lower doses of interleukin 1 at lower glucose concentrations at 24 h being more stimulatory with transition to inhibition directly related to higher glucose levels, higher interleukin 1 doses, and longer exposure. After 48 h, 200 ng/l of interleukin 1 increased insulin release to 220% at 3.3 mmol/l glucose, but at 11 mmol/l glucose a 60% suppression was seen. On the basis of these data we suggest that interleukin l's effect on beta-cells is bimodal: stimulation followed by inhibition. Increasing interleukin 1 dose and ambient glucose concentration shift this response to the left. Experimental results will, and in vivo effects may, depend upon these three variables.

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Henrik Ullits Andersen, Thomas Mandrup-Poulsen, Jørn Egeberg, Steffen Helqvist and Jørn Nerup

Acta Endocrinologica (Copenh) 1989, 120: 92–98

Interleukin-1 concentration should read ng/l instead of fg/1.

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Jørn Nerup, Thomas Mandrup-Poulsen, David Owerbach, Klaus Johansen, Jette Ingerslev and Anne Tybjærg Hansen

Introduction.

Applying the recombinant DNA-technology as related to the insulin-gene in search for the genetic basis and possibly the etiology of type 2 diabetes, we found an intriguing association between a peculiar polymorphic DNA-region flanking the human insulin-gene and atherosclerotic macrovascular disease in type 1 and type 2 diabetics as well as in non-diabetics.

The human insulin-gene is located to the short arm of chromosome 11 in band p15 (1).

The structure of the insulin-gene flanking DNA-sequences has been determined recently (figure 1). About 15.000 basepairs up-stream (5') to the insulin-gene are regions consisting of repetitive sequences, making the 5'-region highly polymorphic, i.e. variable in length (2). The polymorphic 5'-region starts only 363 bp upstream to the insulin-gene.

DNA-fragments containing the 5'-region can be obtained by cutting the short arm of chromosome 11 into small pieces by means of restriction enzymes, i.e. DNA-nucleases, which cut the DNA-helix at sites where

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Henrik U Andersen, Dídac Mauricio, Allan E Karlsen, Thomas Mandrup-Poulsen, Jens H Nielsen and Jørn Nerup

Andersen HU, Mauricio D, Karlsen AE, Mandrup-Poulsen T, Nielsen JH, Nerup J. Interleukin-nitric oxide production from isolated rat islets is modulated by d-glucose and 3-isobutyl-1-methyl xanthine. Eur J Endocrinol 1996:134:251–9. ISSN 0804–4643

Interleukin-1β has been proposed to cause selective β-cell destruction via the induction of nitric oxide synthesis. The cytotoxic effect of interleukin-1β is modulated by the concentration of d-glucose in the medium. The aim of this study was to investigate if d-glucose-mediated modulation of interleukin-1β effects on insulin release from isolated rat islets was related to modulation of nitric oxide production. Further, we wished to investigate the effects of agents increasing the intracellular concentration of cAMP on interleukin-1β-induced nitrite production. We demonstrated that d-glucose potentiated interleukin-1β-induced nitrite production in rat islets without affecting the mRNA level of the inducible nitric oxide synthase. This effect was dissociated from interleukin-1β action on insulin release, since a relative protection against interleukin-1β effects on acute insulin release was found at high (28 mmol/l) concentrations of d-glucose, and blocking nitrite production by the L-arginine analog aminoguanidine, which selectively inhibits the cytokine-inducible nitric oxide synthase, did not result in protection against the inhibitory action of interleukin-1β Neither l-glucose nor the secretagogues l-leucine, tolbutamide and β-isobutyl-1-methyl xanthine shared the potentiating effect of d-glucose, The phosphodiesterase inhibitor β-isobutyl-1-methyl xanthine reduced interleukin-1β-induced nitrite production at 3.3 mmol/l d-glucose, an effect that could be reproduced by the cAMP analog dibutyryl cAMP. Addition of 3-isobutyl-1-methyl xanthine resulted in a threefold reduction in the mRNA level of interleukin-1β-induced inducible nitric oxide synthase. We conclude that interleukin-1β-induced islet nitric oxide synthesis is augmented by d-glucose but not by non-substrate secretagogues, and that secretagogues that elevate cAMP inhibit islet nitric oxide production.

Jørn Nerup, Steno Diabetes Center, Niels Steensens vej 2, DK-2820 Gentofte, Denmark

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Giatgen A. Spinas, Thomas Mandrup-Poulsen, Jens Mølvig, Leif Bæk, Klaus Bendtzen, Charles A. Dinarello and Jørn Nerup

Abstract. Isolated rat islets were incubated either with crude, affinity-purified or recombinant human interleukin-1 for 1 to 6 days. A significant (20–60%) increase of insulin release was observed at low concentrations of all three interleukin-1-containing preparations. In contrast, higher concentrations dose-dependently inhibited the insulin release. The increased insulin secretion occurred at concentrations below those necessary to augment the mitogen response to phytohaemagglutinin of murine thymocytes in vitro. These doses (0.05-0.5 U/ml) correspond to 0.2-2 ng of recombinant interleukin-1 per ml, equal to approximately 0.01-0.1 pmol/ml. In doses of 0.6-1.8 U/ml affinitypurified interleukin-1 significantly increased the islet insulin content per ng of DNA, indicating a stimulation of insulin-biosynthesis. The data support the concept that low concentrations of interleukin-1 may play a role in priming the physiological secretion of insulin.

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Lise D. Wogensen, Thomas Mandrup-Poulsen, Helle Markholst, Jens Mølvig, Åke Lernmark, Jens J. Holst, Charles A. Dinarello and Jørn Nerup

Abstract. The acute effects of recombinant human interleukin-1 beta (rIL-1) on basal and glucose-stimulated insulin release were investigated in the isolated perfused pancreas. At a concentration of 20 μg/l rIL-1 had no effect on basal insulin release, but increased the total amount of insulin released during first and second phase insulin release in response to 20 mmol/l D-glucose in the rat pancreas (P < 0.05). In addition, 26 μg/l of rIL-1 potentiated insulin release in response to square wave infusions of stimulatory concentrations of glucose (11 mmol/l) in the porcine pancreas. We hypothesize that IL-1 in the systemic circulation may affect B cell function in vivo.

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Thomas Mandrup-Poulsen, Jørn Nerup, Jesper I Reimers, Flemming Pociot, Henrik U Andersen, Allan Karlsen, Ulla Bjerre and Regine Bergholdt

The cytokines interleukin 1 (IL-1), interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) are the main common denominators that elicit the acute phase response, a generalized host reaction caused by a variety of pathological processes, i.e. infection, inflammation, tissue injury, neoplastic diseases and physical and psychological stress. It is characterized by activation of the immune system and associated changes in neurological, metabolic and endocrine functions (1), irrespective of the diverse underlying pathological conditions. As the classical hormones, cytokines have both autocrine, paracrine and endocrine effects. However, in contrast to hormones, cytokines do not appear to have any homeostatic importance, but are almost exclusively induced and liberated in tissues and to the circulation in association with cellular injury. Further, cytokines exert their action at lower molar concentrations than most hormones (10−12 to 10−15 mol/l), and their actions are potentiated by several other cytokines. Moreover, instead of the negative

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Thomas Mandrup-Poulsen, Jørn Nerup, Jesper I Reimers, Flemming Pociot, Henrik U Andersen, Allan Karlsen, Ulla Bjerre and Regine Bergholdt

The acute phase response to infection, inflammation, cancer, physico-chemical tissue damage and stress is associated with widespread adaptive alterations in the endocrine system. In a previous paper (1), we have reviewed the regulatory effects of cytokines on the hypothalamicpituitary–adrenal, –testicular and –ovarian axes, on pituitary growth hormone, prolactin, vasopressin and oxytocin secretion, on the renin–angiotensin–aldosterone system and on the placental hormonal system.

Major alterations of substrate mobilization, uptake and metabolism as well as tissue oxidation are results of the endocrine effects of circulating cytokines elicited by the acute phase response. Further, the long-term paracrine effects of synergistically acting proinflammatory cytokines secreted in high local concentrations in a tissue infiltrated by inflammatory cells may alter or inhibit the normal function of mesenchymal and endothelial cells and in some cases even cause cell destruction. There is increasing evidence that these effects of cytokines may contribute to the pathogenesis of immune-mediated target cell