Differential sensitivity to beta-cell secretagogues in cultured rat pancreatic islets exposed to human interleukin-1 beta

The early stages of insulin-dependent diabetes mellitus are characterized by a selective inability to secrete insulin in response to glucose, coupled to a better response to nonnutrient secretagogues. The deficient glucose response may be a result of the autoimmune process directed toward the beta-cells. Interleukin-1 (IL-1) has been suggested to be one possible mediator of immunological damage of the beta-cells. In the present study we characterized the sensitivity of beta-cells to different secretagogues after human recombinant IL-1 beta (rIL-1 beta) exposure. Furthermore, experiments were performed to clarify the biochemical mechanisms behind the defective insulin response observed in these islets. Rat pancreatic islets were isolated and kept in tissue culture (medium RPMI-1640 plus 10% calf serum) for 5 days. The islets were subsequently exposed to 60 pM human recombinant IL-1 beta during 48 h in the same culture conditions as above and examined immediately after IL-1 exposure. The rIL-1 beta-treated islets showed a marked reduction of glucose-stimulated insulin release. Stimulation with arginine plus different glucose concentrations, and leucine plus glutamine partially counteracted the rIL-1 beta-induced reduction of insulin release. The activities of the glycolytic enzymes hexokinase, glucokinase, and glyceraldehyde 3-phosphate dehydrogenase, were similar in control and IL-1-exposed islets. Treatment with IL-1 also did not impair the activities of NADH+- and NADPH+-dependent glutamate dehydrogenase, glutamate-aspartate transaminase, glutamate-alanine transaminase, citrate synthase, and NAD+-linked isocitrate dehydrogenase. The oxidation of D-[6-14C]glucose and L-[U-14C]leucine were decreased by 50% in IL-1-treated islets. Furthermore, there was a significant decrease in the ratios of [2-14C]pyruvate oxidation/[1-14C]pyruvate decarboxylation and L-[U-14C]leucine oxidation/L-[1-14C]leucine decarboxylation, indicating that IL-1 decreases the proportion of generated acetyl-coenzyme-A residues undergoing oxidation. However, in the presence of IL-1 there was a significant increase in L-[U-14C]glutamate oxidation. These combined observations suggest that exposure to IL-1 induces a preferential decrease in glucose-mediated insulin release and mitochondrial glucose metabolism. This mitochondrial dysfunction seems to reflect an impairment in proximal steps of the Krebs cycle. It is conceivable that the IL-1-induced suppression and shift in islet metabolism can be an explanation for the beta-cell insensitivity to glucose observed in the early phases of human and experimental insulin-dependent diabetes mellitus.     

Studies on the mechanisms causing inhibition of insulin secretion in rat pancreatic islets exposed to human interleukin-1 beta indicate a perturbation in the mitochondrial function

This study aimed at a more detailed characterization of the mechanisms by which interleukin 1 (IL-1) inhibits insulin secretion. For this purpose, isolated rat pancreatic islets were kept in tissue culture for 5 days in medium RPMI 1640 plus 10% calf serum. The islets were subsequently transferred to the same culture medium containing various test substances plus 1% human serum with or without 25 U/ml human recombinant IL-1 beta. After a culture period of 48 h the islet structure was examined in the electron microscope and the islet function studied in short term incubations in the absence of IL-1. Islets exposed to IL-1 showed ultrastructural signs of degeneration in 10-20% of the B cells while such changes were not found in other types of islet cells. An increased number of secondary lysosomes and occasional myelin figures were observed in the B cells exposed to IL-1. These ultrastructural alterations were, however, reversed in islets cultured in cytokine-free medium for 6 days after the IL-1 treatment. In islets cultured in the presence of 11.1 mM glucose only, or 11.1 mM glucose plus 10 mM nicotinamide, 61 mM dimethyl area, 2 micrograms/ml indomethacin, 10 microM 4-bromophenacyl bromide or 10 microM nordihydroguaiaretic acid, 10 microM phenantroline, and 0.1 or 1.0 microgram/ml cyclosporin A, IL-1 reduced the insulin release by 64-85%. Culture at 5.6 mM glucose did not modify the IL-1-induced inhibition of insulin release, whereas a significant protective effect was observed at 28 or 56 mM glucose. The DNA content in IL-1-exposed islets cultured at 11.1 mM glucose was decreased by about 20% but not in islets cultured at other glucose concentrations. The D-[5-3H]glucose utilization at 16.7 mM glucose was unaffected by IL-1, whereas the oxidation of D-[6-14C]glucose was reduced by 50%. The present results suggest that IL-1-induced inhibition of insulin secretion is related to a disturbed mitochondrial function. This effect is not counteracted by a poly(ADP-ribose) synthetase inhibitor, a hydroxyl radical scavenger, an iron chelator, a T lymphocyte-specific immunosuppressive drug, or inhibitors of phospholipase A2 or inhibitors of prostaglandin and leukotriene synthesis. Thus, IL-1-induced inhibition of insulin secretion seems not to be mediated by the same mechanisms as those causing alloxan- or streptozotocin-induced damage of B cells. Furthermore, the action of IL-1 does not appear to be mediated via arachidonic acid metabolism. Glucose affords some protection, probably by enhancing the B cell mitochondrial function.(ABSTRACT TRUNCATED AT 400 WORDS)     

Stimulation of proinsulin biosynthesis by K+ in rat pancreatic islets

Glucose-stimulated proinsulin biosynthesis is regulated mainly at the translational level. This study aims at investigating the possible role of the B-cell K⁺ content in such a process. In order to increase the islet cells K⁺ content, rat pancreatic islets exposed to a low D-glucose concentration (e.g., 2.5 mM) were incubated in the presence of 30 or 60 mM K⁺, as distinct from a control extracellular K⁺ concentration of 5 mM. Under these conditions, the K⁺ content of the islets, as judged from the net uptake of ⁸⁶Rb⁺ over 60 min incubation, was increased to a level comparable to that otherwise found in the presence of 16.7 mM D-glucose. In the presence of 2.5–4.0 mM D-glucose, the rise in K⁺ concentration from 5 to 30 and 60 mM caused a progressive increase in the incorporation of l-[4-³H]phenylalanine into both all islet peptides and (pro)insulin. A preferential stimulation of proinsulin biosynthesis was only observed in islets incubated at 60 mM K⁺ in the presence of 4.0 mM D-glucose. In relative terms, the K⁺-induced increase in biosynthetic variables was less pronounced, however, than that otherwise evoked by a rise in D-glucose concentration from 2.5 to 4.0 mM to 5.6 or 16.7 mM. These findings may suggest that the effect of D-glucose to increase the K⁺ content of islet cells represents one modality for coupling a rise in D-glucose concentration to stimulation of proinsulin biosynthesis.     

Adenine nucleotide pattern in rat pancreatic islets exposed to nutrient secretagogues

The effects of d-glucose, d-mannose, d-galactose, d-glyceraldehyde, pyruvate, l-lactate, 2-ketoisocaproate, l-leucine, and/or l-glutamine on the ATP and ADP content of rat isolated pancreatic islets were reevaluated in order to compare changes evoked by these nutrient secretagogues in the islet ATP content and ATP/ADP ratio to their effects upon insulin release. Although being compatible with the fuel concept for nutrient-stimulated insulin secretion, the results of this study also argue against the monolithic view that the adenine nucleotide pattern in islet cells represents the sole coupling factor between metabolic and more distal events in the process of nutrient-stimulated insulin release.     

一氧化氮介导的白细胞介素（IL）—β和IL—6对大鼠胰岛细胞的作用

目的 观察一氧化氮（ＮＯ）在白细胞介素（ＩＬ）－１β、ＩＬ－６对胰岛细胞影响中的作用。方法 应用体外单层培养的大鼠胰岛细胞检测ＩＬ-１β、ＩＬ－６对胰岛细胞内Ｄ ＮＡ、胰岛素含量和细胞活性的影响,并进一步观察一氧化氮合酶抑制剂Ｎ^G－单甲基－Ｌ－精氨酸（Ｌ－ＮＭＭＡ）的作用。结果 以ＩＬ－１β诱导,胰岛细胞亚硝酸盐生成量显著增加（Ｐ〈０．００１）;同时胰岛细胞内ＤＮＡ、胰岛素含及细胞活性（ＭＴＴ值）均     

Nicotinamide partially reverses the interleukin-1 beta inhibition of glucose-induced insulin release in pancreatic islets.

Interleukin-1 beta (IL-1 beta) is known to inhibit glucose-induced insulin release by pancreatic islets. We studied the effect of nicotinamide, an inhibitor of poly[adenosine diphosphate (ADP)-ribose] synthetase and a free-radical scavenger, on this IL-1 beta-induced inhibition using rat pancreatic islets. In static experiments, groups of five islets were incubated for 24 hours in culture medium CMRL-1066, with or without 50 U/mL IL-1 beta, in the presence or absence of nicotinamide (dose range, 0 to 50 mmol/L), and then exposed for 1 hour to either 1.4 or 19.4 mmol/L glucose, 10 mmol/L arginine, or 10 mumols/L glyburide. Basal insulin secretion was 183 +/- 32 pg/islet/h (mean +/- SE, n = 7) and 176 +/- 39 (n = 7) in control islets and in islets exposed to 50 U/mL IL-1 beta, respectively. Glucose-stimulated insulin secretion was significantly reduced (185 +/- 41) in IL-1 beta-exposed islets in comparison to control islets (2,037 +/- 363). In parallel, arginine-stimulated insulin release was inhibited by IL-1 beta exposure (166 +/- 31 pg/islet/h, mean +/- SE, n = 3) in comparison to control islets (1,679 +/- 307). In contrast, IL-1 beta exposure did not significantly reduce glyburide-induced insulin secretion (1,516 +/- 231 and 1,236 +/- 214 in control and IL-1 beta-exposed islets, respectively; mean +/- SE, n = 3). When islets were simultaneously exposed to IL-1 beta and increasing concentrations of nicotinamide, a dose-dependent recovery of glucose-induced insulin secretion was observed, with the maximum effect at 25 mmol/L nicotinamide (1,007 +/- 123, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Haeme-oxygenase 1 expression in rat pancreatic beta cells is stimulated by supraphysiological glucose concentrations and by cyclic AMP

Aim/hypothesis Increased expression of haeme-oxygenase 1 (HO1) and other antioxidant enzymes could improve pancreatic beta-cell survival under stressful conditions, including hyperglycaemia. However, how hyperglycaemia increases islet HO1 expression is not known.Methods Rat islets were pre-cultured for 1 week in RPMI medium containing 10 mmol·l^–1 glucose (G10), and further cultured overnight in G5-G30 plus various test substances. Islet HO1 mRNA and protein expression was measured by semiquantitative RT-PCR, western blot, and immunohistochemistry.Results Islet HO1 mRNA expression was minimal after overnight culture in G10, slightly increased in G5, and increased by five- to ten-fold in G30 in parallel with a heterogeneous increase in beta-cell HO1 protein expression. The effect of G30 was fully inhibited by agents decreasing cytosolic Ca²⁺ (diazoxide, nimodipine), but was only slightly reproduced by agents raising Ca²⁺ (tolbutamide, 30 mmol·l^–1 potassium). It was also suppressed by the ₂-adrenoceptor agonist clonidine, whereas dibutyryl-cyclic-AMP largely increased beta-cell HO1 expression. The induction of HO1 mRNA expression by G30 was independent from changes in medium insulin concentration, but was completely inhibited by a cocktail of antioxidants. In contrast to HO1, islet mRNA expression of glutathione peroxidase and constitutive haeme-oxygenase 2 were not affected by G30, nor by dibutyryl-cyclic-AMP.Conclusion/interpretation High glucose and dibutyryl-cyclic-AMP stimulate expression of HO1 in rat pancreatic beta cells. The inhibition of HO1 expression in G30 by nimodipine, clonidine, and antioxidants, suggests that Ca²⁺ influx and cyclic-AMP are necessary for the generation of oxidative stress by G30, or for the stimulation of beta-cell HO1 expression by increased oxidative stress.Abbreviations HO Heme oxygenase - GPx glutathione peroxidase - TBP TATA-box binding protein - Gn n mmol·l^–1 glucose - [Ca²⁺]_i intracellular Ca²⁺ concentration - cDNA complementary DNA - mRNA messenger ribonucleic acid - NF-B nuclear factor of BAn erratum to this article can be found at     

Culture of mouse pancreatic islets in different glucose concentrations modifies B cell sensitivity to streptozotocin

Summary There have previously been divergent data published regarding the effects of glucose on the diabetogenic effects of streptozotocin. In order to further explore this issue, two separate sets of experiments were performed. In the first, mouse pancreatic islets were maintained in culture for 3 days at different glucose concentrations (5.6,11.1 and 28 mmol/l) and then exposed to streptozotocin. After another 3 days in culture at 11.1 mmol/l glucose, the B cell function was evaluated by measurement of glucose-stimulated insulin release, the number of islets recovered after culture, and the islet DNA and insulin contents. In the second group of experiments islets were first maintained in culture at 11.1 mmol/l glucose, then treated with streptozotocin and subsequently cultured for 6 days at the different glucose concentrations given above. It was found that islets maintained in a medium containing 28 mmol/l glucose before or after streptozotocin exposure showed less signs of damage than islets cultured in 11.1 mmol/l glucose. A similar, but less pronounced, de creased sensitivity to streptozotocin was found in islets precultured in 5.6 mmol/l glucose, in comparison with those islets cultured in 11.1 mmol/l glucose. Culture at 5.6 mmol/l glucose just after streptozotocin treatment did not induce any improvement in islet survival or function. It is suggested that the increased damage induced by streptozotocin to islets precultured at 11.1 mmol/l glucose, in comparison with 5.6 mmol/l glucose, can be related to the fact that an increased metabolic activity of B cells render them more susceptible to the toxin. The improved preservation of islets cultured at 28 mmol/l glucose before or after streptozotocin treatment may reflect an additional effect of glucose, i. e. activation of defense mechanisms in the B cells against cytotoxins.     

Low concentrations of interleukin-1 stimulate and high concentrations inhibit insulin release from isolated rat islets of Langerhans

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 affinity-purified 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.     

Glucose regulates proinsulin and prosomatostatin but not proglucagon messenger ribonucleic acid levels in rat pancreatic islets

Insulin and glucagon are the major hormones involved in the control of fuel metabolism and particularly of glucose homeostasis; in turn, nutrients tightly regulate insulin and glucagon secretion from the islets of Langerhans. Nutrients have clearly been shown to affect insulin secretion, as well as insulin biosynthesis and proinsulin gene expression; by contrast, the effects of nutrients on proglucagon gene expression have not been studied. We have investigated the effect of glucose, arginine, and palmitate on glucagon release, glucagon cell content, and proglucagon messenger RNA (mRNA) levels from isolated rat islets in 24-h incubations. We report here that concentrations of glucose that clearly regulate insulin and somatostatin release as well as proinsulin and prosomatostatin mRNA levels, do not significantly affect glucagon release, glucagon cell content or proglucagon mRNA levels. In addition, though both 10 mM arginine and 1 mM palmitate strongly stimulated glucagon release, they did not affect proglucagon mRNA levels. We conclude that, in contrast to insulin and somatostatin, glucose does not affect glucagon release and proglucagon mRNA levels, and arginine and palmitate do not coordinately regulate glucagon release and proglucagon mRNA levels.     

Stimulation by glucose of the blood flow to the pancreatic islets of the rat

Diabetologia - Blood flow to the pancreatic islets of the rat was estimated with the microsphere technique. Experiments with microspheres of different sizes (diameter 10, 15 or 50 μm) showed...     

Effects of biotin on glucotoxicity or lipotoxicity in rat pancreatic islets

Biotin (vitamin H) plays an important role as a cofactor in glucose or lipid metabolism. We showed that biotin potentiated glucose-induced insulin release in isolated rat islets, while biotin alone did not affect insulin release. Coculture with biotin in islets for 48 hours significantly enhanced glucose-induced insulin release or islet insulin content. Similarly, preproinsulin or pancreatic/duodenal homeobox-1 (PDX-1) mRNA was also enhanced in islets cultured with biotin for 48 hours. Furthermore, we measured effects of biotin on beta-cell function under glucotoxic or lipotoxic states. In islets cultured with high glucose or palmitate for 48 hours, glucose-induced insulin release or islet insulin content deteriorated. Coculture with biotin significantly restored glucose-induced insulin release or islet insulin content together with the restoration of preproinsulin or PDX-1 mRNA. We conclude that biotin exerts its beneficial effects on beta-cell dysfunction induced by glucose or free fatty acids probably through the enhancement of insulin biosynthesis.     

Syntaxin, but not soluble NSF attachment protein (SNAP), biosynthesis by rat pancreatic islets is regulated by glucose in parallel with proinsulin biosynthesis

Summary Recent studies have revealed that soluble N-ethylmaleimide sensitive factor attachment receptor (SNARE)-related proteins, originally identified in neural tissues, are also expressed in pancreatic beta cells. In this study, we investigated the effect of glucose on syntaxin 1 and α/β SNAP biosynthesis in pancreatic beta cells and we demonstrated that syntaxin 1, but not α/β SNAP biosynthesis by rat isolated pancreatic islets was stimulated specifically by glucose nearly in parallel with proinsulin biosynthesis. Stimulation of syntaxin 1 and proinsulin biosynthesis by glucose was dose-dependent (K_m = ∼8 mmol/l) and reached the maximum (about 8–12 fold) at concentrations over 11 mmol/l. In contrast, 22 mmol/l glucose increased α/β SNAP biosynthesis about 2-fold only, similar to the increase in total protein synthesis. Stimulation of syntaxin 1 biosynthesis by glucose was also time-dependent, taking around 3 h to reach the maximum, and was not affected by actinomycin-D, suggesting regulation at the translational level. On the other hand, glucose had a similar stimulating effect on both syntaxin 1 and α/β SNAP biosynthesis by mouse insulinoma βTC3 cells as it did on proinsulin biosynthesis. The evidence showing coordinated stimulation of syntaxin 1 and proinsulin biosynthesis by glucose in rat islets suggested the critical functional role of syntaxin 1 in the insulin exocytotic mechanism. [Diabetologia (1997) 40: 1396–1402] Received: 16. April 1997 and in revised form: 19 August 1997     

Not all insulin secretagogues sensitize pancreatic islets to recombinant human interleukin 1 beta.

The purpose of this study was to test the influence of different insulin secretagogues on interleukin 1 beta mediated injury to isolated rat pancreatic islets. Islets were exposed to interleukin 1 beta for 6 days. During exposure, beta-cells were stimulated with glucose (11 mmol/l vs 3.3 mmol/l) or with non-nutrients as tolbutamide (250 mumols/l), iso-butyl 1-methyl-xanthine (50 mumols/l), or glucagon (10 mg/l). At 3.3 mmol/l of glucose, 60,000 U/l of interleukin 1 beta caused an inhibition of medium insulin accumulation to 62 +/- 5% of control from 48 h to 6 days of exposure, whereas islet DNA content was unaffected. At 11 mmol/l of glucose, interleukin 1 beta dose-dependently decreased medium insulin accumulation (e.g. 60,000 U/l of interleukin 1 beta, 12 +/- 3% of control) and islet content of DNA (60,000 U/l of interleukin 1 beta, 60 +/- 8% of control). During beta-cell stimulation with tolbutamide, interleukin 1 beta caused inhibition of insulin accumulation to 36 +/- 9% of control. In contrast, on islets stimulated with iso-butyl 1-methyl-xanthine or glucagon, the effects of interleukin 1 beta were equivalent to those on non-stimulated islets. These differences were paralleled by differences in the interleukin 1 beta effect on islet morphology. In conclusion, high beta-cell activity (as measured by islet insulin release) may increase islet susceptibility to interleukin 1 beta, however, depending upon the intracellular pathway through which insulin secretion is activated.     

Interleukin-6 affects insulin secretion and glucose metabolism of rat pancreatic islets in vitro

Recently it has been postulated that interleukin-1 (IL-1) locally released by infiltrating mononuclear cells may destroy the pancreatic B cells during the development of insulin-dependent diabetes mellitus. Since IL-1 is a potent inducer of interleukin-6 (IL-6) in various cells, it is conceivable that IL-6 is a second mediator of the IL-1 action. In the present study the effects of IL-6 alone or in combination with IL-1 were studied on pancreatic islet function in vitro after tissue culture and compared with the effects observed after exposure to IL-1 only. Rat pancreatic islets were cultured in medium RPMI 1640 + 10% calf serum with or without the addition of human recombinant IL-6 (500-5000 pg/ml) for 48 h. The medium insulin accumulation was increased by 40-50% after culture with 500-2000 pg/ml IL-6, but was similar to the controls at 5000 pg/ml. When islets were cultured for 18 h only, also 5000 pg/ml IL-6 stimulated the medium insulin accumulation. IL-6 did not affect the islet insulin content and the rates of islet (pro)insulin and total protein biosynthesis. It inconsistently decreased the islet DNA content. In short-term experiments after 48-h culture with IL-6, there was a dose-dependent inhibition of the glucose-stimulated insulin release. On the other hand, islets cultured with IL-6 (5000 pg/ml) exhibited an elevated glucose oxidation and oxygen uptake, but a lower ATP content at 16.7 mM glucose and an unaffected glucose utilization and glutamine oxidation compared to the controls. This raises the possibility that IL-6 had induced a condition with an increased energy expenditure, resulting in an enhanced mitochondrial metabolism of glucose. Islets cultured with human recombinant IL-1 beta (25 units/ml) showed a strong inhibition of the insulin accumulation in the culture medium and of glucose-stimulated insulin release and a marked decrease in the islet DNA and insulin content. A combination of IL-1 (25 U/ml) + IL-6 (1000 pg/ml) did not alter the inhibitory action of IL-1 alone. The present findings thus show that IL-6 induces a dissociation between insulin secretion and glucose oxidation in islets in vitro. This has not been observed in islets exposed to IL-1, which suggests that IL-6 does not solely mediate the inhibitory effects of IL-1 on islet function.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential interleukin-1 receptor antagonism on pancreatic beta and alpha cells. Studies in rodent and human islets and in normal rats

Summary The monokines interleukin-1 and - have been implicated as effector molecules in the immune-mediated pancreatic beta-cell destruction leading to insulin-dependent diabetes mellitus. Here we investigated the effects of interleukin-1 receptor antagonism on insulin and glucagon release of rat, mouse and human islets exposed to recombinant human interleukin-1, and on interleukin-1 induced changes in blood glucose, serum insulin and serum glucagon levels in Wistar Kyoto rats. The interleukin-1 receptor antagonist reduced the co-mitogenic effect of interleukin-1 on mouse and rat thymocytes with a 50% inhibitory concentration of 10- and 100-fold molar excess, respectively. Complete inhibition was obtained with a 100–1,000-fold molar excess. However, at a 100-fold molar excess the interleukin-1 receptor antagonist did not antagonise the potentiating effect of interleukin-1on rat islet insulin accumulation during 3 and 6 h of exposure or of interleukin-1-induced inhibition of insulin release after 24 h. In contrast, interleukin-1-stimulated islet glucagon release was completely antagonised by a 100-fold molar excess of interleukin-1 receptor antagonist. A 10,000-fold molar excess of interleukin-1 receptor antagonist was needed to antagonise interleukin-1 stimulatory and inhibitory effects on rat beta-cell function in vitro. A 100-fold excess of interleukin-1 receptor antagonist could not counteract interleukin-1 effects on mouse and human beta cells, excluding species difference in the efficacy of the human interleukin-1 receptor antagonist. An anti-mouse interleukin-1 receptor type I antibody completely abolished interleukin-1 effects on isolated mouse islets. A 10–100-fold molar excess of interleukin-1 receptor antagonist antagonised interleukin-1-induced fever, hypercorticosteronaemia and hyperglucagonaemia, but not interleukin-1-induced reduction in insulin/glucose ratio in normal rats. In conclusion, our results suggest that antagonism of interleukin-1 effects on beta cells requires higher concentrations of interleukin-1 receptor antagonist than those necessary to block interleukin-1 action on islet alpha cells and other interleukin-1 targets in vitro and in vivo. This may contribute to the understanding of the specificity of the immunological beta-cell destruction leading to insulin-dependent diabetes.