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J Nerup

Publications and source records attributed to J Nerup.

At least 19 recordsLinked to original sources
PubMed1995

Glucose tolerance in patients with cystic fibrosis: five year prospective study.

OBJECTIVES: To study prevalence and incidence of diabetes mellitus in patients with cystic fibrosis. DESIGN: Five year prospective study with annual oral glucose tolerance tests. SETTING: CF Center Copenhagen, Denmark. SUBJECTS: 191 patients with cystic fibrosis aged above 2 years. MAIN OUTCOME MEASURES: Glucose tolerance, plasma glucose concentrations after fasting and after glucose loading, and haemoglobin A1c levels. RESULTS: Prevalence of diabetes increased from 11% (n = 21) to 24% (n = 46) during study, with annual age dependent incidence of 4-9%. Diabetes was diagnosed at median age of 21 (range 3-40). At diagnosis of diabetes, symptoms of hyperglycaemia were present in 33% of patients, fasting hyperglycaemia (> or = 7.8 mmol/l) was seen in 16%, and increased haemoglobin A1c levels (> 6.4%) were seen in 16%. Impaired glucose tolerance implied higher risk for development of diabetes than normal glucose tolerance (odds ratio 5.6). In 58% of cases with impaired glucose tolerance, however, glucose tolerance was normal at next annual test. Normal glucose tolerance was found in only 37% of patients at all five tests. Within this group of patients, median plasma glucose concentrations after fasting and after glucose loading and haemoglobin A1c levels increased by 6-8% during study. CONCLUSIONS: Prevalence and incidence of diabetes in cystic fibrosis patients was high and increased with age. Since hyperglycaemic symptoms, fasting hyperglycaemia, and increased levels of glycated haemoglobin did not reliably identify diabetes mellitus, we recommend annual oral glucose tolerance tests in all cystic fibrosis patients aged over 10 years.

Adolescent↗
PubMed1995

Circulating interleukin-1 receptor antagonist concentrations are increased in adult patients with thermal injury.

OBJECTIVE: To investigate the balance between circulating concentrations of interleukin (IL)-1 and its natural inhibitor interleukin-1 receptor antagonist (IL-1Ra) in human inflammation. DESIGN: Prospective case-control study. SETTING: University hospital burn care unit. PATIENTS: Fifteen patients with second- or third-degree thermal injuries of 7% to 78% of total body surface and 15 healthy age- and sex-matched control subjects. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Median plasma IL-1Ra, but not IL-1 beta or tumor necrosis factor-alpha (TNF-alpha) concentrations were markedly increased on the day of admission in patients with thermal injuries compared with controls (1615 [range 426 to 23,800] vs. 494 [range 196 to 1093] pg/mL; p < .001). In survivors, the median IL-1Ra concentration normalized 12 to 21 days after admission. The concentration of IL-1Ra on the day of admission was weakly positively correlated to the extent and degree of thermal injury (r2 = .46; p < .05). IL-1Ra on days 1 to 3 was highest in three nonsurvivors with inhalation injuries compared with survivors (2166 [range 1362 to 36,624] vs. 1344 [range 665 to 13,085] pg/mL; p < .05). IL-1Ra increased significantly after debridement and skin transplantation (preoperatively 742 [range 488 to 1506] vs. postoperatively 1431 [range 1286 to 2107] pg/mL; p < .01). In nonsurvivors, median IL-1Ra was 3.6-fold higher than IL-1 beta on days 1 to 2 and 36-fold higher than IL-1 beta in three patients with bacteremia. IL-1Ra was studied for its relationship to previously reported parameters of the acute-phase response determined in the same samples from these patients. The increased concentrations of IL-1Ra coincided with a decrease in serum albumin concentration and increases in rectal temperature. However, IL-1Ra did not correlate with rectal temperature, plasma concentrations of endotoxin, IL-1 beta, or TNF-alpha either at admission or in follow-up samples. CONCLUSIONS: Thermal injury causes an increase of circulating IL-1Ra, especially in patients with inhalation injuries. With the current plasma assays for IL-1 beta, IL-1Ra may be a more sensitive marker of human inflammation than IL-1 beta or TNF-alpha.

Adult↗
PubMed1995

Localization of MODY3 to a 5-cM region of human chromosome 12.

Maturity-onset diabetes of the young (MODY) is a heterogeneous disorder that appears to be characterized by a primary defect in insulin secretion. Mutations in an unknown locus (MODY1) on chromosome 20 and the glucokinase gene (MODY2) on chromosome 7 can cause this form of non-insulin-dependent diabetes. Recent genetic studies have identified a third locus on chromosome 12 (MODY3) that is linked to MODY in a group of French families. We have identified three families from Denmark, Germany, and the U.S. (Michigan) showing evidence of linkage with MODY3 and a family from Japan showing suggestive evidence. Analysis of key recombinants in these families localized MODY3 to a 5-cM interval between the markers D12S86 and D12S807/D12S820.

Adult↗
PubMed1995

Two-dimensional gel electrophoresis of rat islet proteins. Interleukin 1 beta-induced changes in protein expression are reduced by L-arginine depletion and nicotinamide.

Interleukin (IL)-1 beta-mediated damage to beta-cells in isolated islets of Langerhans depends upon de novo synthesis of proteins that have not been fully identified. Further, IL-1 beta-induced and tumor necrosis factor alpha-induced islet damage partly depends on the intracellular production of the nitric oxide (NO) radical. IL-1 beta has also been reported to induce the synthesis of cellular defense proteins, e.g., heme-oxygenase and heat shock proteins 70 and 90. Nicotinamide, while in itself inactive, inhibited IL-1 beta-induced NO production in a time- and dose-dependent manner. To enable the identification of IL-1 beta-induced proteins with possible protective and deleterious effects, we characterized the effects of IL-1 beta, nicotinamide, and NO synthesis inhibition by L-arginine depletion on rat islet protein expression detected by high-resolution two-dimensional gel electrophoresis. More than 1,600 proteins were reproducibly detected in control rat islets. Incubation with IL-1 beta-, nicotinamide-, or L-arginine-depleted control medium upregulated 29, 3, and 1 protein, respectively, and downregulated 4, 0, and 1 protein, respectively. Addition of nicotinamide and L-arginine depletion reduced the upregulation of 16 and 20 IL-1 beta-induced proteins, respectively. The identity of these proteins is under study. The demonstrated changes in protein expression caused by IL-1 beta +/- nicotinamide and L-arginine depletion may form the basis for identification of proteins with possible protective and deleterious roles in the initial beta-cell destruction in insulin-dependent diabetes mellitus.

Animals↗
PubMed1994

[Familial aggregation of insulin-dependent diabetes mellitus in Denmark. A nation-wide population study].

This study aimed to assess the prevalence of familial aggregation of insulin-dependent diabetes mellitus (IDDM), among Danish families with a diabetic child and to compare epidemiological data for familial and sporadic cases of IDDM children. All IDDM patients aged 19 years or less treated at paediatric departments or departments of internal medicine were identified and asked to complete a questionnaire regarding diabetes onset and family history. Of 1574 probands identified, 1419 participated (90.2%). Additional cases of IDDM were found in 12.8% of the families. Among these families, in 6.8% the father and in 2.1% the mother were diabetics and in 5.0% at least one of the siblings were diabetics. In familial cases the proband was significantly younger at diabetes onset, the parents were younger at birth of the IDDM child and no differences in gender were observed in contrast to sporadic cases, where more males were found. Thus, heterogeneity in epidemiological characteristics was observed between familial and sporadic cases.

Adolescent↗
PubMed1994

Long-term risk of IDDM in first-degree relatives of patients with IDDM.

Due to a short observation period previous studies may have underestimated prevalence and recurrence risk of IDDM in relatives of IDDM patients. To obtain a more exact life-time risk estimate we identified 310 probands, representative of Danish IDDM patients, characterized by current age more than 50 years, age at onset 40 years or less and diabetes duration of more than 30 years. Family data were obtained from 291 probands. Mean "observation" times (age) (+/- SD) for siblings (n = 553) and offspring (n = 359) were 59.4 +/- 16.1 years and 33.8 +/- 8.8 years, respectively. Of the probands 73 (25.1%) had at least one first-degree relative with IDDM. Seventeen percent had at least one affected sibling. An increase from 10.4% to 22.4% of having first-degree relatives with IDDM among probands with age at onset below 20 years was observed during the period from proband at age 21 years up to 1 September 1992. Among affected siblings 48% of the second cases were affected more than 10 years after the first affected sibling. Using the life-table method cumulative recurrence risks from time of birth were calculated for siblings up to age 30 years of 6.4% and up to age 60 years of 9.6%. For offspring the risk up to age 34 years was 6.3%. In addition, we present a life-table method evaluating the cumulative recurrence risk from time of onset in the proband, as this is the most relevant when giving genetic counselling. In conclusion, the long-term risks of IDDM in siblings and offspring are high compared to that shown in previous reports.

Aged↗
PubMed1994

On the pathogenesis of IDDM.

A model of the pathogenesis of insulin-dependent diabetes mellitus, i.e. the initial phase of beta-cell destruction, is proposed: in a cascade-like fashion efficient antigen presentation, unbalanced cytokine, secretion and poor beta-cell defence result in beta-cell destruction by toxic free radicals (O2- and nitric oxide) produced by the beta cells themselves. This entire process is under polygenetic control.

Animals↗
PubMed1994

Interleukin 1 beta induces diabetes and fever in normal rats by nitric oxide via induction of different nitric oxide synthases.

Substantial in vitro evidence suggests that nitric oxide may be a major mediator of interleukin 1 (IL-1) induced pancreatic beta-cell inhibition and destruction in the initial events leading to insulin-dependent diabetes mellitus. Using NG-nitro-L-arginine methyl ester, an inhibitor of both the constitutive and the cytokine inducible forms of nitric oxide synthase, and aminoguanidine, a preferential inhibitor of the inducible form of nitric oxide synthase, we investigated the impact of inhibiting nitric oxide production on food-intake, body weight and temperature, blood glucose, plasma insulin, glucagon, corticosterone and leukocyte- and differential-counts in normal rats injected once daily for 5 days with interleukin 1 beta (IL-1 beta) (0.8 microgram/rat = 4.0 micrograms/kg). Inhibition of both the constitutive and the inducible forms of nitric oxide synthase prevented IL-1 beta-induced fever, hyperglycaemia, hypoinsulinemia, and hyperglucagonemia, and partially prevented lymphopenia and neutrophilia, but had no effect on IL-1 beta-induced anorexia and changes in plasma corticosterone. Preferential inhibition of the inducible form of nitric oxide synthase using two daily injections of 5 mg/rat of aminoguanidine prevented IL-1 beta-induced hyperglycaemia and hypoinsulinaemia, and slightly reduced the pyrogenicity of IL-1 on 3 out of 5 days. Higher doses of aminoguanidine (100 mg/rat) prevented lymphopenia and neutrophilia. We conclude that nitric oxide produced by the inducible form of nitric oxide synthase, mediates the IL-1 beta-induced inhibition of insulin release and that the effect of IL-1 beta on temperature, pancreatic alpha-cells, and leukocyte differential counts seems to be mediated by nitric oxide produced by the constitutive form of nitric oxide synthase.

Amino Acid Oxidoreductases↗
PubMed1994

Insulin sensitivity and insulin clearance in cystic fibrosis patients with normal and diabetic glucose tolerance.

OBJECTIVE: We studied glucose metabolism and insulin kinetics in cystic fibrosis patients with diabetic and normal glucose tolerance. DESIGN: Measurements of blood glucose and serum free insulin concentrations during hyperinsulinaemic normoglycaemic clamp and post-clamp insulin decay, followed by the calculation of insulin sensitivity (M-value and M/I ratio), insulin clearance rate, serum half-life and apparent distribution space for insulin. SUBJECTS: Cystic fibrosis patients, age range 20-29 years, with diabetes mellitus (n = 10) and normal glucose tolerance (n = 10), and 10 age-matched control subjects. RESULTS: During the glucose clamp, diabetic cystic fibrosis patients needed less glucose than cystic fibrosis patients with normal glucose tolerance and control subjects (M-value), and steady-state serum insulin concentrations were lower in cystic fibrosis patients with diabetic and normal glucose tolerance than in control subjects. The quantity of glucose metabolized per unit of serum insulin concentration (M/I ratio) was similar in the three study groups (median approximately 145 (mumol/kg/min)/(nmol/l); range 70-252). Insulin clearance rates were higher in cystic fibrosis patients with diabetic (24.4 (19.3-29.9) ml/kg/min) and normal (22.6 (14.9-28.4) ml/kg/min) glucose tolerance than in control subjects (17.5 (15.9-24.2) ml/kg/min). Although insulin clearance rates were inversely related to body mass index (R(S) = -0.59, P < 0.001), the higher insulin clearance rates in CF patients cannot be accounted for solely by differences in body mass index since the insulin clearance rates were similarly increased in patients with body mass index above and below 20 kg/m2 (22.7 (14.9-28.4) and 24.4 (19.3-29.9) ml/kg/min, respectively). Serum half-lives for insulin were shorter in cystic fibrosis patients (approximately 4.3 (3.2-7.2) min) than in control subjects (5.9 (3.8-12.5) min), whereas the apparent distribution spaces for insulin were similar in the three study groups (approximately 150 (88-391) ml/kg). CONCLUSIONS: Insulin sensitivity, calculated as the quantity of glucose metabolized per kg body weight per unit of serum insulin concentration, is normal in cystic fibrosis patients with normal glucose tolerance and with well controlled diabetes mellitus. The insulin clearance rate is increased in cystic fibrosis patients with diabetic and normal glucose tolerance, owing to a shorter serum half-life of insulin, whereas the apparent distribution space for insulin is normal.

Adult↗
PubMed1994

Diabetes mellitus in Danish cystic fibrosis patients: prevalence and late diabetic complications.

The prevalences of impaired glucose tolerance (IGT), diabetes mellitus and late diabetic complications were studied in all Danish cystic fibrosis (CF) patients. A total of 311 CF patients were identified with an estimated ascertainment rate above 98%. Glucose tolerance was classified in 278 (89%) patients: the prevalences of IGT and diabetes mellitus were 13.7% (38 patients) and 14.7% (41 patients), respectively, with no sex differences. The prevalence of diabetes mellitus increased with age but not with the severity of CF as compared with age- and sex-matched non-diabetic CF patients. Diabetes was diagnosed at a median age of 20 years (range 3-40 years) and the duration of diabetes was 1.7 years (0.1-17 years). Twenty-eight of the diabetic patients (70%) were treated with insulin, on average 20 (4-90) IU per day. Late diabetic complications were identified in 4 patients (10%) with a duration of diabetes mellitus of 1-17 years: background retinopathy (2 patients), diabetic nephropathy (1 patient), microalbuminuria (1 patient) and neuropathy (2 patients). Thus diabetic CF patients are probably not less prone to develop late diabetic complications than patients with other types of diabetes of equally long duration and comparable glycemic control.

Adolescent↗
PubMed1994

Diabetes mellitus in cystic fibrosis: effect of insulin therapy on lung function and infections.

The effect of insulin therapy on lung function and lung infections was studied in a retrospective case-control design in 18 diabetic cystic fibrosis (CF) patients; 18 non-diabetic CF patients, matched for sex, age and presence of chronic Pseudomonas aeruginosa lung infection, served as controls. Parameters of CF clinical status were collected for six years before and two years after the onset of insulin therapy in the diabetic patients. Before onset of insulin therapy, body mass index (BMI) and forced vital capacity (FVC) in (pre)diabetic patients deviated increasingly from those in control patients. Decreases in BMI and lung function during the past three months before onset of insulin therapy were reverted within three months of insulin therapy. From three months to two years after onset of insulin therapy, differences in BMI and lung function diminished between diabetic and control patients. After two years of insulin therapy, BMI was similar in diabetic and non-diabetic patients and the percentage differences in forced expiratory volume in 1s (FEV1) and FVC between the two groups were similar to those found six years before the onset of insulin therapy. The finding that insulin therapy improves lung function in diabetic CF patients suggests strongly that the insidious decline in lung function seen during the years before the diagnosis of diabetes mellitus results from the pre-diabetic condition. After onset of insulin therapy, the percentages of sputum examinations positive for Haemophilus influenzae and Streptococcus pneumoniae decreased in the diabetic patients, whereas parameters of lung infections with P. aeruginosa and Staphylococcus aureus remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Major histocompatibility complex-encoded antigen processing gene polymorphism in IDDM.

Susceptibility to insulin-dependent diabetes mellitus (IDDM) is greatly influenced by polymorphisms in the genes of the class II region of the human leukocyte antigen (HLA) complex. The complexity of this genetic association and the lack of a direct proof of involvement of HLA class II genes in human IDDM have continued to support speculation on a possible role of genes encoded in the close vicinity of these loci in IDDM. Because the recently discovered transporter associated with antigen processing (TAP) and large multifunctional protease (LMP) genes are encoded in the HLA class II region and are implicated in the processing of antigenic proteins for presentation by HLA class I molecules, they are additional candidates for a role in IDDM pathogenesis. We have analyzed genomic and coding sequence polymorphisms in the LMP2, TAP1, and TAP2 genes of 77 Danish IDDM patients and 102 control subjects. Although patients and control subjects did not differ in TAP1 and LMP2 alleles, we found a striking absence of the TAP2 allele B (long form) in IDDM patients. An analysis of the TAP2 alleles in individual DR types, however, revealed that this phenomenon is likely to be caused by linkage disequilibrium between the two loci. Thus, polymorphisms in the TAP and LMP genes are unlikely to be associated with IDDM.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Monokine antagonism is reduced in patients with IDDM.

Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) have been implicated as immune effector molecules in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). Recently, an increased frequency of the A1/A1 genotype of an IL-1 receptor antagonist (IL-1Ra) gene polymorphism was observed in patients with IDDM. Therefore, we investigated plasma IL-1Ra and soluble TNF p55 receptor (TNFsRp55) levels in 18 men with recent-onset IDDM, 10 men with long-standing IDDM, and 35 age-matched healthy men. No differences in plasma IL-1Ra were found among the three groups. However, when the plasma IL-1Ra levels in the subjects with IDDM and the control subjects were analyzed according to IL-1Ra genotypes, we found a 30% lower level of plasma IL-1Ra in subjects with IDDM carrying the A1/A1 genotype compared with the levels in those carrying the A1/A2 genotype (372 +/- 40 vs. 530 +/- 54 ng/l, respectively, P = 0.025). In contrast, no significant association was seen between plasma IL-1Ra and IL-1Ra genotype in the control subjects. The TNFsRp55 level in heparinized plasma was 17% lower in patients with IDDM than in control subjects (3.93 +/- 0.22 vs. 4.72 +/- 0.24 micrograms/l, respectively, P = 0.038). These findings could not be explained by metabolic derangement in the IDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Glutamic acid decarboxylase (GAD65) autoantibodies in prediction of beta-cell function and remission in recent-onset IDDM after cyclosporin treatment. The Canadian-European Randomized Control Trial Group.

We have investigated whether glutamic acid decarboxylase (GAD) autoantibodies (GAD65 Ab) were affected by cyclosporin therapy and were related to subsequent non-insulin-requiring remission and loss of glucagon-stimulated C-peptide response in 132 recent-onset insulin-dependent diabetes mellitus (IDDM) patients treated with cyclosporin or placebo for 12 months. GAD65 Ab were detected in a quantitative radioligand assay using as tracer recombinant, in vitro translated, human islet [35S]methionine-labeled GAD65. GAD65 Ab were found at onset in 66% (87 of 132) of IDDM patients and in 1% (1 of 100) of healthy control subjects. The prevalence of GAD65 Ab and median GAD65 Ab levels did not change in serum samples taken 3, 6, 9, and 12 months after study entry in either the cyclosporin- or the placebo-treated groups. The presence or absence of GAD65 Ab at study entry did not predict non-insulin-requiring remission in either cyclosporin- or placebo-treated patients. However, the relative (compared with 0 months) glucagon-stimulated C-peptide response was more than 30% lower in GAD65 Ab+ patients receiving placebo at 9 and 12 months compared with the GAD65 Ab- placebo patients (P < 0.035). Islet cell cytoplasmic antibody (ICA) and GAD65 Ab+ placebo-treated patients showed no significant differences in stimulated C-peptide levels compared with those who were ICA- and GAD65 Ab+, suggesting that ICA was not independently associated with loss of beta-cell function.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Nicotinamide prevents interleukin-1 effects on accumulated insulin release and nitric oxide production in rat islets of Langerhans.

Nicotinamide (NA) prevents macrophage- and interleukin-1 (IL-1)-mediated beta-cell damage in vitro as well as diabetes development in animal models of insulin-dependent diabetes mellitus (IDDM). IL-1 beta-mediated inhibition of insulin release and damage to beta-cells are associated with intracellular production of nitric oxide (NO) radicals. Therefore, we studied whether NA prevented IL-1 beta-induced islet NO production, measured as nitrite release from isolated rat islets, and, if so, whether this action was associated with prevention of IL-1 beta-mediated inhibition of insulin release. NA dose- and time-dependently inhibited and delayed IL-1 beta-induced islet NO production. Light microscopy detected that 25 mM of NA protected against IL-1 beta-induced islet damage. Five to 50 mM of NA dose-dependently reduced inhibition of accumulated islet insulin release induced by 150 pg/ml of IL-1 beta. NA was not able to reverse the reduced ability of IL-1 beta-treated islets to respond to an acute glucose challenge. NO or nitrite did not interact directly with NA, because NA did not reduce sodium nitroprusside-generated nitrite. No-synthase inhibition with L-arginine depletion abolished NO production but only partially reduced IL-1 beta-induced inhibition of accumulated insulin release. Complete inhibition of IL-1 beta effects could not be obtained by adding L-arginine analogues to L-arginine-depleted medium, indicating that an NO-independent action of IL-1 beta on islet insulin release may exist.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Genetic susceptibility markers in Danish patients with type 1 (insulin-dependent) diabetes--evidence for polygenicity in man. Danish Study Group of Diabetes in Childhood.

Fifty-five Danish families with two offspring concordant for type 1 diabetes--identified through a nationwide population-based survey, and 57 "true sporadic" cases--matched with familial cases for age at onset, but with no IDDM-affected first-degree relatives and long disease duration, and 110 control subjects were typed for putative genetic susceptibility markers for type 1 diabetes identified from a pathogenetic model. The markers included MHC class I, II and III loci, the manganese superoxide dismutase (MnSOD) locus (chr. 6q), interleukin-1 beta (IL1B), the IL-1 receptor antagonist (IL1RN), and the IL-1 type 1 receptor (IL1RI) loci (each chr. 2q). No significant differences between familial and sporadic cases were found within the MHC region (including the following loci: HLA-DQ, -DR, heat shock protein (HSP) 70, tumour necrosis factor (TNF), HLA-B and -A). In both groups of patients 11% were negative for both DQA1*0301-DQB1*0302 and DQA1*0501-DQB1*0201 genotypes, and 7% of the type 1 diabetics had genotypes unable to encode a susceptibility DQ alpha beta heterodimer. Disease association was found for the IL1RN (p = 0.04) and for the IL1RI (p = 0.03). When comparing controls and only familial cases with type 1 diabetes for the IL1RN polymorphism a difference was observed (p = 0.003). For the IL1B RFLP a trend for difference was observed between familial cases and control subjects (p = 0.046), whereas no differences between sporadic cases and control subjects could be demonstrated neither at the IL1B nor at the IL1RN loci. A difference in the MnSOD pattern was observed between sporadic cases and controls (p = 0.04).

Adolescent↗
PubMed1994

Interleukin-1 beta (IL-1) does not reduce the diabetes incidence in diabetes-prone BB rats.

The cytokine interleukin 1 beta (IL-1) has been implicated as a pathogenetic factor in the initial events leading to insulin-dependent diabetes mellitus. Previous studies investigating the impact of IL-1 on diabetes incidence in spontaneously diabetic rodent models have been conflicting. IL-1 induces anorexia and previous studies are hampered by the lack of pair-fed controls to the IL-1 treated animals. We report that daily injections of 4.0 micrograms/kg/day of recombinant human IL-1 (rhIL-1) for 13 weeks from 25-30 days of age did not alter the incidence of diabetes in the diabetes-prone (DP) BB rats (75%) when compared to pair-fed, vehicle treated controls (55%, p = 0.18), or to unhandled DP BB rats (80%, p = 0.71). However, IL-1 induced significantly higher blood glucose concentrations in the prediabetic period (p < 0.00005) and at diabetes onset (p < 0.00005) in the DP BB rats and caused episodes of blood glucose concentrations > 11 mmol/l in the prediabetic period in 11/20 DP BB rats compared to 4/27 diabetes-resistant (DR) BB rats and 4/28 Wistar Furth (WF) rats (both p < 0.004), compared to DP BB). Further, rhIL-1 induced fever in 11 weeks in the DP BB rats compared to 3 weeks in the DR BB and 6 weeks in the WF rats. Using high performance size exclusion chromatography specific anti-rhIL-1-antibodies were demonstrated in DR BB and WF, but not in DP BB rats. These antibodies neutralized the inhibitory effect of rhIL-1 on insulin secretion from isolated islets of Langerhans in vitro. The reduced pyrogenic and endocrine effect of rhIL-1 in the DR BB and WF rats compared to the DP BB rats could be explained by the impaired ability of the DP BB rats to produce anti-rhIL-1-antibodies. In conclusion, administration of rhIL-1 modulated the prediabetic period, and produced higher blood glucose concentrations at diagnosis, but did not change the diabetes incidence in DP BB rats. The results are not in conflict with the hypothesis that IL-1 is a pathogenetic factor in IDDM, caused by high local concentrations of rat IL-1 in the islets during early insulitis. The results also show the necessity of pair-feeding of the control group to the rhIL-1 group when interpreting data from experiments investigating rhIL-1 effects on diabetes development in animal models.

Animals↗