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Biomedical subjects

J Nerup

Publications and source records attributed to J Nerup.

315 records · Page 18Linked to original sources
PubMedDate not supplied

Polymorphism in 5' flanking region of human insulin gene. Relationships with atherosclerosis, lipid levels, and age in three samples from Denmark.

Variations in the DNA sequence flanking the 5' region of the human insulin gene (U- and L-alleles) were studied in relation to atherosclerosis, lipid levels, and age in three groups of atherosclerotic individuals and in nonatherosclerotic controls. The atherosclerotic groups comprised a postmyocardial infarction group with a mean age of 48 years, a group of individuals operated on for carotid stenosis with a mean age of 62 years, and a group of 85-year-olds with clinical coronary disease, peripheral arterial disease, or both. All 331 individuals were unrelated Caucasians of Danish ancestry. There were no significant differences (p greater than 0.05) in genotype distribution or allele frequencies between atherosclerotic and nonatherosclerotic individuals, but in the 85-year-olds, there was evidence (p less than 0.10) for a lower U-allele frequency in nonatherosclerotic women compared to atherosclerotic women. In nonatherosclerotic women, there was a significant decrease in U-allele frequency with age (60 to 85 years). This decrease does not prove conclusively, but is compatible with, the hypothesis that the U-allele predisposes to, or the L-allele protects against, atherosclerosis. The possible effect of the U-allele on the development of atherosclerosis does not seem to be mediated through conventional risk factors.

Aged↗
PubMedDate not supplied

In vitro inhibition of insulin release by blood mononuclear cells from insulin-dependent diabetic and healthy subjects: synergistic action of IL-1 and TNF.

Previous studies have demonstrated that peripheral blood mononuclear cells (BMC) from type 1 (insulin-dependent) diabetic patients inhibit insulin release (IR) from rat or mouse islet cells in vitro. This phenomenon is of great interest as a model for islet graft rejection. We found that lipopolysaccharide (LPS)-stimulated BMC of healthy donors and type 1 diabetic patients suppress both basal and stimulated insulin secretion. To study whether this inhibition was due to soluble mediators we added supernatants of LPS-stimulated BMC or recombinant human interleukin-1 beta (IL-1) and tumor necrosis factor-alpha (TNF) at concentrations comparable to those found in the supernatants to rat islet cells. The inhibitory effect of BMC on islet cells could be transferred by supernatants of LPS-stimulated BMC. We found that neither IL-1 nor TNF alone inhibit IR from dispersed adult rat islet cells. However, the combination of IL-1 and TNF was highly effective. Ultrafiltration of supernatants of LPS-stimulated BMC through a PM-10 membrane (10 kDa cutoff) deprived the supernatants of the inhibitory activity indicating that only intact IL-1 and TNF (m.w. about 17 kDa), but not smaller IL-1 and TNF fragments, were responsible for the effects on islet cells. These data suggest that activation of BMC and cytokine release at islet graft site may result in an early loss of graft function. Islet transplantation using microcapsules not permeable for molecules with m.w. > 10 kDa would be preferable.

Adult↗
PubMedDate not supplied

Epidemiologic studies of insulin-dependent diabetes mellitus.

The incidence of insulin-dependent diabetes mellitus (IDDM) in Denmark in the years 1970--1976 was 13.3 per 100,000 in the age group 0--29 yr. This incidence is almost identical to that found in 1924 in Denmark in the same age group. The prevalence of insulin-consumers is 3.2 per 1,000. Comparison is made with incidence and prevalence data from other studies of Caucasian populations.

Adolescent↗
PubMedDate not supplied

Studies of the HLA system and insulin-dependent diabetes mellitus.

The relationship between the HLA system and insulin-dependent diabetes mellitus (IDDM) is reviewed. Data compiled by the HLA and Disease Registry reveal that HLA-B8 and/or Dw3 are associated with IDDM in all populations studied so far, but further population studies in non-Caucasian populations should be performed. In Caucasians, HLA-Dw2 renders protection against IDDM while HLA-Dw3 and Dw4 are associated with susceptibility to IDDM. The exact mode of inheritance of susceptibility to IDDM remains to be established. Involvement of at least two genes is likely. Heterogeneity of IDDM is highly possible and should be a matter of major interest in diabetes research.

Diabetes Mellitus↗
PubMedDate not supplied

Effect of guar gum on 24-hour insulin requirements of insulin-dependent diabetic subjects as assessed by an artificial pancreas.

The effect of guar gum on insulin requirements, mean blood glucose (MBG), and mean amplitude of glycemic excursions (MAGE) was investigated in seven insulin-dependent diabetic subjects without endogenous insulin secretion by means of an artificial pancreas (Biostator). Fifty-four hours after the withdrawal of long-acting insulin, the patients were controlled for two consecutive days by the artificial pancreas, under standardized identical conditions, except for the ingestion of guar gum before meals on the second day. The 24-h insulin requirements were significantly reduced by 12.4% on the day with guar gum (P < 0.05). No statistically significant effects were observed on MGG and MAGE.

Adolescent↗
PubMedDate not supplied

Strain-dependent difference in inducible nitric oxide synthesis (iNOS) expression in rat pancreatic islets correlates with interferon regulating factor 1 (IRF-1) and heat shock protein 70 (HSP70) expression.

UNLABELLED: Nitric oxide (NO) may be a necessary but not sufficient mediator of cytokine-mediated, selective beta-cell destruction. Previously, we have described a difference in NO-dependent IL-1beta sensitivity in vivo and in vitro of pancreatic islets from two rat strains, Brown Norway (BN) and Wistar Kyoto (WK), the latter being the more sensitive strain. Here we investigated whether strain-dependent, differential islet iNOS expression was associated with differences in islet expression of the IL-1 receptor type 1(IL-1RI) or interferon regulating factor 1 (IRF-1), and/or caused differences in HSP70 expression, a marker of cell defence against oxidative stress. METHODS: isolated islets from both rat strains were exposed to increasing concentrations of IL-1beta (0-150 pg/ml) for 24 hours or for varying culture periods (4-48 hours) to 15 pg/ml of IL-1beta. MEASUREMENTS: accumulated insulin and nitrite release into incubation medium, and islet mRNA and protein expression of iNOS, IL-1RI, IRF-1 and HSP70 by semi-quantitative RT-PCR and Western blotting. RESULTS: Higher insulin and lower nitrite release into the incubation medium were seen for BN compared to WK rats islets in both dose- and time-response experiments. IRF-1 expression preceded iNOS expression and was more pronounced in WK than in BN islets. No strain differences were observed for islet expression of IL-1RI. A strain-dependent HSP70 expression in response to IL-1beta with the highest levels in WK rat islets following iNOS expression was seen. CONCLUSION: There was a strain-dependent difference in iNOS expression which was associated with IRF-1 and HSP70 expression.

Animals↗
PubMedDate not supplied

Restriction fragment length polymorphism of HLA and non-HLA genes in DR3/4 heterozygous Danish insulin-dependent diabetic patients and healthy individuals: reassessment of the influence of alpha DX and insulin-linked polymorphic loci, and new splits of DQw3 haplotypes.

We have investigated restriction fragment length polymorphism (RFLP) of HLA and non-HLA regions of the genome in the homogeneous Danish population. Insulin-dependent diabetes mellitus (IDDM) patients and healthy individuals were selected for being HLA-DR 3/4 heterozygous to evaluate the influence of genes other than DR on disease susceptibility. Five different probes were used: HLA alpha and beta DQ (chromosome 6), the Ins 310 genomic fragment which detects a polymorphic region 5' to the insulin gene (chromosome 11), and cDNA for the constant regions of the T cell receptor alpha and beta genes (chromosomes 14 and 7). Fifteen cells homozygous for the HLA-D region were used to obtain reference DNA patterns. This allowed us to describe four splits among the HLA-DQw3 haplotypes (DQw3.1 to DQw3.4). The two new haplotypes DQw3.3 and DQw3.4 do not code for the TA10 serological marker which is found on DQw3.1 positive cells. One-hundred per cent of IDDM patients were typed as DQw3.2 versus 68 per cent for controls (p = 0.003). However, our results do not indicate a role for the Ins 310 or for the alpha DX locus region in IDDM susceptibility, in contrast to previous reports by others. The restriction enzymes that we have used did not reveal significant differences between DNA patterns of patients and controls with probes for the constant region of the T cell receptor genes.

Biomarkers↗
PubMedDate not supplied

Mechanisms of pancreatic beta-cell destruction in type I diabetes.

The pathogenetic mechanisms leading to beta-cell destruction and insulin-dependent diabetes mellitus (IDDM) are major histocompatibility complex (MHC) nonrestricted and are MHC associated and beta-cell specific. The macrophage peptide hormone interleukin 1 (IL-1) may be the primary MHC-nonrestricted beta-cell-destructive molecule. Beta-Cell death most likely results from free radical induction by IL-1. Thus, islet cell-specific antibodies and cytotoxic T-lymphocytes are secondary in importance and time. The potentiation of IL-1 effects on beta-cells by tumor necrosis factor alpha (TNF), another macrophage hormone controlled by a gene in the HLA region on chromosome 6, may account for the MHC association of IDDM. In the experimental model of IDDM etiopathogenesis described, release of beta-cell antigen, processed and presented by macrophages to helper T-lymphocytes, initiates a self-perpetuating and self-limiting circuit of cytokine production of which IL-1 is beta-cell cytotoxic. As postulated, the IL-1 effect is potentiated by TNF, whereas IL-1 and/or TNF production is controlled in a quantitative way by HLA-D genes.

Diabetes Mellitus, Type 1↗