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J Nerup

Publications and source records attributed to J Nerup.

At least 199 records · Page 11Linked to original sources
PubMed1985

Insulin-gene flanking sequences, diabetes mellitus and atherosclerosis: a review.

A highly polymorphic locus flanking the human insulin gene contains two major size classes of DNA restriction fragments, which segregate in families as stable genetic elements. The L-allele, i.e. fragments with an average size of about 600 base-pairs seems to be a weak genetic marker for Type 1 (insulin-dependent) diabetes mellitus, whereas the U-allele, i.e. fragments of an average size of about 2500 base-pairs hitherto has been associated with Type 2 (non-insulin-dependent) diabetes mellitus and diabetic hypertriglyceridaemia. The most recent reports on this subject do not confirm an association between the U-allele and Type 2 diabetes. Our own studies indicate that the U-allele is a fairly strong marker for the development of atherosclerosis (relative risk for U-carriers 3.36). The putative functions of the polymorphic region in atherogenesis and the relation of this region to other genetic markers for atherosclerosis are not known.

Alleles↗
PubMed1985

Increased reduction in fasting C-peptide is associated with islet cell antibodies in type 1 (insulin-dependent) diabetic patients.

A cohort of 82 patients with Type 1 (insulin-dependent) diabetes was followed prospectively for 24 months, and 54 of them for 30 months, to study the relationship between fasting levels of immunoreactive C-peptide and titres of islet cell antibodies. After diagnosis, fasting C-peptide rose temporarily for 1-6 months of insulin therapy and declined continuously thereafter. While islet cell antibodies were present among 55% of the newly diagnosed patients, only 31% remained positive at 30 months. Their antibody titres decreased from 1:81 at diagnosis to 1:3. Only 3 patients (4%) who were islet cell antibody negative at diagnosis became positive later. The median C-peptide values among the persistently islet cell antibody positive patients decreased from 0.11 pmol/ml at 18 months, to 0.09 pmol/ml at 24 months, to 0.06 pmol/ml at 30 months compared to 0.18 (p = 0.04), 0.15 (p = 0.05) and 0.16 (p less than 0.003) pmol/ml, respectively, for the islet cell antibody negative patients. The median slope for the latter was -0.09 compared to -0.19 for the islet cell antibody positive patients (p = 0.01). These differences were reflected in increasing dosages of insulin, since patients remaining antibody-positive for 30 months were given 1.3-1.4 times more insulin (p = 0.01-0.004) than the antibody negative patients. This study demonstrates that islet cell antibodies may be a useful marker for predicting an increased rate by which endogenous B cell function is lost in Type 1 diabetes.

Adolescent↗
PubMed1985

Cytokines cause functional and structural damage to isolated islets of Langerhans.

Cytokines are soluble, antigen non-specific, non-immunoglobulin mediators produced and secreted by blood mononuclear cells interacting in the cellular immune-response. To test the possibility that cytokines participate in the autoimmune destruction of the pancreatic beta-cells leading to insulin-dependent diabetes mellitus, isolated human or rat islets of Langerhans were incubated for 7 days with cytokine-rich, cell-free supernatants of blood mononuclear cells from healthy human donors stimulated with or without purified protein derivative of tuberculin or phytohaemagglutinin. Glucose stimulated insulin-release, and contents of insulin and glucagon in islets incubated with cytokine-rich supernatants were markedly reduced. This impairment of islet function was due to a cytotoxic effect of cytokine-rich supernatants as judged by disintegration of normal light-microscopic morphology.

Animals↗
PubMed1985

Islet cell antibodies in insulin-dependent (type 1) diabetic children treated with plasmapheresis.

Plasma levels of islet cell cytoplasmic and cytotoxic antibodies were determined in 10 children with insulin-dependent diabetes mellitus (IDDM) treated with plasmapheresis shortly after diagnosis, and in 9 children with IDDM treated by conventional means alone. Islet cell cytoplasmic antibody (ICA) titers were determined by indirect immunofluorescence using unfixed sections of human pancreas, and islet cell cytotoxic antibody levels were determined in a complement-dependent antibody-mediated cytotoxicity (C'AMC) assay using a human fetal cloned insulin-producing cell line (JHPI-1) as target. Before plasmapheresis, ICA was present in 7 out of 10 children and C'AMC was positive in 4. Four successive treatments with plasmapheresis did not consistently decrease plasma levels of ICA or C'AMC. ICA was present in 15 out of the total 19 children at diagnosis, and titers of ICA decreased in 12 out of 15 subjects by at least 1 degree of dilution (1:3) at 18-30 months follow-up, whether or not they had been treated with plasmapheresis; C'AMC was positive in 6 out of the 18 children at diagnosis and decreased in 2 out of 6. Plasma levels of C-peptide did not differ at diagnosis but remained higher in the plasmapheresis treated diabetic children at 3 and 18-30 months follow-up. Neither ICA titers nor C'AMC levels correlated with plasma C-peptide responses at 18-30 months. It is concluded that plasmapheresis decreases ICA and C'AMC but is followed rapidly by a rebound effect, and does not affect the rates at which these islet cell antibodies decrease with increasing duration of IDDM.

Adolescent↗
PubMed1984

Relation between breast-feeding and incidence rates of insulin-dependent diabetes mellitus. A hypothesis.

The variations in incidence rates of insulin-dependent diabetes mellitus (IDDM) in childhood within and between genetically very similar Scandinavian populations and the variations in incidence rates with time are difficult to explain. Epidemiological data show that the incidence of childhood IDDM may now be declining and suggest an inverse correlation between breast-feeding frequency and IDDM in childhood. Case-control data show that diabetic children were breast-fed for shorter periods of time than their healthy siblings and the population at large and that a smaller proportion of diabetic children were ever breast-fed. It is postulated that insufficient breast-feeding of genetically susceptible newborn infants may lead to beta-cell infection and IDDM later in life.

Adolescent↗
PubMed1984

DNA sequences flanking the insulin gene on chromosome 11 confer risk of atherosclerosis.

The allelic frequency of DNA restriction fragments of a large size class (U alleles) in the polymorphic region flanking the 5'-end of the human insulin gene on chromosome 11 was 2 X 5 times higher in a group of patients with extensive atherosclerosis than in subjects in whom atherosclerosis could not be demonstrated by coronary arteriography and careful clinical examination. The U alleles apparently do not confer risk of atherosclerosis through conventional risk factors such as body weight or blood pressure or levels of blood glucose, triglycerides, cholesterol, or lipoproteins.

Adult↗
PubMed1984

Smoking habits and prevalence of clinical diabetic microangiopathy in insulin-dependent diabetics.

All patients having insulin-dependent diabetes with onset before 30 years of age and a duration of disease of 12-40 years who visited a diabetes centre within one year were registered. 97% (n = 668) answered a WHO questionnaire on cigarette smoking. The smoking habits were compared to the frequency of proliferative retinopathy and/or diabetic nephropathy (persistent proteinuria). The prevalence of diabetic nephropathy was significantly higher among heavy smokers (greater than 10 cigarettes a day for more than one year) than among non-heavy smokers, 19.2% versus 12.1% (p less than 0.02). An increasing frequency of nephropathy was found with increasing cigarette consumption (p less than 0.01). No difference in the prevalence of proliferative retinopathy was found between smokers and non-smokers. It is concluded that cigarette smoking is a risk factor for the development of nephropathy in insulin-dependent diabetics.

Adult↗
PubMed1984

Thyroid-stimulating immunoglobulins in insulin-dependent diabetes mellitus.

Increased frequencies of thyroid diseases and thyroid microsomal antibodies have been observed in insulin-dependent diabetes mellitus. However, the exact prevalence of thyroid-stimulating immunoglobulins has not been established. In the present study these antibodies were measured by both a radioreceptor and an adenylate-cyclase stimulation assay. In forty-six patients with insulin-dependent diabetes mellitus without endogeneous insulin production (C-peptide concentration less than or equal to 0.06 nmol 1(-1)) the receptor assay was positive in ten and the stimulation assay in fifteen patients. The immunoglobulins of four patients inhibited the adenylate cyclase, and one of these was positive in the receptor assay. In nine patients with post-prandial C-peptide 0.07-0.19 nmol 1(-1), five had adenylate-cyclase-stimulating antibodies, while none were positive in the receptor assay. Thyroid hormones and thyrotropin concentrations were not different in the forty-six patients without endogenous insulin production with thyroid-stimulating immunoglobulins compared with patients without these antibodies. Patients with thyroid-stimulating immunoglobulins required a daily median amount of 0.71 IE of insulin kg-1 compared to median of 0.57 IE kg-1 in patients without these antibodies (P less than 0.03), despite a similar degree of diabetic regulation. The level of tri-iodothyronine was correlated to the antibody level in patients with adenylate-cyclase-stimulating antibodies. While the prognostic and possibly pathogenetic importance of these antibodies in Graves' disease have been established, their significance in insulin-dependent diabetes mellitus remains to be demonstrated.

Adenylyl Cyclases↗
PubMed1984

Spontaneous in vitro immunoglobulin secretion at the diagnosis of insulin-dependent diabetes.

Blood mononuclear cells obtained from 17 newly diagnosed insulin-dependent diabetic (IDDM) patients treated with insulin for 5-7 days were assessed for the number of spontaneous and pokeweed mitogen (PWM)-stimulated immunoglobulin-secreting cells in a reverse haemolytic plaque assay. The spontaneous in vitro immunoglobulin secretion was evanescent and decreased in individual patients within 1-4 months of insulin treatment. Compared to matched controls, 53% (9/17) of the IDDM patients had an elevated spontaneous secretion of immunoglobulin, 41% (7/17) for IgG, 35% (6/17) for IgM, and 35% (6/17) for IgA. The quantities of PWM-stimulated IgG, IgM, or IgA secreting cells in IDDM were comparable to the controls. The IDDM patients with spontaneous immunoglobulin secreting cells had higher fasting C-peptide levels compared to the patients with immunoglobulin-producing cells within the normal range (P less than 0.05). The average titre of islet cell cytoplasmic antibodies was 1:26 in (9 out of 9 were positive) patients with, compared to 1:1 in patients (4 out of 8 were positive) without spontaneous secretion (P = 0.025). These results suggest that the clinical onset of IDDM is associated with a polyclonal B lymphocyte activation and that higher levels of fasting C-peptide islet cell antibodies are associated with this immunoregulatory abnormality.

Adolescent↗
PubMed1983

Analysis of islet cell antibodies on frozen sections of human pancreas.

The sensitivity and specificity of the assay for islet cell cytoplasmic antibodies in human serum were examined using cryostat sections from fresh frozen pancreas. The specificity of the assay was close to 100% while the sensitivity was 40%-98% depending on the pancreas used. Inter-observer variation was 12-27%. End-point titres of islet cell antibodies varied with the sensitivity of each pancreas. End-point titration of the antibodies in two different laboratories using the same pancreas was significantly correlated (Spearman test p less than 0.001). We conclude that a reliable determination of islet cell antibody titres in human serum requires careful characterization of the sensitivity and specificity of each pancreas used as a source of frozen sections, in the indirect immunofluorescence assay.

Adolescent↗
PubMed1983

Genetics of diabetes in Nauru: effects of foreign admixture, HLA antigens and the insulin-gene-linked polymorphism.

Genetic factors play a major role in predisposition to diabetes in the Micronesian population of Nauru. In people aged 60 years and older, 83% of full-blooded Nauruans were diabetic compared with 17% of those with ancestral foreign admixture, as detected by HLA typing. HLA distributions also showed a small increased risk for early onset of diabetes (less than 46 years) associated with HLA-Bw22 (Bw56). Variation in the restriction fragment length of DNA near the insulin gene was found, but was not associated with diabetes. The distribution in fragment lengths, previously reported in Caucasoids, was observed in healthy Polynesians, Melanesians and Micronesians.

Adult↗