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Biomedical subjects

M Knip

Publications and source records attributed to M Knip.

At least 127 records · Page 7Linked to original sources
PubMed1998

Autoantibodies associated with Type I diabetes mellitus persist after diagnosis in children.

To study the persistence of Type I (insulin-dependent) diabetes mellitus associated autoantibodies and their relation to genetic risk markers and clinical characteristics of the disease after clinical manifestation, serum samples were obtained from 90 children and adolescents at diagnosis and 2, 5 and 10 years later. The samples were analysed for islet cell antibodies (ICA) by immunofluorescence and for antibodies to glutamic acid decarboxylase (GADA), intracellular portion of the protein tyrosine phosphatase related IA-2 antigen (IA-2A) and insulin autoantibodies by specific radiobinding assays. Of the subjects tested 79% were positive for IA-2A at diagnosis, 62% for GADA, 81% for ICA and 28% for insulin autoantibodies, but the prevalence of IA-2A, GADA and ICA decreased substantially as a function of increasing duration of the disease (p < 0.05 or less), their levels following the same pattern (p < 0.001 for all three autoantibodies). Two thirds of the subjects still tested positive for at least one autoantibody specificity after the first 10 years of the disease and 42% had two or three antibodies detectable. An increase over the initial antibody concentrations after the diagnosis was seen more often for GADA than for ICA (p < 0.001) or IA-2A (p < 0.05). In conclusion, autoantibodies associated with Type I diabetes appear to persist longer than expected after manifestation of the clinical disease, possibly due to small scale continuous beta-cell regeneration after diagnosis or to structural and/or functional mimicry between exogenous proteins and beta-cell antigens or both.

Adolescent↗
PubMed1998

Prepubertal girls with insulin-dependent diabetes mellitus have higher exogenous insulin requirement than boys. Childhood Diabetes in Finland Study Group.

In a population based study, the prescribed insulin dose of 348 prepubertal children with insulin-dependent diabetes mellitus (IDDM) was analysed 2 years after the diagnosis of diabetes. Girls had an insulin dose 13.6% higher than that in boys. When children younger than 5 years of age at diagnosis were analysed separately, the difference in insulin dose between boys and girls remained. The increased insulin dose in girls was not explained by possible differences in endogenous insulin secretion, body mass index, metabolic control or the number of daily insulin injections. Our observations indicate that prepubertal girls with IDDM have a poorer insulin sensitivity than boys.

Adolescent↗
PubMed1998

Folate, vitamin D, and iron intakes are low among pregnant Finnish women.

OBJECTIVE: To evaluate dietary habits and nutrient intake of Finnish pregnant women, to relate these to the use of dietary supplements, and to explore possible dietary variations according to age and education. DESIGN: A random dietary survey using two five day estimated food records. SETTING: Pregnant women from 13 maternity clinics in the city of Oulu, Finland. SUBJECTS: One hundred and eighteen pregnant women in their third trimester. MAIN RESULTS: The main sources of energy were cereal products and milk products. The consumption of fish and poultry was low. Women with a higher educational level consumed more vegetables, fruit, fruit juices, and tea and less sausages, inner organs and coffee than women with a lower educational level. Younger women (< 25 y) consumed more sugar and pork and less berries, butter and inner organs than older women. On average 15% of the total energy was supplied by protein, 33% by fats, 52% by carbohydrates, and 12% by sucrose. Compared to the Nordic nutrition recommendations, the proportion of polyunsaturated fatty acids and the intake of dietary fibre were low and the intake of sugar high. The intakes of vitamins and minerals met or exceeded the recommended allowances, except for vitamin D, folate, and iron. Of the subjects 70% used dietary supplements. With the exception of vitamin D, folate, and iron, both the supplement users and non-users had an adequate nutrient intake from their diet. CONCLUSIONS: A balanced diet covers the increased nutrient requirements during pregnancy, with the exception for vitamin D, folate, and iron. The use of dietary supplements during pregnancy is excessive and partly focused on the wrong nutrients. Young and less educated, and smoking pregnant women need more nutritional guidance.

Adult↗
PubMed1998

Autoimmune and clinical characteristics of type I diabetes in children with different genetic risk loads defined by HLA-DQB1 alleles. Childhood Diabetes in Finland Study Group.

1. The impact of different genetic risk loads defined by HLA-DQB1 alleles on the autoimmune and clinical characteristics of 647 children and adolescents with recent-onset Type I diabetes was evaluated in a prospective population-based study. The subjects were divided into four groups based on HLA-DQB1 genotypes: DQB1*0302/0201 (high risk), *0302/x (moderate risk), *0201/y (low risk) and *z/z (decreased risk). 2. Close to two thirds (62.3%) of the subjects possessed a high or moderate risk genotype. A decreased frequency of positivity for islet cell antibodies (ICA) and insulin autoantibodies (IAA) (76.8% compared with 85.3%; P = 0.05, and 30.5% compared with 50.8%, P = 0.0006, respectively) but not of positivity for antibodies to the 65 kDa isoform of glutamate decarboxylase was observed in children with the DQB1*0201/y genotype compared with other children. Among ICA-negative subjects, those with the DQB1*0201/y genotype had higher serum C-peptide levels over the first 2 years after the diagnosis of Type I diabetes than those with other genotypes (P = 0.028). 3. Our data provide some evidence of HLA-DQB1-determined heterogeneity in the autoimmune and clinical characteristics of childhood Type I diabetes at the time of the clinical manifestation. This suggests differences between children with various HLA-DQB1 genotypes in the pace and/or intensity of the beta-cell destructive process leading to clinical Type I diabetes.

Adolescent↗
PubMed1998

Unaltered antioxidant activity of plasma in subjects at increased risk for IDDM.

Evidence suggests that free oxygen radicals are involved in the destruction of islet beta-cells in insulin-dependent diabetes mellitus (IDDM). Therefore, we determined the plasma antioxidant activity in 51 healthy unaffected children and adolescents randomly chosen from a study of beta-cell autoimmunity in schoolchildren in northern Finland. Twenty-two subjects tested positive for one or more IDDM-associated autoantibodies and 9 subjects had at least two of the three antibodies tested (antibodies against islet cells, ICA; glutamic acid decarboxylase, GADA; insulin, IAA). There was no significant association of total plasma antioxidant potential, plasma concentrations of alpha-tocopherol, ascorbic acid, protein thiols, or uric acid with the presence of ICA, GADA, or IAA. A reduced first-phase insulin response to intravenous glucose was also not associated with reduced plasma antioxidant activity. These results indicate that the plasma antioxidant activity is not decreased in subjects at increased risk for IDDM. Furthermore, the results suggest that the clinical onset of IDDM is not preceded by signs of increased systemic oxidative stress in plasma.

Adolescent↗
PubMed1998

Distribution of insulin-dependent diabetes mellitus (IDDM)-related HLA alleles correlates with the difference in IDDM incidence in four populations of the Eastern Baltic region.

The high incidence of insulin-dependent diabetes mellitus (IDDM) in Finland contrasts strikingly with the low rates in the neighbouring populations of countries in the Eastern Baltic region: Estonia, Latvia and Russia. To evaluate the possible contribution of genetic factors to these differences, the frequencies of HLA-DQB1 alleles and relevant DQB1-DQA1 or DQB1-DRB1 haplotypes associated with IDDM risk or protection were analysed among IDDM patients and control subjects from these four populations. An increased frequency of HLA-DQB1*0302, DQB1*02-DQA1*05 and DQB1*0302-DRB1*0401 was observed in subjects with IDDM in all studied populations, whereas the prevalence of DQB1*0301 and DQB1*0602 and/or *0603 was decreased among patients. The degree of IDDM risk associated with HLA alleles analysed here did not differ significantly between the populations. Comparisons of the distribution of IDDM-related HLA alleles and haplotypes in the background populations revealed its consonance with IDDM incidence. The combined frequency of high risk genotypes was significantly higher among Finns than in other populations studied. Our data support the hypothesis that variance in the dispersion of HLA alleles is the genetic basis of variation of IDDM incidence observed in the Eastern Baltic region.

Alleles↗
PubMed1998

Prediction and prevention of type 1 diabetes.

Clinical type 1 diabetes represents end-stage insulitis resulting from progressive beta-cell destruction over an asymptomatic period that may last for years. This knowledge and recent advances in our ability to identify individuals at increased risk for clinical disease have paved the way for trials aimed at preventing or delaying the clinical onset of type 1 diabetes. Individuals at risk for type 1 diabetes can be identified by a positive family history, or by genetic, immunological or metabolic markers. These markers can also be combined to achieve a higher positive predictive value. As long as there is no effective preventive modality available for clinical use, screening for the identification of risk individuals can be considered ethically acceptable only in the context of sound research protocols. Prevention of type 1 diabetes can be implemented at three different levels, out of which primary prevention includes all strategies aimed at decreasing the risk of developing type 1 diabetes in individuals without any signs of beta-cell damage. Secondary prevention aims to reduce the incidence of type 1 diabetes by stopping beta-cell destruction in individuals with signs of such a process, while the objective of tertiary prevention is to restore beta-cell function or prevent complications in patients with overt type 1 diabetes. At present, one primary prevention trial and four comprehensive secondary prevention trials are in progress. Common features of these intervention trials are that the recruitment of patients fulfilling the inclusion criteria is time-consuming and the trials must proceed for a long time, as clinical disease is the end point. The secondary prevention trials also require extensive screening for the identification of eligible patients. The ongoing intervention trials may, however, represent a new era in type 1 diabetes, i.e. the beginning of the end of this complicated disease.

Antibodies↗
PubMed1998

Pituitary function in children with hydrocephalus before and after the first shunting operation.

OBJECTIVE: Children with shunted hydrocephalus experience slow linear growth in prepuberty, accelerated pubertal maturation and a reduced final height. A substantial proportion of these patients have a poor growth hormone (GH) response to stimulation and reduced pituitary volume. The basic mechanisms behind these phenomena are still unknown, but one can hypothesize that an unphysiological intracranial pressure (ICP) may be involved. This study was undertaken to investigate the effect of increased ICP on pituitary function. DESIGN: Twenty-one children (nine males) aged 4 months to 15 years were evaluated for pituitary function before and after their first shunting operation. METHODS: A clinical examination was performed, bone age was determined and a combined pituitary stimulation test was performed to evaluate GH, luteinizing hormone, follicle-stimulating hormone, cortisol, thyrotropin and prolactin secretion. RESULTS: GH concentrations were significantly higher 10 and 15 min before the operation (P=0.04 and P=0.03 respectively) than after it. The basal levels of insulin-like growth factor-I (IGF-I) tended to be higher before the operation than afterwards and those of its binding protein-3 (IGFBP-3) were significantly so (P<0.01). CONCLUSIONS: The higher GH response to GH releasing hormone and circulating IGFBP-3 levels in children with hydrocephalus before compared with after their first shunting operation raise the possibility that the reduced GH secretion and retarded linear growth observed in children with shunted hydrocephalus may be a consequence of decreased ICP and/or the lack of physiological pressure variations.

Adolescent↗
PubMed1998

Islet cell antibodies are less predictive of IDDM among unaffected children in the general population than in sibs of children with diabetes. The Childhood Diabetes in Finland Study Group.

OBJECTIVE: To examine the controversial issue of whether islet cell antibodies (ICAs) have a higher predictive value for progression to clinical IDDM in first-degree relatives of patients with diabetes than in the general population. RESEARCH DESIGN AND METHODS: ICAs were analyzed with standard immunofluorescence in two population-based groups: 765 sibs of children with recent-onset diabetes and 1,212 unaffected Finnish children <20 years of age at initial screening. Those positive for ICAs were additionally tested for antibodies to GAD (GADAs) and the protein tyrosine phosphatase-related IA-2 antigen (IA-2As). Subsequently, these subjects were observed for the manifestation of clinical IDDM over the next 7 years. RESULTS: The frequency of both detectable ICAs and ICA levels > or =20 Juvenile Diabetes Foundation units (JDF U) was significantly higher among the sibs than in the general population (7.8 vs. 4.1% and 4.8 vs. 2.0%, respectively; P < 0.001). The prevalence of GADAs (37/60 vs. 3/48; P < 0.001) and IA-2As (31/60 vs. 0/48; P < 0.001) was increased among ICA-positive sibs compared with ICA-positive individuals from the background population. Over the next 7 years, 24 sibs (3.1%) and 3 unrelated children positive for ICAs (0.3%) progressed to clinical diabetes. The positive predictive value of ICAs was thus 6% in the general population and 40% among the sibs (P < 0.001), or 13 and 59%, respectively (P < 0.001), with an antibody cutoff level of 20 JDF U. The positive predictive value was related to the number of positive autoantibodies in sibs, which was 57% in those with three antibodies, 50% in those with two antibodies, and only 6% in those with ICAs alone. CONCLUSIONS: These data show that the frequency of multiple autoantibodies is substantially lower in ICA-positive children representing the general population than in ICA-positive sibs of children with IDDM. As a consequence, the predictive value of ICAs for IDDM is higher in sibs of affected children than in the general population. This finding must be taken into account when planning intervention trials aimed at preventing or delaying the manifestation of clinical diabetes in individuals from the general population who test positive for ICAs.

Adolescent↗
PubMed1998

Plasma insulin-like growth factor-I and its binding proteins 1 and 3 during continuous nonoral and oral combined hormone replacement therapy.

OBJECTIVE: We determined the effects of continuous combined nonoral and oral estrogen-progestin therapy on plasma levels of insulin-like growth factor-I (IGF-I) and its binding proteins 1 (IGFBP-1) and 3 (IGFBP-3). DESIGN: Forty women complaining of climacteric symptoms were randomized to receive either transdermal estradiol patches (50 microg daily) in combination with an intrauterine system releasing 20 microg of levonorgestrel daily or an established regimen of an oral dose of 2 mg of estradiol and 1 mg of norethisterone acetate daily for 1 year. Fifteen women in the nonoral therapy group and 17 in the oral therapy group completed the 1-year prospective study. RESULTS: Plasma levels of IGF-I decreased significantly in the oral therapy group, but no changes were observed in the plasma levels of its binding proteins. Transdermal estrogen in combination with intrauterine levonorgestrel did not induce any change in plasma IGF-I, whereas the plasma levels of IGFBP-3 decreased. IGFBP-1 concentrations increased, which may be related to the induction of this protein into the endometrium by the intrauterine levonorgestrel delivery. CONCLUSIONS: Both the nonoral and oral continuous combined estrogen-progestin therapies used in this study produced only minor changes in the circulating concentrations of IGF-I and its binding proteins.

Administration, Cutaneous↗
PubMed1997

Interaction of genetic and environmental factors in the pathogenesis of insulin-dependent diabetes mellitus.

The current concept of the pathogenesis of insulin-dependent diabetes mellitus (IDDM) is based on the view that environmental factors, either alone or in combination, trigger in a genetically, susceptible individual an autoimmune process which leads to the destruction of the insulin-secreting beta cells. The identification of environmental risk factors for IDDM is of utmost importance with regard to possibilities for implementing preventive measures. Studies on the interaction between genetic and environmental factors may be complicated by the observations that genetic markers, e.g. HLA risk alleles, may vary from one population to another, and combinations of predisposing genes may differ between populations. In addition, the role of a given environmental trigger in initiating the autoimmune process may be variable in various individuals depending on the genetic set-up and other host-related characteristics. As prevention trials are already being initiated, and genetic screening is essential in the identification of individuals at increased risk of IDDM, it is crucial to learn more about the interaction of genetic and environmental factors in this disease.

Animals↗
PubMed1997

Poor beta-cell function after the clinical manifestation of type 1 diabetes in children initially positive for islet cell specific autoantibodies. The Childhood Diabetes in Finland Study Group.

The prognostic significance of islet cell specific autoantibodies at the diagnosis of Type 1 (insulin-dependent) diabetes mellitus for the persistence of residual beta-cell function over the first 2 years of clinical disease was evaluated in a prospective population-based study. Seven hundred and eighty probands, aged 0.8-14.9 years, were examined for islet cell antibodies (ICA) and insulin autoantibodies (IAA), while 769 probands were studied for antibodies to glutamic acid decarboxylase (GAD65A). They were subsequently observed for 2 years. Lower serum C-peptide concentrations and higher requirement of exogenous insulin during the follow-up period were observed in the group of probands positive for at least one of the antibodies, especially for ICA or IAA. We conclude that the residual beta-cell function after the presentation of Type 1 diabetes is less in children initially positive for islet cell specific autoantibodies than in those testing negative at diagnosis. This might reflect possible heterogeneity in the pathogenesis of childhood diabetes. It also demonstrates that ICA and IAA negativity at the diagnosis of Type 1 diabetes is not associated with a smaller amount of functioning beta-cell mass, but the absence of antibodies probably reflects a slower beta-cell destructive process and a longer duration of preclinical disease.

Adolescent↗
PubMed1997

Steroid 21-hydroxylase autoantibodies in insulin-dependent diabetes mellitus. Childhood Diabetes in Finland (DiMe) Study Group.

We have studied the sera from 304 patients with insulin-dependent diabetes mellitus (IDDM) for steroid 21-hydroxylase (P450c21) autoantibodies by an in vitro translation and immunoprecipitation assay. Autoantibodies to P450c21 were found in 7 patients with IDDM (2.3%). When the IDDM patients with P450c21 antibodies were analyzed for their HLA, 6 of them (86%) belonged to the HLA DQB1*0201-positive group. A strong correlation (r = 0.91, P < 0.001) of immunoprecipitation results was observed with adrenocortical autoantibodies detected by indirect immunofluorescence, indicating that the adrenal autoantibodies in patients with IDDM were anti-P450c21 autoantibodies. The levels of P450c21 autoantibodies were significantly higher (P < 0.05) in patients with IDDM than in 13 (9 P450c21 autoantibody positive) patients with Addison's disease. Although the occurrence of P450c21 antibodies in IDDM was relatively low, antibody-positive patients had high antibody levels and may have an ongoing subclinical process of adrenal autoimmunity.

Addison Disease↗
PubMed1997

Pituitary size and function in children and adolescents with shunted hydrocephalus.

OBJECTIVE: Most previous reports of endocrine disorders in children with shunted hydrocephalus have been case reports and there is a lack of systematic information on pituitary anatomy and function among these children. We have obtained these data in a large group of individuals with shunted hydrocephalus. DESIGN: A controlled cross-sectional study. PATIENTS: Fifty-four children and adolescents with shunted hydrocephalus were studied for pituitary anatomy and function. They had 54 age- and sex-matched controls (group I). The mean age of the patients and controls was 12.6 years and the mean shunting period 10.6 years. There was a second control group (II) for the magnetic resonance imaging (MRI) and a third control group (III) for the radiography of the sella turcica. MEASUREMENTS: The anatomy was visualized by MRI of the pituitary gland and by radiography of the sella turcica. The functional evaluation included an arginine-insulin test and a combined stimulation test with corticotrophin releasing factor (CRF), GnRH and TRH. RESULTS: The patients were shorter (height 148.4 cm vs 153.7 cm, P < 0.05 and relative height -0.5 SDS vs 0.4 SDS, P < 0.05) and had a higher BMI than the control group I (20.6 kg/m2 vs 18.0 kg/m2, P < 0.001). They had also a greater pituitary height than the control group II (5.8 mm vs 5.1 mm, P < 0.01). The patients had significantly lower basal GH levels (P < 0.001) than controls I. Sixteen patients (30%) had a poor GH response (< 20 mU/l) in the arginine-insulin test. Pituitary height was significantly lower among these patients than in those with a normal response (4.7 mm vs 6.3 mm, P < 0.01), who had an increased pituitary height compared to controls II (5.1 mm, P < 0.01). The area under the curve (AUC) for GH correlated with the pituitary volume (r = 0.50, P < 0.001). The patients had higher basal FSH and LH concentrations than controls I (P < 0.001). The peak to basal ratios of FSH and LH were increased in the prepubertal patients and that of LH at Tanner pubertal stage II in the females. The basal FSH and LH levels correlated with the pituitary volume (r = 0.50 and r = 0.54, P < 0.001 for), as did FSH AUC and LH AUC (r = 0.48 and r = 0.75, P < 0.001 for both). CONCLUSIONS: These observations indicate that children with shunted hydrocephalus have an increased pituitary size on average. About one-third of these patients had signs of reduced GH secretion and significantly lower pituitary height, which probably contributes to their poor linear growth. Increased pituitary size was associated with enhanced gonadotrophin secretion, which may result in early puberty in children with shunted hydrocephalus.

Adolescent↗
PubMed1997

Analysis of an interferon-gamma gene (IFNG) polymorphism in Danish and Finnish insulin-dependent diabetes mellitus (IDDM) patients and control subjects. Danish Study Group of Diabetes in Childhood.

A CA-repeat polymorphism within the first intron of the interferon (IFN)-gamma gene was analyzed. This polymorphism was recently demonstrated to be associated with insulin-dependent diabetes mellitus (IDDM) in Japanese subjects. We typed 266 IDDM patients and 195 control subjects of Danish Caucasoid origin. No significant differences in allele or genotype frequencies between patients and control were observed. In addition, we typed 168 IDDM and 110 control subjects of Finnish origin. A significant disease association of the studied IFN-gamma allelic pattern was found (p = 0.029). Analysis of data according to HLA-DQB1 susceptibility status did not reveal heterogeneity of risk at the IFN-gamma locus in either of the populations. Fifty-five Danish and 94 Finnish IDDM multiplex families with at least two affected siblings (660 individuals) were typed to test for transmission disequilibrium (TDT). No evidence for overall transmission disequilibrium using either an allele-wise (p = 0.42; combined data) or a genotype-wise analysis (p = 0.21; combined data) could be detected. Thus, the modest significance level observed in the Finnish case-control study and the failure to replicate it by the TDT provide little support for the hypothesis that the IFN-gamma gene microsatellite is associated with IDDM.

Adolescent↗
PubMed1997

Insulin-like growth factors and their binding proteins in the venous effluents of ovary and adrenal gland in severely hyperandrogenic women.

Insulin and insulin-like growth factors (IGF) are thought to play an important role in the pathogenesis of excessive androgen production. To explore this question further we measured the concentrations of IGF-I and -II and their binding proteins (IGFBP-1 and-3) in adrenal and ovarian vein samples of severely hyperandrogenic women (serum testosterone > 5 nmol/l) collected as part of their diagnostic work-up. The concentration of IGF-II was slightly but not significantly higher in the ovarian vein than in the adrenal and peripheral veins. The concentrations of IGF-I and IGFBP were identical in both the adrenal and ovarian veins and did not differ from those in the peripheral circulation. The concentration of IGFBP-1 was negatively correlated (r = -0.60, P > 0.05) with insulin and IGFBP-3 showed a strong positive correlation with IGF-1 (r = 0.90, P > 0.01). These results indicate that neither the ovary nor the adrenal gland contributes significantly to the circulating pool of IGF or their binding proteins in severely hyperandrogenic subjects. Hyperinsulinaemia is associated with low circulating IGFBP-1 concentrations and IGFBP-3 seems to be an excellent indicator of the peripheral IGF-I concentration. The concentrations of IGF-I suggested decreased somatotrophic activity in these obese, hyperinsulinaemic subjects.

Adrenal Glands↗