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Biomedical subjects

M Knip

Publications and source records attributed to M Knip.

At least 181 records · Page 10Linked to original sources
PubMed1995

Insulin-like growth factor binding proteins in prepubertal children with insulin-dependent diabetes mellitus.

To study the possible role of insulin-like growth factor binding proteins (IGFBPs) in the discrepancy between normal or only slightly retarded growth and substantially reduced concentrations of insulin-like growth factor I (IGF-I) in prepubertal children with insulin-dependent diabetes mellitus (IDDM), we measured the plasma concentrations of IGF-I, IGFBP-1, IGFBP-2 and IGFBP-3 and free insulin in 24 prepubertal diabetic subjects and 12 control children. In addition, the growth hormone response to exercise was evaluated. The diabetic children had significantly decreased peripheral IGF-I levels (8.2 + 1.1 (SEM) vs 16.7 + 2.5 nmol/l; p < 0.001), whereas the concentrations of free insulin were increased (217 + 14 vs 103 + 21 pmol/l; p < 0.001). The concentrations of IGFBP-1 and IGFBP-3 were of the same magnitude in both groups. The diabetic children had significantly increased levels of IGFBP-2 (465 + 13 vs 416 + 14 micrograms/l; p = 0.029), which were inversely related to the circulating IGF-I levels (r = -0.35; p = 0.034). The diabetic and control children had comparable growth hormone responses to exercise. Diabetic children with poor glucose control had even lower IGF-I levels than those with moderate metabolic control (6.0 + 0.8 vs 10.3 + 1.7 nmol/l; p = 0.037). No differences could be observed in the plasma concentrations of various IGFBPs between these two groups of diabetic subjects. The absence in prepubertal diabetic children of increased IGFBP-1 levels observed in adolescent and adult patients with IDDM may contribute to their maintained linear growth, despite definitely decreased IGF-I concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Body Height↗
PubMed1995

Insulin gene region-encoded susceptibility to IDDM maps upstream of the insulin gene.

The gene region on chromosome 11p15.5 known to be involved in insulin-dependent diabetes mellitus (IDDM) susceptibility was recently mapped to a 4.1-kilobase region including the insulin gene. The region contains 10 candidate polymorphisms that are in strong linkage disequilibrium. By genotyping 7 of these 10 polymorphisms and the tyrosine hydroxylase microsatellite in Finnish Caucasoid IDDM patients and control subjects, we demonstrate that many of the polymorphisms found to be associated with IDDM in other Caucasoid populations do not show any association in this Finnish population. Of the polymorphisms typed, only those at -23 Hph I and the variable number of tandem repeats (VNTR) sites confer significant relative risk. Furthermore, we have demonstrated that the -23 Hph I polymorphism cannot explain the association. Comparison of the genotypic patterns observed here and previously suggests that the VNTR is the most likely candidate for IDDM2. The VNTR is located adjacent to defined regulatory DNA sequences affecting insulin gene expression, which suggests a possible effect on expression of insulin or one of the neighboring genes, tyrosine hydroxylase or insulin-like growth factor 2.

Chromosome Mapping↗
PubMed1995

A prospective study of the role of coxsackie B and other enterovirus infections in the pathogenesis of IDDM. Childhood Diabetes in Finland (DiMe) Study Group.

Coxsackievirus B infections have been associated with clinical manifestation of insulin-dependent diabetes mellitus (IDDM) in several studies, but their initiating role in the slowly progressing beta-cell damage is not known. This is the first prospective study designed to assess the role of coxsackie B and other enterovirus infections in the induction and acceleration of this process. Three separate series were studied: 1) an intrauterine exposure series comprising 96 pregnant mothers whose children subsequently manifested IDDM and 96 control mothers whose children remained nondiabetic; 2) a cohort of 22 initially unaffected siblings of diabetic children who were followed until they developed clinical IDDM (mean observation time, 29 months) and 110 control siblings who remained nondiabetic; 3) a case-control series comprising 90 children with newly diagnosed IDDM and 90 control subjects. Enterovirus infections were identified on the basis of significant increases in serum IgG, IgM, or IgA class antibodies against a panel of enterovirus antigens (capture radioimmunoassay). Enterovirus antibodies were significantly elevated in pregnant mothers whose children subsequently manifested IDDM, particularly in cases in which IDDM appeared at a very young age, before the age of 3 years (P < 0.005). Serologically verified enterovirus infections were almost two times more frequent in siblings who developed clinical IDDM than in siblings who remained nondiabetic (mean, 1.0 vs. 0.6 infections/follow-up year; P < 0.001). This difference was seen both close to the diagnosis of IDDM and several years before diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1995

Human leukocyte antigen identity and DQ risk alleles in autoantibody-positive siblings of children with IDDM are associated with reduced early insulin response. Childhood Diabetes in Finland (DiMe) Study Group.

To investigate the relationship between human leukocyte antigen (HLA)-associated genetic factors and the development of beta-cell dysfunction, we performed sequential intravenous glucose tolerance tests (IVGTTs) on 81 islet cell antibody (ICA)-positive and/or insulin autoantibody-positive healthy siblings of children with newly diagnosed insulin-dependent diabetes mellitus (IDDM). A lower glucose disappearance rate (Kg) (P < 0.5) and decreased first-phase insulin response (FPIR) (P < 0.05) were observed on multiple occasions in HLA-identical siblings compared with the haploidentical or nonidentical ones. Siblings carrying the DQB1*0302/0201, -0302/x, or -0201/x genotype also had lower FPIRs (P < or = 0.05) at several time points than those with no DQB1 risk genotype. When all IVGTTs were taken into account, DQB1*0302/0201 heterozygous siblings had an abnormally low FPIR (< 45 mU/l; 3rd percentile) in at least one test more often than did siblings with no DQB1 risk genotype (50.0% vs. 6.1%; P = 0.001). Siblings carrying either the DQB1*0602 or the DQB1*0603 protective allele had lower serum peak ICA and glutamic acid decarboxylase (GAD)65 antibody levels (P = 0.023 and 0.007, respectively) and higher FPIRs on several occasions (P < 0.05) than those with the DQB1 risk genotypes. Progression to IDDM was related to both HLA identity and the presence of the DQB1*0302/0201 genotype. Normal Kg and FPIR levels were observed in siblings who were positive for only insulin autoantibody, and none of them developed IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Slow prepubertal linear growth but early pubertal growth spurt in patients with shunted hydrocephalus.

OBJECTIVE: To evaluate growth and to compare anthropometric measures and the degree of physical maturation in children with shunted hydrocephalus with those in healthy children. METHODS: One hundred fourteen patients (62 male) and 73 healthy subjects (38 male) 5 to 20 years of age were analyzed for growth data and current auxology, stage of puberty, and bone age. RESULTS: Boys with hydrocephalus were shorter than control boys during their first 8 years of age, and no catch-up growth was observed until puberty. Girls with hydrocephalus were of the same size at birth as the control girls, but their linear growth retarded during the first years of life, leading to reduced relative height between the age of 5 to 8 years. The pubertal growth spurt occurred earlier in boys with hydrocephalus (age at midgrowth spurt, 12.1 vs 13.3 years), and a similar trend was seen in girls (10.0 vs 10.7 years). The final height was again reduced, especially in boys. Patients with hydrocephalus were more obese than control subjects, girls more often than boys. Relative bone age was retarded in prepubertal (-0.42 vs 0.32 SD) and accelerated in pubertal patients (0.54 vs -0.19 SD). CONCLUSIONS: Children with hydrocephalus experience slow linear growth in prepuberty, but they have an earlier adolescent growth spurt. Together these factors result in a reduced final height. An increase in relative weight emerges in the preadolescent period, and this phenomenon is accentuated after puberty, leading to an increased prevalence of obesity.

Adolescent↗
PubMed1994

Plasma insulin-like growth factor I and its binding proteins 1 and 3 in postmenopausal patients with breast cancer receiving long term tamoxifen.

BACKGROUND: Insulin-like growth factor I (IGF-I) is a potent mitogen for breast cancer cells. The majority of IGF-I in plasma is bound to IGF binding proteins (IGFBPs), which modulate the biologic effects of IGF-I. METHODS: Plasma concentrations of IGF-I, IGFBP-I, and IGFBP-3 were compared between 40 postmenopausal breast cancer patients receiving long term tamoxifen therapy and 39 breast cancer patients receiving no hormonal treatment. In an additional group of seven patients, serum levels of IGF-I and IGFBP-1 were determined before and during treatment at 6 and 12 months. RESULTS: The tamoxifen and the control groups did not differ with respect to age, parity, age at menopause, or body mass index. There were no significant differences in the mean concentrations (+/- standard error of the mean) of IGF-I (10.0 +/- 0.4 nmol/l and 11.2 +/- 0.5 nmol/l, respectively) and IGFBP-3 (3.2 +/- 0.1 mg/l and 3.1 +/- 0.1 mg/l, respectively), whereas the mean value of IGFBP-1 was significantly higher in the tamoxifen group (6.0 +/- 0.6 micrograms/l versus 2.8 +/- 0.3 micrograms/L, P = 0.0001). No significant differences were found in the insulin levels. During the treatment, concentrations of IGF-I decreased at 6 months and began increasing at 12 months. IGFBP-1 levels increased at 6 months and remained elevated at 12 months. CONCLUSIONS: The tamoxifen-induced increase in IGFBP-1 plasma levels may be an important mechanism modulating IGF-I action at the tissue level.

Age Factors↗
PubMed1994

HLA-DQB1 genotypes and islet cell antibodies in the identification of siblings at risk for insulin-dependent diabetes (IDDM) in Finland. Childhood Diabetes in Finland (DiMe) Study Group.

The risk of progression to IDDM can be evaluated by diabetes-related autoantibodies such as cytoplasmic islet cell antibodies (ICA) or genetic determinants as markers. In this prospective study we wanted to estimate the predictive value of the combination of these markers in siblings of diabetic children. A sample of 770 siblings was observed from the time of diagnosis in the index case for a median period of 5.8 years (range 0.01-7.3 years) for development of ICA and insulin autoantibodies (IAA) and progression to clinical diabetes. The most important susceptibility and protection associated DQB1 alleles were defined by four sequence-specific oligonucleotide probes. DNA samples were available from 89 originally non-diabetic ICA positive siblings of whom 28 presented with IDDM during the study period, as well 100 randomly chosen ICA negative control siblings. More than half (11/28; 55%) of the siblings who had the high risk DQB1 genotypes progressed to clinical IDDM compared to 6/37 (16%) of those who had protective/neutral genotypes (P = 0.006). Of all genotyped secondary cases, 36% (n = 33) had a genotype associated with the highest risk (DQB1*0302/0201), whereas 27% had genotypes without any susceptibility alleles (P values < 0.0001 and = 0.0002, respectively, compared with ICA negative siblings). The results demonstrate the feasibility of the combination of genetic and immunological markers in the prediction of the risk for IDDM within families.

Adolescent↗
PubMed1994

Diet, cow's milk protein antibodies and the risk of IDDM in Finnish children. Childhood Diabetes in Finland Study Group.

Associations of infant feeding patterns and milk consumption with cow's milk protein antibody titres were studied in 697 newly-diagnosed diabetic children, 415 sibling-control children and 86 birth-date- and sex-matched population-based control children in the nationwide "Childhood Diabetes in Finland" study. IgA and IgG antibody titres to the proteins of cow's milk formula, BLG and BSA, and IgM antibody titres to cow's milk formula proteins were measured by ELISA. Several inverse correlations were observed between the duration of breast-feeding or age at introduction of dairy products and antibody titres, and positive correlations were observed between milk consumption and antibody titres in all three populations studied. Multivariate analyses which included the infant feeding variables, milk consumption and current age simultaneously showed that the earlier the introduction of dairy products and the greater the consumption of milk was, the higher several antibody titres were. High IgA antibody titres to cow's milk formula were associated with a greater risk of IDDM both among diabetic-population-control and diabetic-sibling-control pairs when adjusted for other cow's milk antibody titres, dietary variables and in diabetic-sibling-control pairs also for ICA. The results suggest that young age at introduction of dairy products and high milk consumption during childhood increase the levels of cow's milk antibodies and that high IgA antibodies to cow's milk formula are independently associated with increased risk of IDDM.

Adolescent↗
PubMed1994

Natural history of preclinical IDDM in high risk siblings. Childhood Diabetes in Finland Study Group.

To learn more about the preclinical phase of IDDM we observed for a median period of 46.5 months (range 0.5-69 months) a group of 57 siblings positive for ICA and/or IAA when first screened within 6 months of the diagnosis of the proband. Sequential blood samples and IVGTTs were obtained at intervals of 6-12 months. Seventeen siblings (29.8%) presented with IDDM during the observation period. The duration of the known preclinical period ranged from 0.5 to 51 months (median 29 months). The converters were younger than the other siblings (P < 0.05) and had higher initial ICA levels (P < 0.01). In addition they had a lower FPIR in the first IVGTT (P < 0.001). On all subsequent tests the converters had higher ICA levels and a lower FPIR (P < 0.05 or less), a lower glucose elimination rate from the third test onwards (P < 0.01 or less) and higher IAA levels at 3 years (P < 0.05). Some variation could be observed in the FPIR in the converters with an initial increase and subsequent decrease (P < 0.05 for both). Their levels of complement-fixing ICA increased up to 18 months (P < 0.05) and IAA levels up to 3 years (P < 0.01). Those high risk siblings who progress to clinical IDDM are characterized by young age, strong and increasing signs of islet-cell specific autoimmunity, reduced insulin secreting capacity and emerging glucose intolerance. The present observations seem to be incompatible with the hypothesis of beta-cell destruction occurring at a constant, predictable rate.

Adolescent↗
PubMed1994

Multi-locus analysis of HLA class II genes in DR2-positive IDDM haplotypes in Finland. The "Childhood Diabetes in Finland" (DiMe) Study Group.

In this study we characterized the haplotypes found in IDDM patients that normally confer resistance to the disease in order to localize the polymorphisms relevant for the protection. We studied 15 DR2-positive subjects with IDDM for their DRB1, DRB5 and DQB1 genes using RFLP, polymerase chain reaction (PCR), oligonucleotide typing, and in some specific cases direct sequencing after allele-specific PCR. In addition we analyzed 39 DR2-positive, IDDM non-associated haplotypes representing those haplotypes that are not inherited to probands and hence are present only in healthy family members. The frequency of the DRB1*1501-DRB5*0101-DQB1*0602 haplotype was slightly decreased among diabetic patients (80% vs. 92%). In addition, two unconventional haplotypes DRB1*1501-DRB5*0101-DQB1*05031 and DRB1*1501-DRB5*0101-DQB1*0502 were found in patients with IDDM while all the control ones were conventional. The sequencing of the DQB1*0602 allele present in IDDM haplotypes showed no differences when compared to the controls. These results support the primary but not absolute role of DQ in the protection against IDDM. An additional role of factors centromeric to DQB1 gene was suggested by findings based on the bi-allelic TaqI RFLP polymorphism of the DQA2 gene. All DR2-DQB1*0602 IDDM haplotypes were associated with the 2.1-kb fragment while in the control group the 2.1-kb and 1.9-kb fragments were evenly distributed.

Alleles↗
PubMed1994

Information value of magnetic resonance imaging in shunted hydrocephalus.

OBJECTIVE: To study the role of magnetic resonance imaging (MRI) in evaluating children with shunted hydrocephalus. METHODS: Sixty one asymptomatic children with shunted hydrocephalus or cystic cerebrospinal fluid collections were studied by cranial MRI. The information obtained from the images was classified into three categories: provided (1) a new diagnosis, (2) additional information, or (3) no essential new information. The findings were compared with those of the last follow up computed tomograms. RESULTS: MRI provided a new diagnosis in seven cases (11.5%), and additional information was obtained in 34 (55.7%) cases. In 20 cases (32.8%) no essential new information was obtained. MRI visualised white matter lesions and corpus callosum pathology more often than computed tomograms. CONCLUSIONS: MRI provided new important information in cases of children with shunted hydrocephalus to such an extent that it can be recommended as the primary imaging method for every child with this disorder.

Adolescent↗
PubMed1994

Pituitary size assessed with magnetic resonance imaging as a measure of growth hormone secretion in long term survivors of childhood cancer.

We investigated 37 long term survivors of childhood cancer to study the relationship among growth, GH secretion, and pituitary size. The median follow-up time after diagnosis was 13.2 yr. The pituitary gland was visualized with magnetic resonance imaging. Radiated patients (n = 25) had a reduced relative height and showed a greater reduction in relative height after diagnosis than nonradiated patients (n = 12). The patients had lower spontaneous nocturnal GH secretion than controls due to a reduced peak amplitude. Spontaneous GH secretion was lower in radiated patients than in nonradiated subjects. The patients had lower plasma insulin-like growth factor-I (IGF-I) and serum IGF-binding protein-3 (IGFBP-3) concentrations than the controls. Radiated subjects had decreased IGF-I and IGFBP-3 concentrations compared to nonradiated subjects. Half of the patients (20 of 37) evaluated with magnetic resonance imaging had a reduced pituitary size (pituitary height, < -2 SD score). Radiated subjects had smaller pituitary glands than nonradiated ones. Seventeen of 20 patients (85%) with reduced pituitary size had decreased nocturnal GH release. There was a positive correlation between nocturnal GH secretion, plasma IGF-I, and serum IGFBP-3 levels, on the one hand, and pituitary height, on the other. These results indicate that cranial radiation may result in tissue damage, leading to decreased pituitary size, reduced spontaneous GH secretion, and impaired linear growth. The finding of reduced IGF-I levels in both radiated and nonradiated patients combined with decreased IGFBP-3 concentrations in radiated patients, indicates that cytotoxic chemotherapy may induce hepatic damage resulting in decreased IGF-I synthesis.

Adolescent↗
PubMed1994

Disproportionately elevated proinsulin levels precede the onset of insulin-dependent diabetes mellitus in siblings with low first phase insulin responses. The Childhood Diabetes in Finland Study Group.

The objective of this study was to test whether levels of proinsulin immunoreactivity (PIM) relative to those of insulin immunoreactivity (IRI) or C-peptide are changed and related to subclinical beta-cell dysfunction in siblings of insulin-dependent diabetes mellitus (IDDM) patients. Twenty-three siblings, previously found positive for islet cell antibodies and/or insulin autoantibodies, were divided into 2 groups according to their first phase insulin response (FPIR) to i.v. glucose tolerance tests (IVGTTs) sequentially performed during an observation period of 2 yr. Eleven siblings had diminished FPIR on at least 1 occasion (group 1), whereas 12 siblings had a normal FPIR on all occasions studied (group 2). All underwent a further IVGTT (0.5 g glucose/kg BW), and serum samples were taken at 0, 1, 3, 6, 10, 20, 30, 40, 50, and 60 min. The 2 groups had comparable median age, female/male ratio, weight, height, fasting blood glucose, immunoreactive insulin, C-peptide, and insulin autoantibodies levels, but group 1 had significantly higher islet cell antibodies levels. Fasting median PIM/IRI and PIM/C-peptide ratios were 2- to 3-fold higher in group 1 [10.5% (range, 1.8-93.8%) vs. 5.2% (range, 1.9-14.3%) and 3.3% (range, 0.4-23.1%) vs. 1.3% (range, 0.7-2.6%; P < 0.05]. Fasting PIM/C-peptide ratios correlated inversely with FPIRs (rs = -0.68; P < 0.01). During glucose stimulation, maximal responses of IRI and C-peptide were 4-fold lower in group 1, and the time of maximal responses of IRI and C-peptide occurred later in group 1 than in group 2. In contrast, no difference in maximal responses of PIM was found, but the time of maximal responses of PIM occurred later in group 1. Nine of 11 siblings in group 1 presented with IDDM 1-28 months after the test, compared to none in group 2. In group 1 a paradoxical inhibitory response of PIM was observed during the first 6 min of the IVGTT. These data indicate that fasting PIM/IRI and/or PIM/C-peptide ratio reflects subclinical beta-cell dysfunction in prediabetic subjects with evidence of immunological beta-cell assault and suggests that an elevated ratio may be an additional marker for later development of IDDM.

Adolescent↗