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M Knip

Publications and source records attributed to M Knip.

At least 37 records · Page 2Linked to original sources
PubMed2004

The human leukocyte antigen genotype has a modest effect on the insulin gene polymorphism-associated susceptibility to type 1 diabetes in the Finnish population.

In addition to the known human leukocyte antigen (HLA)-associated risk, polymorphisms of insulin gene region show association with type 1 diabetes. We analyzed possible interactions between the HLA class II genotypes and -2221 MspI (insulin) INS gene polymorphism in Finnish population, using a series of 1331 diabetic children and 2222 healthy newborns. C/C genotype was increased among diabetic children compared to the controls (83.2 vs 70.1%). This genotype was slightly more common in diabetic children with low or moderate HLA-associated risk than in those with high risk, but INS gene effect was clear in all major HLA-risk genotypes and, thus, can be used as an additional risk prediction marker, irrespective of HLA genotypes.

Child↗
PubMed2004

Isolation of enterovirus strains from children with preclinical Type 1 diabetes.

AIMS: To develop methods for isolation of enterovirus strains from subjects with preclinical Type 1 diabetes and evaluate if their presence in stools is associated with beta-cell damage. METHODS: The study subjects were participants of the Finnish Type 1 Diabetes Prediction and Prevention Study (DIPP). The prospectively followed birth cohort comprised 12 children who turned positive for diabetes-associated autoantibodies during the follow-up (case children) and 53 controls matched for date of birth, sex and HLA-DQB1 alleles. Altogether, 878 stool samples were analysed for the presence of enterovirus RNA by RT-PCR followed by virus isolation and partial sequencing of viral genome. Enterovirus antibodies and RNA were simultaneously analysed from serum. RESULTS: Eleven enterovirus infections were diagnosed in case children and 42 infections in control children by the presence of viral RNA in stools. The proportion of children who were repeatedly enterovirus RNA-positive stools was higher among case than control children (42% vs. 11% of children; P=0.02). Combined serum (antibody and RT-PCR) and stool analyses indicated at least one enterovirus infection in 83% of the case children before the appearance of autoantibodies, while only 42% of the control children had infection by the same age (P=0.006). Twelve enterovirus strains were isolated from case children and 38 strains from control children. CONCLUSIONS: This protocol makes it possible to isolate a large number of enterovirus strains from prediabetic subjects. The findings suggest that enterovirus infections may be associated with the beta-cell damaging process.

Autoantibodies↗
PubMed2003

The HLA-DR phenotype modulates the humoral immune response to enterovirus antigens.

AIMS/HYPOTHESIS: Enterovirus infections are among the environmental risk factors potentially contributing to the pathogenesis of Type 1 diabetes. The aim of this study was to evaluate virus-host interaction by analysing the enterovirus antibody levels in subjects carrying different HLA-DR alleles associated with either increased or decreased risk of Type 1 diabetes. METHODS: Antibodies against coxsackievirus B4 were measured to study immune responses induced by natural enterovirus infections and against poliovirus 1 to study immune responses induced by immunisation by enterovirus antigens (vaccine). Antibodies against the mumps virus were measured as a control. Study subjects included siblings of children with Type 1 diabetes taking part in the Childhood Diabetes in Finland (DiMe) Study and carrying either HLA-DR risk (DR3 and/or DR4) or protective (DR2) alleles. RESULTS: Children with either the HLA-DR3 or HLA-DR4 allele and those with both these risk alleles had higher Coxsackie B4 antibody levels than children carrying the HLA-DR2 allele ( p=0.01, p=0.01 and p=0.008, respectively). High responders (IgG levels higher than 75 percent) were also more frequent among genetically susceptible children compared to children with the protective DR2 allele (27% vs 12%) ( p<0.009). The same trend was seen for poliovirus antibodies, while mumps antibody levels had a different pattern (high responders more common among DR2-positive subjects). CONCLUSIONS/INTERPRETATION: Diabetes-associated HLA-DR risk alleles were associated with a strong immune responsiveness and protective alleles with a weak responsiveness against enterovirus antigens. This phenomenon should be taken into consideration in serological case-control studies and it might play a role in virus-induced beta-cell damage.

Antibody Formation↗
PubMed2003

Soluble adhesion molecules in pre-clinical Type 1 diabetes: a prospective study.

AIMS: This prospective case-control study aimed at evaluating the time course of serum concentrations of soluble adhesion molecules; intercellular adhesion molecule-1 and L-selectin in siblings with signs of pre-clinical Type 1 diabetes in order to relate these concentrations to autoantibody status and to assess whether these markers could discriminate between those siblings who progressed to clinical diabetes and those who remained non-diabetic. METHODS: Serum levels of soluble adhesion molecules were measured with enzyme-linked immunosorbent assays in autoantibody-positive initially healthy siblings of diabetic children who progressed to clinical disease during the observation period of 10 years and in sex- and age-matched autoantibody-positive siblings who have remained unaffected. RESULTS: The intraindividual and interindividual variability in the concentrations of soluble adhesion molecules was conspicuous both among the progressors and non-progressors. Integrated concentrations (area-under-the curve) of intercellular adhesion molecule-1 over a period of 6 to 48 months before the diagnosis was higher in the progressors ( p=0.035), the difference being most evident 18 to 24 months before diagnosis ( p=0.015). The integrated concentrations of soluble L-selectin were similar in progressors and non-progressors over the total pre-clinical period. There were no differences in the integrated concentrations of soluble adhesion molecules in relation to the initial or maximal number of autoantibodies detected during the follow-up. CONCLUSION/INTERPRETATION: These observations suggest that the process of destructive insulitis could be initiated approximately 4 years before the manifestation of clinical diabetes, being most active about 1.5 years before diagnosis. Peripheral concentrations of soluble intercellular adhesion molecule-1 or L-selectin are not helpful in the identification of those prediabetic subjects who will progress to clinical disease over the next 10 years, since there is substantial overlapping in these concentrations between progressors and non-progressors.

Adolescent↗
PubMed2003

Temporal changes in the frequencies of HLA genotypes in patients with Type 1 diabetes--indication of an increased environmental pressure?

AIMS/HYPOTHESIS: The incidence of Type 1 diabetes has increased 2.5 times during the time period from 1966 to 2000 in Finland-a general trend seen in almost all developed countries that can only be explained by environmental factors. The aim of this study was to test the possible effect of a changing environment on distribution of genotypes associated with disease susceptibility. METHODS: HLA DRB1-DQA1-DQB1 genes and two diabetes-associated polymorphisms at IDDM2 and IDDM12 were analyzed. The frequencies of genotypes were compared between cases diagnosed with childhood-onset Type 1 diabetes during the period of 1939-1965 (n=367) and those diagnosed between 1990 and 2001 (n=736). Chi-square statistics or the Fisher's Exact test were used for the comparison of frequencies of analyzed haplotypes and genotypes in the two groups. RESULTS: The frequencies of (DR3) -DQA1*05-DQB1*02 and (DR4) -DQB1*0302 risk haplotypes and the high risk (DR3) -DQA1*05-DQB1*02/DRB1*0401-DQB1*0302 genotype were higher while proportion of patients carrying protective haplotypes-(DR15) -DQB1*0602 and (DR1301) -DQB1*0603-or protective genotypes was lower in patients diagnosed before 1965 as compared to those who developed disease after 1990. No temporal variation was found in the frequencies of genotypes at IDDM2 and IDDM12. CONCLUSION/INTERPRETATION: Our data suggest that the need for genetic susceptibility to develop Type 1 diabetes has decreased over time due to an increasing environmental pressure and this results in a higher disease progression rate especially in subjects with protective HLA genotypes.

Child↗
PubMed2003

Fasting serum insulin and lipid levels in men with epilepsy.

BACKGROUND: Previous studies suggest that obese women taking valproate (VPA) for epilepsy are insulin resistant. OBJECTIVE: To assess the effects of antiepileptic drugs on serum insulin and lipid levels in men with epilepsy. METHODS: Body mass index (BMI) and fasting serum concentrations of insulin and lipids were measured in 102 men with epilepsy who were treated with VPA, carbamazepine (CBZ), or oxcarbazepine (OXC) monotherapy. Thirty-two healthy men served as control subjects. RESULTS: Obesity was not more common among VPA-treated men than among other men with epilepsy or the control subjects. However, the obese VPA-treated men had higher serum insulin levels (p < 0.001) than the obese control subjects despite similar BMI. CBZ and OXC did not have any significant effect on any of the measurements. Fasting serum insulin concentrations above the normal range were observed in seven obese VPA-treated patients (35%) but in only one obese control subject (5%). Five obese VPA-treated patients (25%) and one obese control subject (5%) had serum triglyceride levels above the normal range, and a low high-density lipoprotein/total cholesterol ratio was observed in two obese VPA-treated patients (10%). CONCLUSIONS: Obese valproate-treated men have high serum insulin levels, indicating insulin resistance. Moreover, some of the valproate-treated men cluster cardiovascular risk factors such as obesity, hyperinsulinemia, and elevated serum triglyceride concentrations. CBZ and OXC do not seem to have any significant effects on serum insulin or lipid levels in men with epilepsy.

Adolescent↗
PubMed2003

HLA DR-DQ-encoded genetic determinants of childhood-onset type 1 diabetes in Finland: an analysis of 622 nuclear families.

The diabetes predisposing effect of HLA genes is defined by a complex interaction of various haplotypes. We analyzed the disease association of HLA DRB1-DQA1-DQB1 genotypes in a large nuclear family cohort (n = 622) collected in Finland. Using the affected family based artificial control approach we aimed at characterizing all detectable disease-specific HLA haplotype and genotype effects. The DRB1*0401-DQB1*0302 haplotype was the most prevalent disease susceptibility haplotype in the Finnish population followed by (DR3)-DQA1*05-DQB1*02 and DRB1*0404-DQB1*0302. DRB1*0405-DQB1*0302 conferred the highest disease risk, although this haplotype was very rare. The DRB1*04-DQB1*0304 was also associated with increased disease risk, an effect detected for the first time in the Finnish population. The following haplotypes showed significant protection from the disease and are listed in decreasing order of the strength of their effect: (DR7)-DQA1*0201-DQB1*0303, (DR14)-DQB1*0503, (DR15)-DQB1*0602, DRB1*0403-DQB1*0302, (DR13)-DQB1*0603, (DR11/12/13)-DQA1*05-DQB1*0301, (DR1)-DQB1*0501. In addition to the DRB1*0401/0404-DQB1*0302/(DR3)-DQA1*05-DQB1*02 genotype and DRB1*04-DQB1*0302 homozygous genotypes, heterozygous combinations DRB1*0401-DQB1*0302/(DR13)-DQB1*0604, approximately /(DR8)-DQB1*04, approximately /(DR9)-DQA1*03-DQB1*0303, approximately /(DR1)-DQB1*0501 and approximately /(DR7)-DQA1*0201-DQB1*02 were also disease-associated. As a new finding in this population, the (DR3)-DQA1*05-DQB1*02 homozygous and (DR3)-DQA1*05-DQB1*02/(DR9)-DQA1*03-DQB1*0303 heterozygous genotypes conferred disease susceptibility. Similarly, the DRB1*0401-DQB1*0302/(DR13)-DQB1*0603 genotype was disease predisposing, implying that DQB*0603-mediated protection from diabetes is not always dominant. Comparison of our findings with published data from other populations indicates a significant disease-specific heterogeneity of the (DR8)-DQB1*04, (DR7)-DQA1*0201-DQB1*02 and (DR3)-DQA1*05-DQB1*02 haplotypes.

Adult↗
PubMed2003

Enterovirus infections as a risk factor for type I diabetes: virus analyses in a dietary intervention trial.

This study evaluated the possible role of enterovirus infections in the pathogenesis of type I (insulin-dependent) diabetes in a prospective dietary intervention trial. Children participated in the second pilot of the Trial to Reduce IDDM in Genetically at Risk (TRIGR) project. They were randomized into two groups receiving either a casein hydrolysed formula (Nutramigen) or a regular formula, whenever breast milk was not available over the first 6-8 months of life. Altogether 19 children who turned positive for autoantibodies associated with type I diabetes by 2 years of age and 84 matched control children were analysed for enterovirus antibodies and enterovirus RNA in serum. Enterovirus infections were common during the first 2 years of life and more frequent among boys than girls (P = 0.02). Autoantibody-positive children had more enterovirus infections than autoantibody-negative children before the appearance of autoantibodies (0.83 versus 0.29 infection per child, P = 0.01). The average levels of IgG antibodies to echovirus antigen were also higher in autoantibody-positive than in autoantibody-negative children (P = 0.0009). No difference was found in the frequency of enterovirus infections between children receiving the casein hydrolysed formula or regular formula. These results suggest that enterovirus infections are associated with the induction of beta-cell autoimmunity in young children with increased genetic susceptibility to type I diabetes.

Antibodies, Viral↗
PubMed2003

Humoral beta-cell autoimmunity is rare in patients with the congenital rubella syndrome.

The congenital rubella syndrome (CRS) is associated with increased risk for diabetes and thyroid disease. However, the mechanisms by which the rubella virus may cause these diseases are poorly characterized. Previous studies were carried out before modern immunological methods were available. The present study aimed at evaluating whether autoimmune mechanisms are involved in the pathogenesis by analysing antibodies to biochemically characterized autoantigens. The incidence of clinical diabetes, thyroid disease, coeliac disease and related antibodies (islet cell antibodies, ICA; insulin autoantibodies, IAA; antibodies to the tyrosine phosphatase related IA-2 molecule, IA-2 A and glutamic acid decarboxylase, GADA; thyroid peroxidase, TPO; tissue transglutaminase, TTGA; and gliadin, AGA) and HLA risk genotypes were analysed in 37 subjects affected by or exposed to rubella during fetal life (mean age 22.5 years). One patient had diabetes and four patients had clinical hypothyroidism at the time of the examination. ICA, IAA, GADA or IA-2 A were not detected in any of the patients, while five patients tested positive for TPO antibodies. Coeliac disease or TTGA were not observed. Eight patients carried the HLA-DR3-associated HLA-DQB1*02-DQA1*05 haplotype. These results provide no evidence of an increased frequency of markers for humoral beta-cell autoimmunity in patients with CRS suggesting that diabetes in CRS may be caused by other than autoimmune mechanisms.

Adult↗
PubMed2003

A linkage analysis of the CTLA4 gene region in Finnish patients with type 1 diabetes.

The cytotoxic T-lymphocyte antigen 4 (CTLA4) region on 2q33 has been shown to be linked to, and associated with, type 1 diabetes (T1D) and suggested to be one of the loci contributing to diabetes aetiology. The polymorphisms responsible for the effect are yet not defined, and the findings reported for the known markers have been discrepant in various populations. We analysed 15 markers around the CTLA4 gene in 138 Finnish affected sib-pair families. A maximum multipoint LOD score (MMLS) of 0.83 at the CTLA4-(AT)n microsatellite was obtained for the whole data set. When stratified, the MMLS increased to 2.61 in the IBS2 (identical by state 2) dataset. In a transmission/disequilibrium test (TDT), some sex-specific effects were observed in transmissions of alleles of CTLA4-(AT)n and D2S105 in siblings. The transmission of the CTLA4 +49 A/G single nucleotide polymorphism (SNP) did not deviate from the expected frequency in this study. In conclusion, our study confirms the linkage of the CTLA4 region to T1D in the Finnish population. In addition, the observations suggest that the polymorphism actually involved in the disease is not the CTLA4 +49 A/G SNP but a polymorphism in linkage disequilibrium with CTLA4 markers and probably closer to CTLA4-(AT)n than to the CTLA4 +49 A/G SNP.

Antigens, CD↗
PubMed2003

Natural course of preclinical type 1 diabetes in siblings of affected children.

AIM: To define the dynamics of preclinical type 1 diabetes in siblings of affected children and to characterize the siblings experiencing a progressive process. METHODS: From 801 families taking part in the "Childhood Diabetes in Finland" (DiMe) Study, 715 initially unaffected siblings were graded into four stages of preclinical type 1 diabetes based on the initial number of disease-associated autoantibodies detectable close to the time of diagnosis of the index case, while another classification system covering 641 of the siblings was based on a combination of the initial number of antibodies and the first-phase insulin response (FPIR) to intravenous glucose. RESULTS: Based on the first classification, there was a total of 95 siblings with initial signs of prediabetes, out of whom 34 (36%) progressed, 26 (27%) remained stable and 35 (37%) regressed during prospective observation for a median of 3.6 y (range 0.01-9.8 y). The siblings who progressed were younger, had a higher initial number of detectable autoantibodies, higher initial levels of various antibodies, with the exception of insulin autoantibodies, lower FPIR and a retarded glucose elimination rate in the first intravenous glucose tolerance test as compared with those that regressed. According to the second classification there were 41 siblings with initial signs of prediabetes, among whom 23 (56%) progressed, 14 (34%) remained stable and 4 (10%) regressed during the observation period. CONCLUSION: These data show that almost half of the siblings with signs of prediabetes at the time of diagnosis of the index case progressed further in their preclinical disease process during prospective observation. Young age, a strong humoral immune response to beta-cell antigens and reduced insulin secretory capacity appeared to be characteristic of those with a progressive process. Advanced and late prediabetes seem to represent a point of no return, as regression from these stages to no prediabetes was extremely rare.

Adolescent↗
PubMed2003

Genetic modification of risk assessment based on staging of preclinical type 1 diabetes in siblings of affected children.

We set out to study the association between human leukocyte antigen-defined genetic disease susceptibility and the stage of preclinical type 1 diabetes and whether genetic predisposition affects the natural course of preclinical diabetes in initially nondiabetic siblings of affected children. A total of 701 initially unaffected siblings were graded into four stages of preclinical type 1 diabetes based on the initial number of disease-associated autoantibodies detectable close to the time of diagnosis of the index case: no prediabetes (no antibodies), early (one antibody specificity), advanced (two antibodies), and late prediabetes (three or more antibodies). Another classification system covering 659 siblings was based on a combination of the initial number of antibodies and the first-phase insulin response (FPIR) to iv glucose: no prediabetes (no antibodies), early (one antibody specificity, normal FPIR), advanced (two or more antibodies, normal FPIR), and late prediabetes (at least one antibody, reduced FPIR). Genetic susceptibility to type 1 diabetes was defined by human leukocyte antigen identity and DR and DQ genotypes. There was a higher proportion of siblings with late prediabetes initially among those with strong genetic disease susceptibility than among those with decreased genetic predisposition (16.7% vs. 0.5%; P < 0.001 for DQB1 genotypes according to the first classification), whereas there was a higher proportion of siblings with no signs of prediabetes among those with genotypes conferring decreased risk (91.2% vs. 70.4% among those with high-risk DQB1 genotypes; P < 0.001 according to the first classification). Autoantibodies alone were more sensitive in the prediction of future diabetes in siblings than when combined with genetic susceptibility. Genetic susceptibility played a role in whether the initial prediabetic stage progressed (progression in 29.6% of the high-risk siblings compared with 6.6% of the siblings with DQB1 genotypes conferring decreased risk; P < 0.001 according to the first classification) and whether overt type 1 diabetes became manifest or not. Genetic susceptibility has an impact on both the initiation and progression of the autoimmune process leading to clinical diabetes in siblings of affected children.

Adolescent↗
PubMed2003

Tooth by tooth survival analysis of dental health in girls with epilepsy.

AIM: The aim of this study was to analyse, tooth by tooth, the timing of caries attacks leading to dental restoration in girls with epilepsy. STUDY DESIGN: The series comprised 60 girls with epilepsy, 8-18 years old, treated in the Departments of Paediatrics or Neurology of the Oulu University Hospital. A group of healthy age matched girls served as control. METHODS: A tooth by tooth survival analysis of the time between tooth eruption and caries attacks to a stage leading to the restorations of the permanent teeth was conducted retrospectively using data from the dental health records with annual examinations. RESULTS: The rate of dental restorations placed due to caries was constantly higher in the girls with epilepsy than in their controls. STATISTICS: The difference was significant between the first molars (p=<0.03), second molars (p=<0.02) and central incisors (p=<0.02) in the maxilla. CONCLUSION: The present observation supports the hypothesis that factors related to epilepsy, the antiepileptic medication in particular, might increase the risk of caries.

Adolescent↗
PubMed2002

Signs of beta-cell autoimmunity and HLA-defined diabetes susceptibility in the Finnish population: the sib cohort from the Type 1 Diabetes Prediction and Prevention Study.

AIMS/HYPOTHESIS: To assess the role of HLA-defined genetic diabetes susceptibility in the appearance of signs of beta-cell autoimmunity in a series of children derived from the general population. METHODS: Tests for five HLA DQB1 alleles and four diabetes-associated autoantibodies were carried out on 1,584 older sibs of infants with an increased HLA-defined genetic risk of Type 1 diabetes. The DQB1 genotypes were classified into those conferring high (* 02/0302), moderate (* 0302/x; where x indicates * 0302 or a non-defined allele), low (* 0301/0302, * 02/0301, * 02/x, * 0302/0602, * 0302/0603; where x indicates * 02 or a non-defined allele) or decreased risk (other genotypes). RESULTS: Both islet cell antibodies (ICA) and GAD65 antibodies (GADA) were more frequent among the sibs with the high-risk genotype than among those with a low or decreased risk. Insulin autoantibodies and IA-2 antibodies (IA-2A) were more prevalent in the high-risk than low-risk sibs. Sibs with moderate-risk genotypes tested positive for ICA, GADA and IA-2A more often than sibs with genotypes conferring decreased risk. Autoantibody titres were also dependent on the genetic risk with high risk sibs having the highest values. Sibs carrying high-risk or moderate-risk genotypes tested positive for multiple antibodies (> or =2) more often than did the sibs with low or decreased genetic risk. CONCLUSIONS/INTERPRETATION: The data show that HLA-defined susceptibility to Type 1 diabetes has an effect on both the quality and quantity of humoral beta-cell autoimmunity in unaffected children derived from the general population.

Antibodies↗
PubMed2002

First-phase insulin response in young healthy children at genetic and immunological risk for Type I diabetes.

AIMS/HYPOTHESIS: A reduced first-phase insulin response to intravenous glucose is perceived as a sign of far-advanced deterioration of beta-cell function during the development of Type I (insulin-dependent) diabetes mellitus, but data on insulin responses at the onset of diabetes-related autoimmunity are lacking. We studied the first-phase insulin responses of small children soon after observed seroconversion to autoantibody positivity. METHODS: In the Type I Diabetes Prediction and Prevention Study newborn infants are screened for HLA-DQB1-associated genetic risk for Type I diabetes and those with increased risk are followed-up for the emergence of islet-cell antibodies. If antibodies are detected, autoantibodies to three other antigens (insulin, GAD65 and IA-2) are also measured. To measure first-phase insulin responses, intravenous glucose tolerance tests were carried out in 52 (1 to 5-year-old) children who had recently seroconverted to islet-cell antibody positivity. RESULTS: The first-phase insulin response was subnormal (<38 mU/l, the 5(th) percentile of insulin responses of 20 islet-cell antibody negative healthy children at this age) in 22 of the 52 children (42%). Stepwise multiregression analysis showed that islet-cell antibody greater than 20 JDFU (p=0.0005), insulin autoantibodies (p=0.0009) and an increasing number of positive autoantibodies (p=0.0011) were independent predictors of low first-phase insulin response. CONCLUSION/INTERPRETATION: A decreased first-phase insulin response could be an early phenomenon in the course of prediabetes in young children, implying a rapid autoimmune destruction or loss of function of beta cells as well as possible metabolic compensation mechanisms, since 11 out of the 22 high risk children remain nondiabetic for a considerable period of time despite low insulin responses.

Autoantibodies↗