Insulin-dependent diabetes mellitus associated with dermatitis herpetiformis: evidence for heterogeneity of HLA-associated genes.
Explore the source record for details and available documents.
Adolescent↗
Biomedical subjects
M Knip
Publications and source records attributed to M Knip.
HLA-DQB1 alleles and absence of Asp 57 as susceptibility factors of IDDM in Finland.
It has been proposed that negatively charged aspartic acid at position 57 of the HLA-DQ beta-chain determines resistance to development of insulin-dependent diabetes mellitus (IDDM), whereas genetic susceptibility to IDDM correlates with a neutral amino acid residue. The disease rate is very low in Oriental populations with high frequencies of Asp 57. This raises a question whether the high incidence of IDDM in Finland could be explained by the distribution of this disease marker. In this study, the polymerase chain reaction products of 86 diabetic patients and 115 nondiabetic control subjects were analyzed with seven sequence-specific oligonucleotide probes. Only 25.5% of the diabetic subjects were phenotyped as Asp 57+ compared to 82% of control subjects, which suggests that Asp 57 negativity is a definite risk marker for developing IDDM in Finnish patients. However, the susceptibility conferred by various non-Asp and Asp haplotypes was not equally strong: DQw8 was the most important risk marker and DQw6 the most protective one. The frequency of Asp 57+ DQw4 was similar in diabetic patients and control subjects. The highest genotype-associated relative risk was defined by DQw2/DQw8 heterozygosity (RR 91), whereas it was 13 for non-Asp homozygosity. In the control subjects, the frequency of Asp 57+ phenotypes was higher than in several white populations with lower IDDM incidence figures. We conclude that the disease risk in Finland appears to be most strongly related to specific Asp 57- alleles, although other HLA- or non-HLA-associated genes may also contribute to IDDM susceptibility in this population.
Adolescent↗
Serum insulin and other cardiovascular risk indicators in children, adolescents and young adults.
We wanted to determine the levels of fasting serum insulin during growth, the tracking of serum insulin, and the correlation of serum insulin with other coronary heart disease risk indicators in children and young adults. In 1986 2433 subjects, aged nine to 24 were studied, and insulin data were available from the same population in 1980 and 1983. Serum insulin levels showed a peak during puberty in both sexes and the decline in insulin continued after the age of 21. Tracking of serum insulin was only moderate, especially in females and young boys. Serum insulin correlated positively with body mass index, concentrations of serum triglycerides, and blood pressure, and inversely with the concentration of high density lipoprotein cholesterol. High triglycerides, high systolic blood pressure, and low level of high density lipoprotein cholesterol clustered among subjects within the highest insulin quartile. Our results suggest that the insulin resistance phenomenon, caused mainly by obesity and leading to unfavourable levels of other coronary heart disease risk indicators, is already developing in children and young adults. This suggests that preventing obesity in early life is important.
Adolescent↗
Aetiology of insulin-dependent diabetes mellitus--a cornucopia for research?
Explore the source record for details and available documents.
Adult↗
[Treatment of obesity in children and adolescents].
Weight development was compared in 48 obese children, 6-15 years of age, who during a 12-month period underwent treatment either individually, in groups, or as part of the school health services. Those treated intensively by groups or individually manifested a relative weight reduction of 10-14 per cent at the 12-month follow-up, as compared with seven per cent in those treated by the school health services, but at five-year follow-up relative weight reduction was much the same in all three categories. Thus, group treatment of childhood obesity would appear to be the best alternative as it yields fairly rapid relative weight reduction with beneficial metabolic changes, and entails less investment in personnel resources.
Adolescent↗
HLA-DQ beta-chain restriction fragment length polymorphism as a risk marker in type 1 (insulin-dependent) diabetes mellitus: a Finnish family study.
Finnish Type 1 (insulin-dependent) diabetic families were analysed for HLA-DQ beta-chain polymorphism using a short intron-specific probe. A simple hybridization pattern was obtained in which all fragments were associated significantly with Type 1 diabetes. The simultaneous presence of two different risk markers, the allelic 12-kilobase and 4-kilobase fragments were strongly associated with Type 1 diabetes since 50% of the patients had this combination compared with only 2% of the control subjects. The cosegregated 7.5/3.0 kilobase fragments, which were associated with HLA-DR2 and DRw6 were not detected among the diabetic patients but were present in 48% of the control subjects. Our results provide further support for the location of susceptibility determining factors in the HLA-DQ gene area. The clear-cut, simple restriction fragment length polymorphism pattern obtained here, which bears a resemblance to a two allelic system, therefore makes this method applicable for estimating the risk of Type 1 diabetes at the population level.
Adolescent↗
Lack of association of T cell receptor beta-chain constant region polymorphism with insulin-dependent diabetes mellitus in Finland.
Allelic polymorphism in the T cell receptor constant beta-chain gene region has been reported to be associated with autoimmune diseases, including insulin-dependent diabetes mellitus (IDDM). The present analysis of 164 children and adolescents with IDDM and 193 controls for BqlII polymorphism using a TcR-C beta cDNA probe revealed two allelic restriction fragments with sizes of 10.5 kb (U) and 9.6 kb (L). No particular association was observed between the RFLP genotypes and IDDM (UU 27% versus 31%; UL 53% versus 52%; and LL 20% versus 17%, in diabetic subjects and controls, respectively), nor were any differences found between patients with various HLA risk antigens. The frequency of heterozygotes was 52% in 63 DR3-positive diabetic subjects and 53% in 73 DR3-negative ones. The results do not support any involvement of the TcR constant region genes in susceptibility to IDDM.
Adolescent↗
Myelin basic protein stimulates insulin and glucagon secretion from rat pancreatic islets in vitro and in vivo.
The effect of myelin basic protein on insulin and glucagon secretion from rat pancreatic islets was studied in vivo and in vitro. The myelin basic proteins isolated from bovine, human and rat brains all stimulated insulin secretion in a similar fashion. In a static incubation of isolated pancreatic islets, myelin basic protein at doses of 15.6-250 micrograms in a 0.5-ml reaction volume (1.7 X 10(-6) to 2.7 X 10(-5) M) significantly stimulated hormone release. Maximal stimulation, obtained at the 250-micrograms dose, was 6.5-fold greater than control for insulin secretion and 6.7-fold greater than control for glucagon secretion. In the case of glucagon no saturation was observed, but saturation was obvious for insulin release at doses of myelin basic protein of 62.5-250 micrograms, larger doses causing permeabilization of the islet membranes as indicated by leakage of acid phosphatase. At a 100-micrograms dose the time course of insulin secretion induced by myelin basic protein indicated a fast initial release, and after the first 2 h only a little more insulin was released. At the lower doses of myelin basic protein (11 and 33 micrograms) the secretion rate was nearly constant after the first hour. Significant stimulation of glucagon release by myelin basic protein was seen after 60 min, the rate of release being roughly constant at 33- and 100-micrograms doses thereafter. At the 11-micrograms dose significant stimulation of hormone release was observed only after a 4-h incubation.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Metabolic and hematologic effects and immune complex formation related to pertussis immunization.
Selected metabolic, hematologic, and immunologic functions were evaluated in 3- to 6-mo-old Finnish infants who received whole-cell pertussis-component diphtheria and tetanus toxoids and pertussis vaccine, adsorbed (DTP) vaccine, and in 4- to 6-y-old Los Angeles children who received either a licensed DTP vaccine or an acellular pertussis component DTP vaccine. One d after immunization, there was an increase in total leukocytes and neutrophils and a decrease in lymphocytes in all vaccinees. In 4- to 6-y-old children the leukocytosis and neutrophilia were greater in recipients who received the standard DTP vaccine than in vaccinees who received an acellular pertussis component DTP vaccine. In infants there was an increase in the mean plasma insulin concentration but no change in the glucose concentration 24 h after immunization; no increase in the mean plasma insulin was noted in the 4- to 6-y-old children. Three 4- to 6-y-old vaccinees had higher circulating immune complex concentrations after immunization and two of these children had high clinical reaction scores. The etiology of adverse reactions after DTP immunization is multifactorial. In contrast with findings in animals, our findings do not demonstrate a clinically significant effect due to lymphocytosis-promoting factor on glucose metabolism in vaccinated children. Neutrophilia in vaccinees is probably due to endotoxin, and some reactions may be due to circulating immune complexes.
Antigen-Antibody Complex↗
[Has the diabetes gene been found?].
Explore the source record for details and available documents.
Amyloid↗
Comparison of children with type 1 (insulin-dependent) diabetes in northern Finland and southern Ontario: differences at disease onset.
This study was undertaken to evaluate whether differences in Type 1 diabetes incidence in two separate geographical locations are associated with any differences in biochemical and immunological features at the onset of the disease. We studied all children under 16 years of age who presented at the time of diagnosis with Type 1 diabetes to the children's hospitals in Oulu (n = 43) and Toronto (n = 87) during 1984-1985. At onset children from Northern Finland had lower blood glucose and HbAlc levels, and higher C-peptide concentrations than those from Southern Ontario (p's less than 0.01). The group from Northern Finland also had a higher incidence of multiplex families (18.6 vs 4.6%, p less than 0.01). Amongst the Finnish group, those from multiplex families had a higher C-peptide concentration and lower frequency of ketoacidosis than those from simplex families (p's less than 0.05). Thus differences do exist at the onset of diabetes in these groups from geographical locations with greatly different incidences of Type 1 diabetes.
Adolescent↗
A comparison of childhood and adult type I diabetes mellitus.
The incidence rate of insulin-dependent (Type I) diabetes mellitus is bimodal: one peak occurs close to puberty, and the other in the fifth decade. To evaluate possible differences in these forms of the disease, we examined the clinical, biochemical, autoimmune, and genetic features of 82 children and adolescents (1.3 to 18.2 years old) and 44 adults (20.0 to 55.8 years old) when they presented with Type I diabetes. The mean (+/- SEM) duration of symptoms before diagnosis was longer in the adults (7.5 +/- 1.0 vs. 3.9 +/- 0.4 weeks; P less than 0.001), and their serum C-peptide concentrations at diagnosis were higher (0.29 +/- 0.03 vs. 0.17 +/- 0.01 nmol per liter; P less than 0.001), suggesting that they had more residual beta-cell function. There were no significant differences between the two groups in sex ratio, blood glucose levels, hemoglobin A1 values, degree of metabolic decompensation, or frequency of Type I diabetes in first-degree relatives. Thirty-four of 80 children tested (42.5 percent) were positive for insulin autoantibodies, as compared with only 1 of 26 adults (3.8 percent; P less than 0.001). However, the frequencies of islet-cell autoantibodies were similar in the adults and children (conventional autoantibodies, both 81 percent; complement-fixing autoantibodies, 46.2 percent and 60 percent). More children than adults were heterozygous for both HLA-Dw3/4 antigens (26.6 percent vs. 9.8 percent; P less than 0.05) and HLA-DR3/4 antigens (36.6 percent vs. 12.5 percent; P less than 0.05). We conclude that Type I diabetes that begins in adulthood is characterized by a longer symptomatic period before diagnosis, better preservation of residual beta-cell function, and lower frequencies of insulin autoantibodies and HLA-D3/D4 heterozygosity than Type I diabetes that begins in childhood or adolescence.
Adolescent↗
Clinical significance of urinary C-peptide excretion in children with insulin-dependent diabetes mellitus.
In order to evaluate the accuracy of urinary C-peptide determination and the clinical significance of C-peptiduria for the early course of insulin-dependent diabetes (IDDM), the rate of urinary excretion of C-peptide was determined in 32 children and adolescents with IDDM and correlated with serum C-peptide concentration, urinary excretion of albumin and beta 2-microgloublin and with the glomerular filtration rate (GFR) measured in terms of the clearance of 99mTc-DTPA. The age of the subjects ranged from 9.1 to 17.1 years (mean 13.1) and the duration of diabetes from 0.3 to 11.9 years (mean 4.6). There was a good correlation between postprandial serum C-peptide concentration and the 24-hour urinary C-peptide excretion rate (r = 0.81; p less than 0.001). GFR and urinary albumin excretion were slightly elevated in the diabetic patients as compared with non-diabetic subjects (p less than 0.05 and p less than 0.001, respectively), but C-peptide excretion was unrelated to the degree of hyperfiltration or albuminuria, neither was there any correlation between the excretion rate of beta 2-microglobulin and C-peptide. Glycaemic control was poorer in the diabetic children who had only trace amounts of C-peptide in their urine (less than 0.05 nmol/m2/24 h) than in those with minimal (0.05-1.0 nmol/m2) or moderate 24-hour urinary C-peptide excretion (greater than 1.0 nmol/m2). It is concluded that urinary C-peptide excretion serves very well to reflect residual beta-cell function and is unrelated to the slight renal hyperfunction and albuminuria often seen in diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Nocturnal release of immunoreactive growth hormone-releasing hormone and growth hormone in normal children.
To evaluate the role of growth hormone-releasing hormone (GHRH) in the physiologic release of growth hormone (GH) we studied the nocturnal secretion of immunoreactive GHRH (ir-GHRH) and its relationship to GH release and various stages of sleep in six prepubertal (three boys) and six pubertal children (two boys) with normal stature. Their ages ranged from 8.1 to 14.9 yr and their bone ages from 6.8 to 14.8 yr. Blood was withdrawn continuously between 2200-0600 h at a constant rate of 5 mL/20 min. The EEG was simultaneously registered. The ir-GHRH and GH data were analyzed by a discrete-pulse detection algorithm (Pulsar). The number of nocturnal ir-GHRH pulses varied from 0-8 (median 7) and the number of GH peaks from 2-6 (median 3). Pubertal children had significantly more (p less than 0.05) ir-GHRH pulses and the pulse amplitude was higher (p less than 0.05) than in the prepubertal children. There were no significant differences in the GH parameters between the two groups. The ir-GHRH peaks were not significantly related to any specific sleep stage. The majority of the GH pulses (71%) were associated with slow wave sleep (p less than 0.001). Two-thirds (69%) of the GHRH peaks preceded closely or coincided with GH pulses (p less than 0.02). Pubertal subjects had more isolated ir-GHRH peaks than prepubertal children (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Increased non-enzymatic glycosylation and reduced solubility of skin collagen in insulin-dependent diabetic patients.
The solubility of skin collagen into acetic acid and by pepsin digestion and the degree of non-enzymatic glycosylation of collagen (ketoamine linkage) in these fractions was determined in skin specimens from 27 insulin-dependent diabetic subjects and from 17 age-matched controls. Glycosylation in acid soluble collagen specimen was significantly increased in the diabetics, 1.9 +/- 1.8 (SD)ng of hexose/micrograms of hydroxyproline in comparison to the controls. 0.9 +/- 0.8 ng of hexose/micrograms of hydroxyproline. No significant difference in this respect was noted in pepsin soluble collagen specimens. The solubility of collagen into acetic acid and by pepsin digestion were significantly reduced in the diabetics. No clear relationships between non-enzymatic glycosylation or collagen solubility and diabetic late complications (nephropathy, retinopathy or limited joint mobility) were noted. We suggest (a) that equilibrium levels of early glycosylation products are different in acid and pepsin soluble collagen specimens. (b) ketoamine linkage glycosylation products by themselves are not directly involved in diabetic late complications and (c) the solubility in acid and digestibility of collagen by pepsin may be an indicator, even though nonspecific, of increased amounts of advanced glycosylation end products.
Collagen↗
Insulin autoantibodies at the clinical manifestation of type 1 (insulin-dependent) diabetes--a poor predictor of clinical course and antibody response to exogenous insulin.
To study the possible clinical significance of the appearance of insulin autoantibodies prior to the diagnosis of Type 1 (insulin-dependent) diabetes, and their value in predicting the antibody response to exogenous insulin, we observed 46 newly diagnosed diabetic children and adolescents over the year following diagnosis for the occurrence and duration of clinical remission, daily insulin dose, metabolic control, residual B-cell function, insulin-binding antibodies and conventional as well as complement-fixing islet cell antibodies. Insulin-binding antibodies were determined using both monoiodinated human and porcine insulin. Sixteen children (34.7%) were positive for insulin autoantibodies upon diagnosis of Type 1 diabetes. These subjects were significantly younger (6.2 +/- 1.0 versus 10.8 +/- 0.8 years; mean +/- SEM, p less than 0.001), and their haemoglobin A1 levels were lower (14.1 +/- 0.6 versus 16.0 +/- 0.8%, p less than 0.05) at diagnosis than in the insulin autoantibody negative group. There were no significant differences in the occurrence and duration of clinical remission between insulin autoantibody-positive and -negative test groups. Daily insulin dose, haemoglobin A1 and serum C-peptide concentrations were of the same magnitude in both groups after the diagnosis, and no association could be found between the presence of insulin autoantibodies at diagnosis and persistently positive islet cell antibodies. In tests conducted 3 months after diagnosis, the group of patients with insulin autoantibodies showed significantly higher levels (p less than 0.05) of antibodies binding human insulin than the group negative for insulin autoantibodies, but no significant differences could be found between the insulin binding titres of the two groups in subsequent analyses.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Relationship between serum insulin autoantibodies, islet cell antibodies and Coxsackie-B4 and mumps virus-specific antibodies at the clinical manifestation of type 1 (insulin-dependent) diabetes.
In order to elucidate the possible relationship between insulin autoantibodies (IAA), conventional (ICA-IgG) and complement-fixing (CF-ICA) islet cell antibodies and Coxsackie-B4 and mumps virus-specific antibodies (IgG, IgM and IgA classes), we studied 194 children and adolescents with newly diagnosed Type 1 (insulin-dependent) diabetes. Sixty-one (31.4%) of the subjects were IAA-positive at diagnosis and 73.8% (45/61) of these also had ICA-IgG compared to 51.1% (68/113, p less than 0.01) of IAA-negative children. CF-ICA showed no significant association with IAA. The levels of IAA were significantly higher in the patients with ICA-IgG compared to those without [5.9 +/- 1.6% (SEM) vs 2.5 +/- 0.3%, p less than 0.01]. The patients positive for IAA were younger at diagnosis than the IAA-negative ones; (7.1 +/- 0.5 vs 9.3 +/- 0.3 years, p less than 0.001) and this was also true for ICA-IgG-positive children (8.1 +/- 0.4 vs 9.4 +/- 0.5 years, p less than 0.05) in comparison to ICA-IgG-negative subjects. No significant associations were found between IAA or ICA on the one hand and a positive family history of Type 1 diabetes or metabolic derangements at diagnosis on the other. Subjects negative for ICA were more frequently positive for mumps virus specific IgG antibodies than the ICA-positive patients (50/80 vs 53/111, p less than 0.05), and Coxsackie-B4 virus-specific IgA antibodies were more common in the CF-ICA-negative than the CF-ICA-positive children (53/111 vs 29/80, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Reduced insulin removal and erythrocyte insulin binding in obese children.
To study the relationship between childhood obesity, weight loss, hyperinsulinaemia and the erythrocyte insulin receptor, we measured the plasma concentrations of immunoreactive insulin (IRI) and C-peptide and the binding of 125I-insulin to erythrocytes in 12 obese children with a mean age +/- SD of 11.4 +/- 2.5 years and a mean relative weight score +/- SD of 4.8 +/- 1.4 and 12 age-matched normal-weight children. Eight obese children were re-evaluated after 1 year's participation in a weight reduction programme. The obese children had higher fasting plasma concentrations of IRI (P less than 0.01) and C-peptide (P less than 0.05) and a lower C-peptide to IRI molar ratio (P less than 0.01) than the normal-weight children. The obese children had in addition a reduced erythrocyte insulin binding (P less than 0.05 or less) over the physiological range of circulating insulin concentration. There was a negative correlation (r = -0.60; P less than 0.01) between the insulin tracer binding and the relative weight. The weight reduction programme resulted in a decrease of 1.0 SD (P less than 0.05) in the mean relative weight score. At the end of the therapy the obese children had lower fasting blood glucose levels (P less than 0.05) and lower plasma IRI concentrations at 90 min (P less than 0.05) after an oral glucose load than at the onset of therapy. There were no significant differences between the insulin binding characteristics at the commencement and at the end of the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood Glucose↗