A model for the involvement of MHC class II proteins in the development of type 1 (insulin-dependent) diabetes mellitus in response to bovine serum albumin peptides.
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Amino Acid Sequence↗
Biomedical subjects
M Knip
Publications and source records attributed to M Knip.
Long-term effects of weight reduction on serum lipids and plasma insulin in obese children.
The long-term metabolic effects of weight reduction on serum lipids and plasma insulin were evaluated in 32 obese children with a mean (+/- SD) relative weight of 160.9 +/- 20.1% before and after active treatment for 1 y and after observation for another 4 y. The obese subjects had higher serum triglyceride and plasma insulin concentrations initially but lower high-density-lipoprotein (HDL)-cholesterol concentrations and a lower ratio of HDL cholesterol to total cholesterol (TC) than 29 normal-weight children. There was a decrease of 15.8% in relative weight over the first year with a parallel decrease in serum triglyceride and plasma insulin, whereas HDL cholesterol and the ratio of HDL cholesterol to TC increased (P < 0.001). These changes remained stable over the second year. At 5 y the obese subjects still had a reduced weight (12.8% lower than initially) and higher HDL cholesterol. These results indicate that weight reduction in obese children is associated with a change in serum lipids toward normal and reduced peripheral hyperinsulinemia.
Adolescent↗
Defective HLA class II expression in monocytes of type 1 diabetic patients. The Childhood Diabetes in Finland Study Group.
Activation of T-helper cells is modulated by the intensity of HLA class II expression on antigen-presenting cells. We evaluated whether any abnormalities could be found in the expression of HLA-DR and -DQ molecules on monocytes in type 1 diabetic subjects. DR and DQ molecules were induced by human recombinant interferon-gamma on cultured peripheral blood monocytes obtained from children with type 1 diabetes (N = 28), their siblings (N = 18) and unrelated healthy controls (N = 21). The response in DQ induction varied considerably between different individuals, but the average responsiveness was significantly lower in patients compared to siblings and unrelated controls. In addition to the diabetic subjects deficient DQ induction was also observed in three siblings. One of them had high levels of islet cell antibodies and presented with diabetes 6 months later, and another had active rheumatoid arthritis. The response in DR induction was also slightly lower in patients than in siblings, but did not differ from that in unrelated controls. The results suggest abnormalities in the regulation of HLA class II expression in type 1 diabetic subjects possibly reflecting the ongoing autoimmune process.
Adolescent↗
Clinical characteristics and circulating collagen and laminin metabolites in insulin-dependent diabetic children with joint and skin manifestations.
One hundred seventy-four children and adolescents with insulin-dependent diabetes mellitus were examined for joint contractures and skin manifestations in their hands. Joint contractures were found in 52 (29.8%) and skin manifestations in 29 (16.6%) patients. To eliminate the possible confounding effects of age and duration of diabetes on the variables to be studied, patients younger than 7 y and with a duration of diabetes shorter than 3 y were excluded from the subsequent analyses. Of the remaining 108 children, those with joint contractures had lower serum concentrations of the 7-S domain of type IV collagen and the P1 fragment of laminin than the other patients (p = 0.033) but higher mean glycated Hb levels (p = 0.048). A clear association was noted between the occurrence of joint contractures and skin changes (p = 0.007). Background retinopathy was found in six patients (5.6%), three of whom had stage II joint contractures (p = 0.064). The children with skin changes and those with combined joint and skin manifestations more often had insulin-dependent diabetes mellitus in their first-degree relatives (p = 0.038 and p = 0.043, respectively). No difference in relative height was found between the groups. No association could be seen between disease susceptibility antigens in the HLA-D locus and joint or skin manifestations. The lower levels of circulating collagen and laminin metabolites in the diabetic children with joint contractures suggest that these patients are characterized by a reduced turnover of basement membranes in tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Markers of type I and type III collagen synthesis in serum as indicators of tissue growth during pregnancy.
The concentrations of the carboxy-terminal propeptide of type I procollagen (PICP) and the amino-terminal propeptide of type III procollagen (PIIINP) in serum were followed prospectively as indicators of synthesis of the respective collagens in 266 healthy primiparas during the second and third trimesters of pregnancy. The PIIINP concentration increased 2-fold during the third trimester; the median value was 10.0 micrograms/L at gestational week 40, with a range from 4.6-32.7 micrograms/L (reference interval for nonpregnant women, 1.7-4.2 micrograms/L). A significant increase also took place in the PICP concentration. The frequency distributions of the two parameters were near normal at week 26. They started to broaden out at week 32 and were wide at week 38. In severe preeclampsia, PIIINP tended to increase more than in normal pregnancies of the same duration. The increase in PIIINP correlated significantly with maternal weight gain and the birth weight of the infant, but not with other parameters related to pregnancy or delivery. At gestational week 38, there was a significant correlation between the circulating concentrations of insulin-like growth factor-I and PIIINP or PICP, but not between human placental lactogen and PICP, and only a weak association between human placental lactogen and PIIINP. This suggests that insulin-like growth factor-I is involved in the regulation of type I and type III collagen synthesis during pregnancy.
Adolescent↗
Hormonal enteroinsular axis in newborn infants of insulin-treated diabetic mothers.
To study whether the increased glucose levels in the amniotic fluid during diabetic pregnancies induce an early maturation of the hormonal enteroinsular axis, we measured blood glucose levels and plasma concentrations of C-peptide, pancreatic glucagon, enteroglucagon, and gastric inhibitory polypeptide (GIP) in cord blood from 18 newborn infants of insulin-treated diabetic mothers (IDM) and 18 infants of nondiabetic mothers. In addition, we studied the same parameters in 20 IDM and 12 control infants before and after their first feed comprising human milk (5 mL/kg), given by nasogastric tube at the age of 2 h. The IDM had significantly higher blood glucose levels and plasma C-peptide concentrations in their cord blood than the control infants, which was followed postnatally by a substantial fall in these levels, whereas a more modest decrease could be seen in the control infants. Circulating enteroglucagon and GIP concentrations at the age of 2 h were significantly higher than those observed in cord blood in both the IDM and the control infants, but the IDM had significantly lower blood glucose levels, higher plasma C-peptide, and lower enteroglucagon concentrations before the first feed. There was a significant increase in blood glucose levels after the feed in both the IDM and the control infants, and the concentrations 2 h after feeding were of the same magnitude in the two groups. No significant C-peptide response could be observed in either group, but the IDM continuously had higher C-peptide concentrations. A significant enteroglucagon and GIP response could be seen in the IDM, whereas the controls exhibited only a GIP response. However, no significant differences were found between the two groups in the absolute postprandial plasma concentrations of these hormones. Our results show rapid, substantial postnatal changes in circulating concentrations of enteroinsular hormones in both IDM and control infants. Enteral feeding with human milk corrects early postnatal hypoglycemia within 2 h in most IDM without causing any exacerbation of their hyperinsulinemia. The absence of any C-peptide response to the first feed and of any observed differences between IDM and normal infants in absolute concentrations of enteroglucagon and GIP after the first feed suggests that the enteroinsular axis matures postnatally in both groups of infants.
Blood Glucose↗
Insulin administration via a subcutaneous catheter. Effects on absorption.
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Absorption↗
Seven years of remission in a type I diabetic patient.
OBJECTIVE: To analyze factors contributing to a long-term remission in a patient with type I diabetes. RESEARCH DESIGN AND METHODS: The patient was treated with cyclosporin for 16 mo after a short duration of symptoms. During the 7-yr follow-up, we tracked his glycemic control, oral glucose tolerance, insulin sensitivity, endogenous insulin secretion, and beta-cell immunology. The results are compared with those of matched diabetic patients and healthy control subjects. RESULTS: Insulin therapy was discontinued after 5 wk. Thereafter the patient had normal fasting and home blood glucose concentrations and near-normal HbA1c without insulin therapy for 7 yr. During this period, he maintained islet cell antibodies, although his basal and glucagon-stimulated C-peptide concentrations were normal. He participated in active physical training and had an insulin sensitivity higher than in sedentary control subjects or trained diabetic patients and equal to that in healthy athletes. His oral glucose tolerance decreased gradually and became diabetic during the last 3 yr. CONCLUSIONS: In this patient, an early start of cyclosporin therapy probably contributed to the maintenance of endogenous insulin secretion, and insulin sensitivity was high because of physical training. Consequently, the patient was able to maintain normoglycemia without exogenous insulin therapy for 7 yr.
Adolescent↗
A bovine albumin peptide as a possible trigger of insulin-dependent diabetes mellitus.
BACKGROUND: Cow's milk has been implicated as a possible trigger of the autoimmune response that destroys pancreatic beta cells in genetically susceptible hosts, thus causing diabetes mellitus. Studies in animals have suggested that bovine serum albumin (BSA) is the milk protein responsible, and an albumin peptide containing 17 amino acids (ABBOS) may be the reactive epitope. Antibodies to this peptide react with p69, a beta-cell surface protein that may represent the target antigen for milk-induced beta-cell--specific immunity. METHODS: We used immunoassays and Western blot analysis to analyze anti-BSA antibodies in the serum of 142 children with insulin-dependent diabetes mellitus, 79 healthy children, and 300 adult blood donors. Anti-ABBOS antibodies were measured in 44 diabetic patients at the time of diagnosis, three to four months later, and one to two years later. RESULTS: All the diabetic patients had elevated serum concentrations of IgG anti-BSA antibodies (but not of antibodies to other milk proteins), the bulk of which were specific for ABBOS: The mean (+/- SE) concentration was 8.5 +/- 0.2 kilofluorescence units (kfU) per microliter, as compared with 1.3 +/- 0.1 kfU per microliter in the healthy children. IgA antibodies were elevated as well, but not IgM antibodies. The antibody concentrations declined after diagnosis, reaching normal levels in most patients within one to two years. The initial decline involved anti-ABBOS--specific antibodies almost exclusively. Much lower serum concentrations of anti-BSA antibodies were found in all 379 control subjects, but only 2.5 percent of them had small amounts of ABBOS-specific IgG. CONCLUSIONS: Patients with insulin-dependent diabetes mellitus have immunity to cow's-milk albumin, with antibodies to an albumin peptide that are capable of reacting with a beta-cell--specific surface protein. Such antibodies could participate in the development of islet dysfunction.
Antibodies↗
Weight loss, body composition and risk factors for cardiovascular disease in obese children: long-term effects of two treatment strategies.
Two treatment strategies were compared to determine their effects on weight loss, body composition and risk factors for cardiovascular disease (CVD) in 32 obese children (relative weight > 120%) aged 6-15 years. Modes of therapy included individual (Group I) or group treatment (Group II). The children were treated for 1 year and observed during the second year. Relative body weight decreased by 16.6% in Group I (p < 0.001) and by 15.8% (p < 0.01) in Group II during the first year; in both groups the lower relative body weight was maintained during the year of observation. No changes were observed in linear growth or lean body mass. Weight reduction was accompanied by increased high-density lipoprotein cholesterol (HDL-C) levels, increased ratio of HDL-C to total cholesterol, and reduced triglyceride concentrations in both groups. Fasting plasma insulin concentrations decreased significantly in Group I. In conclusion, intensive treatment produced significant weight loss, improved serum lipid profile and reduced hyperinsulinemia. These changes, if sustained, may reduce the risk of CVD later in life.
Adolescent↗
Tumour necrosis factor-beta gene RFLP alleles in Finnish IDDM haplotypes. The Childhood Diabetes in Finland (DiMe) Study Group.
The genes located between class II and class I HLA genes including polymorphic tumour necrosis factor (TNF) genes may contribute to the disease susceptibility in IDDM. Restriction fragment polymorphisms of the TNF-beta gene have been found to be fixed in the major IDDM susceptibility haplotypes, the B62,DR4 haplotype being associated with the 10.5-kb fragment and the B8,DR3 haplotype with a 5.5-kb fragment. We studied this TNF polymorphism in a sample of diabetic families. In all IDDM-associated haplotypes (n = 129) the 5.5-kb allele was more frequent than in haplotypes found only in healthy family members (n = 112) (58.1% versus 40.2%, P < 0.01). Among IDDM haplotypes the B62,DR4 haplotype was characterized by the 10.5-kb TNF fragment, whereas two other common Finnish IDDM-associated DR4 haplotypes--A24,B39,DR4 and A2,B56,DR4--had the 5.5-kb TNF fragment. Both IDDM-associated and non-associated DR3 positive haplotypes were linked to the 5.5-kb fragment. The distribution of various combinations of TNF alleles in IDDM probands (n = 63) did not differ from that expected according to the Hardy-Weinberg distribution. Our results indicate that the 10.5-kb allele of TNF-beta gene as such is not a risk factor contributing to DR4/DQ8-associated susceptibility. Alternatively, there may be heterogeneity in pathogenetic effector mechanisms.
Alleles↗
Evaluation of growth hormone secretion and treatment.
The secretion of growth hormone (GH) is regulated by a complex system that includes both neurotransmitters and feedback by hormonal and metabolic substrates. Over the last few years it has been recognized that GH release varies over a wide spectrum from deficient to excessive secretion. The diagnosis of GH deficiency is based on a combination of anthropometric and clinical signs on the one hand and an inadequate stimulated and/or spontaneous GH secretion on the other. There is no distinct boundary between deficient and sufficient GH secretion. The cut-off limit for normal GH release is accordingly relative and has increased over the past decade from 5 to 10 micrograms/l. The effect of GH therapy on growth can be evaluated only after treatment for at least 6 months. There is, therefore, an indisputable need for methods that would reflect growth response soon after the start of treatment. There are several promising biochemical candidates, e.g. the aminoterminal propeptide of type III procollagen, the carboxyterminal propeptide of procollagen I and the bone Gla-protein, which may turn out to be useful early indicators of the growth response to long-term GH therapy.
Growth Hormone↗
Long-term weight control in obese children: persistence of treatment outcome and metabolic changes.
Maintenance of achieved weight loss and clinical and biochemical changes were studied in 48 obese children (relative weight greater than 120%) over a three-year period after active treatment for one year and initial observation for another year. The control group comprised 29 normal weight children (relative weight less than 120%). The children were 6-16 years old at the beginning of the study. The successful weight loser was defined as a child with a decrease of at least 10% in relative weight at the end of the initial two year study period. Twenty-two subjects (49%) were treated successfully while 23 children were unsuccessful. Three obese children dropped out of the study. In successful children the relative body weight decreased by 24.7% (P less than 0.001) during the initial two-year period, and the lower body weight was maintained during the subsequent observation. The relative height also decreased significantly in the successful subjects but was still normal at the end of the study. Success in weight reduction was associated with increased HDL-cholesterol (HDL-C) levels, increased ratio of HDL-C to total cholesterol and reduced concentrations of triglyceride and plasma insulin. All of these changes were maintained throughout the five year study period. In normal weight children concentrations of serum lipids and plasma insulin remained unchanged during the five years. In conclusion, initial success in weight loss was associated with long-term favourable changes in the serum lipid profile and reduced hyperinsulinemia. A majority of the initially successful weight losers (14 of 22) managed to maintain their reduced weight up to five years.
Adipose Tissue↗
No association between rheumatoid arthritis and insulin dependent diabetes mellitus: an epidemiologic and immunogenetic study.
To acquire more information on the controversial question of a possible association between rheumatoid arthritis (RA) and insulin dependent diabetes mellitus we searched for insulin dependent diabetes mellitus among patients hospitalized due to RA in 2 rheumatism hospitals in Finland. Nine subjects with insulin dependent diabetes mellitus were found among an annual number of 1460 patients admitted to one of the hospitals due to RA. These figures give a frequency of insulin dependent diabetes mellitus in patients with RA of 0.6% (95% confidence interval 0.2-1.0%), which does not exceed the prevalence of insulin dependent diabetes mellitus among the middle aged population of Finland in general (0.5-0.6%). Accordingly, no overrepresentation of homozygosity for HLA-DR4 was found among the total number of 25 patients with RA as well as insulin dependent diabetes mellitus, though the opposite might be expected as these diseases have a common DR4 association--RA with DR4 and DR1 and insulin dependent diabetes mellitus with DR4 and DR3. Instead, an increased frequency of DR1 (p less than 0.0002) and the antigen combination DR1/4 (p less than 0.01) was found in the subjects with both RA and insulin dependent diabetes mellitus compared with the subjects with insulin dependent diabetes mellitus alone.
Adult↗
[Can type-1 diabetes in children be prevented?].
Increased knowledge of the etiopathogenesis of Type 1 diabetes has focused great interest on the possibilities of preventing the disease. Type 1 diabetes is considered to be a chronic autoimmune disease characterized by gradual beta-cell destruction mediated by autoreactive T-lymphocytes during an asymptomatic prediabetic phase of varying duration. Both experimental and epidemiologic data indicate that nutritional cow milk exposure early in life may play a critical role in the initiation of beta-cell destruction. Accordingly a primary prevention study has been planned to test the hypothesis that dietary elimination of cow milk proteins over the first 9 months of life will decrease the subsequent risk of childhood type 1 diabetes in high risk infants. The possibility of identifying prediabetic individuals before decisive loss of beta-cell function by various islet cell-specific autoantibodies enables measures of secondary prevention in the prediabetic phase. There are indications from experimental and human studies that nicotinamide, a water-soluble group B vitamin, may be effective in preventing or delaying the presentation of diabetes. A European multicentre study will be initiated in the near future to explore whether oral nicotinamide can prevent or delay the clinical manifestation of Type 1 diabetes in high risk first degree relatives of diabetic children. We have to wait for the results of these intervention studies for years, and similarly other prevention strategies have to be tested in large-scale long-lasting clinical trials. Nevertheless, prevention of childhood diabetes may become a reality in the next century.
Child↗
Predictors of weight reduction in obese children.
The characteristics of successful and unsuccessful weight losers were studied in 48 obese children (relative weight > 120%) aged 6-15 years who were treated for 1 year and observed for another. Successful weight loss was defined as a decrease in relative weight of > or = 0.8 in the standard deviation score (SDS) at the end of the study. Thirty-two children were treated intensively, 16 with individual counselling and 16 in group therapy, while the remaining 16 children were treated conventionally in a school health care setting. Three children dropped out of the study. In 2 years, the relative body weight decreased by 1.7 SDS in those who were successful weight losers (n = 21, 47%), but remained unchanged in those who had been unsuccessful (n = 24). At baseline there were no differences between the two groups. At 1 year, the successful weight losers had lower body weight (P < 0.05), less lean body mass (0.05) and lower fasting concentrations of circulating insulin (P < 0.01) than the unsuccessful children did. A decrease in mothers' body mass index (BMI) and in documented energy intake over the first year as well as energy intake at 1 year were significant predictors of success at 2 years. The combination of these three predictors resulted in correct classification of about 3/4 of the cases as successful or unsuccessful weight losers. It appears, however, difficult to develop a clinically useful model for predicting the treatment outcome in obese children.
Adolescent↗
Lack of glucose-induced functional maturation during long-term culture of human fetal islet cells.
To investigate the long-term effects of glucose on the function of human fetal islets we cultured islet-like cell clusters (ICC) obtained from 12 human fetuses with a mean age of 16.1 weeks in media containing 2.8, 11.1 or 16.7 mM glucose. On the 8th day of culture, the ICC that had been maintained in 16.7 mM glucose contained 60% less insulin than the ICC cultured in 2.8 mM glucose. However, insulin release was similar in both groups, and was not affected by a 24-h incubation in high vs. low glucose. Also (pro) insulin biosynthesis was not significantly affected. During a 24-day culture period, the total release of insulin and glucagon was similar in all glucose concentrations. The ICC released about 75% of their insulin content but only 15% of their glucagon content during the last 48 h of the 24-day culture period, again regardless of glucose concentration in media. Insulin release was insensitive to acute glucose and leucine challenges in perifusion experiments after culture for 1, 5, 8 or 16 days in 11.1 mM glucose, whereas glucagon was always a potent stimulus. In conclusion, the function of cultured young human fetal islet cells is remarkably independent of glucose, even during prolonged exposure. Moreover, the primary role of glucagon in fetal life may be that of a paracrine stimulator of beta-cell function.
Arginine↗
Effects of medroxyprogesterone acetate on liver glucose metabolism in rats with streptozotocin induced diabetes mellitus.
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Animals↗