Early seroconversion and rapidly increasing autoantibody concentrations predict prepubertal manifestation of type 1 diabetes in children at genetic risk.

AIMS/HYPOTHESIS: The aim of the study was to investigate the timing of the appearance of autoantibodies associated with type 1 diabetes between birth and puberty, the natural fate of these autoantibodies and the predictive power of autoantibody concentrations for early progression to clinical diabetes. METHODS: Children were recruited to the Type 1 Diabetes Prediction and Prevention Project, an ongoing study based on HLA-conferred genetic risk. Autoantibodies against islet cells, insulin, GAD65 and islet antigen 2 were analysed at 3-12 month intervals, starting from birth. RESULTS: During the follow-up, 1,320 children (18.4% of the cohort of 7,165 children) were autoantibody positive in at least one sample. Altogether, 184 autoantibody-positive children progressed to type 1 diabetes. Seroconversion occurred at an early age in the progressors (median 1.5 years), among whom 118 (64%) and 150 (82%) seroconverted to autoantibody positivity before the age of 2 and 3 years, respectively. The incidence of seroconversion peaked at 1 year of age. Compared with other autoantibody-positive children, the median autoantibody levels were already markedly higher 3 to 6 months after the seroconversion in children who later progressed to diabetes. CONCLUSIONS/INTERPRETATION: Early initiation of autoimmunity and rapid increases in autoantibody titres strongly predict progression to overt diabetes before puberty, emphasising the importance of early life events in the development of type 1 diabetes.

Dynamics of diabetes-associated autoantibodies in young children with human leukocyte antigen-conferred risk of type 1 diabetes recruited from the general population.

This study characterized the dynamics of islet cell antibodies (ICA), insulin antibodies (IAA), glutamic acid decarboxylase antibodies (GADA), and IA-2 antibodies (IA-2A) in 1006 children recruited from the general population due to human leukocyte antigen (HLA) DQB1-conferred risk for type 1 diabetes (T1D). By the age of 5 yr, 13.8% of the children had had one or more autoantibodies in at least one sample drawn at 3- to 12-month intervals from birth, whereas 6.1% had had one or more of the three autoantibodies to biochemically defined antigens in at least two consecutive samples. The cumulative frequencies of positivity for at least two antibodies ranged from 3.2-4.4%. Seventy-five children (7.5%) had at least once ICA, 83 (8.3%) had IAA, 46 (4.6%) had GADA, and 33 (3.3%) had IA-2A. IAA were transient more frequently than the other antibodies (P < or = 0.03) and fluctuated between positivity and negativity more often than ICA (P = 0.001). The genetically high risk children were positive for each autoantibody reactivity more often (P < or = 0.03) than the moderate risk subjects. Thirteen of the 1006 children (1.3%) presented with T1D by the age of 5 yr. The most sensitive predictors of T1D were ICA and IAA, whereas the most specific predictor was IA-2A. Positivity for at least two autoantibodies of IAA, GADA, and IA-2A had the highest positive predictive value for T1D (34%). We conclude that the frequency of various diabetes-associated autoantibodies increases at a relatively stable rate at least up to the age of 5 yr. Persistent positivity for two or more autoantibodies appears to reflect destructive progressive beta-cell autoimmunity, whereas positivity for a single autoantibody may represent harmless nonprogressive or even regressive beta-cell autoimmunity.

Intranasally administered insulin intended for prevention of type 1 diabetes--a safety study in healthy adults.

BACKGROUND: Intranasally applied insulin is one of the antigen-specific therapies currently tested in clinical type 1 diabetes prevention trials, for example, in the Type 1 Diabetes Prediction and Prevention Study (DIPP). The possibility that the therapy may cause hypoglycaemia or local irritation and the poorly known immunological safety of mucosal application of the antigen in healthy subjects prompted this study. METHODS: We used a randomised, placebo-controlled, double-blinded crossover study design with 3-week treatment periods to study the effects of once-daily intranasal application of human short-acting insulin without absorption-enhancing adjuvants in 20 non-diabetic adults. The selected 60 IU dose of insulin was equivalent to the weight-based dose used for the DIPP children. We investigated self-monitored blood glucose concentrations, nasal insulin effects and induction of diabetes-associated autoantibodies. RESULTS: The two treatment periods showed no differences in blood glucose concentrations or in the frequency of blood glucose values higher than 3.0 mmol/L. Of the eight measured hypoglycaemic values, only one, which occurred during placebo therapy, was associated with symptoms. Rhinoscopy revealed no nasal irritation, and mucociliary clearance, nasal airway patency and nasal airflow resistance were not affected by the insulin therapy. Eleven subjects complained of transient nasal stinging or unpleasant odour and one subject reduced the dose because of nasal irritation. The treatment did not induce production of any of the four diabetes-associated autoantibodies. CONCLUSIONS: Short-term use of intranasal insulin without absorption enhancers was predominantly well tolerated, the risk of hypoglycaemia was minimal and no objective nasal adverse effects were detected.

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.

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.

Natural history of beta-cell autoimmunity in young children with increased genetic susceptibility to type 1 diabetes recruited from the general population.

The aim of this study was to evaluate the frequency and predictive value of diabetes-associated autoantibodies, such as islet cell antibodies (ICA) and autoantibodies to insulin (IAA), GAD65 (GADA), and the IA-2 molecule (IA-2A) in genetically susceptible children from the general population during the first 2 yr of life. Of 12,170 newborn infants, 1,005 with increased genetic risk of type 1 diabetes (high risk, human leukocyte antigen DQB1*02/*0302; moderate risk, DQB1*0302/x, where x = other than *02, *0301, or *0602) were monitored for ICA, IAA, GADA, and IA-2A at 3- to 6-month intervals from birth up to a minimum age of 2 yr. In addition, all 15 genetically susceptible children from the general population who had participated in regular immunological follow-up and developed clinical type 1 diabetes by the end of April 2000 were analyzed for the development of autoantibodies. Among 1,005 children, 63 (6.3%) tested positive for at least one autoantibody, 31 for ICA (3.1%), 48 for IAA (4.8%), 23 for GADA (2.3%), and 13 for IA-2A (1.3%) at least once by the age of 2 yr. Both ICA and IAA identified 95% [95% confidence interval (CI), 77.2-99.9%] of those who tested persistently positive for multiple (> or = 2) antibodies at the age of 2 yr, GADA identified 86% (CI, 65.1-97.1%), and IA-2A identified 55% (CI, 32.2-75.6%). Close to half of the antibody-positive children (29 of 63) reverted back to antibody negativity. Autoantibodies disappeared more often among those who tested positive for IAA than among those who tested positive for other autoantibodies (P < or = 0.021). Among the 15 children who developed type 1 diabetes, the disease sensitivity of ICA was 80% (CI, 51.9-95.7%), that of IAA was 93% (CI, 68.0-99.8%), that of GADA was 60% (CI, 32.3-83.7%), and that of IA-2A was 40% (CI, 16.3-67.7%). These results suggest that IAA are characterized by high sensitivity, early appearance, and high frequency of transient antibody positivity, whereas ICA detected with a thoroughly standardized assay appear to be more specific for the screening of beta-cell autoimmunity in young children with increased genetic susceptibility to type 1 diabetes in the Finnish population, which has the highest incidence of type 1 diabetes in the world.

Health-related quality of life in type 1 diabetes without or with symptoms of long-term complications.

OBJECTIVE: To measure subjective health-related quality of life (HRQoL) of patients with type 1 diabetes and describe the influence of symptoms of diabetes-related long-term complications on HRQoL. METHODS: The 15-D health-related quality of life measure (15D) was used to measure HRQoL of a representative sample of Finnish insulin-treated patients expected to have type 1 diabetes. Background data were gathered with a separate questionnaire. A tobit (censored regression) model was constructed to estimate the effects of symptoms of complications on HRQoL and to separate these effects from those of other health problems and aging. RESULTS: The 15D scores declined markedly with increasing age, and the prevalence of symptoms of long-term complications increased. The tobit regression model showed that these symptoms have a significant negative influence on HRQoL. The model explained over 50% of the variation in the 15D scores. CONCLUSIONS: High prevalence of symptoms of long-term complications combined with their significant negative influence on HRQoL causes substantial losses in terms of quality of life and utility from both individual and societal perspectives. Thus, the importance of secondary prevention, i.e., prevention of complications by better metabolic control, and also the so-far theoretic possibility to prevent type 1 diabetes itself is emphasized.

Rotavirus infections and development of diabetes-associated autoantibodies during the first 2 years of life.

Rotavirus, the most common cause of childhood gastroenteritis, has been implicated as one of the viral triggers of diabetes-associated autoimmunity. To study the possible association between rotavirus infections and the development of diabetes-associated autoantibodies, we measured the prevalence of rotavirus antibodies in serum samples collected at 3-6-month intervals up to the age of 2 years from 177 children selected from consecutive newborns because they carried HLA-DQB1 alleles associated with increased risk for type 1 diabetes. Twenty-nine of the children developed at least two of four diabetes-associated autoantibodies (ICA, IAA, GADA or IA-2A) during the first 2 years of life (the cases), whereas 148 children remained autoantibody-negative matched with the cases for date of birth, gender, living region and HLA-DQB1 alleles. The temporal association between the development of the first-appearing diabetes-associated autoantibody and rotavirus infections was studied by analysing whether the cases had a diagnostic increase in rotavirus antibody titre more often during the 6-month period that preceded seroconversion to autoantibody positivity than the controls. By the age of 12 months one of the 13 case children (7%), who had a serum sample drawn at that age and who had developed at least one type of diabetes-associated autoantibodies, had experienced a rotavirus infection, while 12 of the 61 (20%) autoantibody-negative control children had had a rotavirus infection. By 18 months, four of the 22 autoantibody-positive cases (18%) and 18 of the 89 controls (20%) had rotavirus antibodies, and by the age of 24 months the respective numbers were five of the 27 cases (19%) and 32 of the 113 (28%) controls. A rotavirus infection occurred during the 6 months preceding the sample which was positive for an autoantibody in four of the 25 periods (16%) for which both necessary samples were available, while the controls had a rotavirus infection during 55 of the 370-such periods (15%). Accordingly, our data suggest that rotavirus infections are unlikely triggers of beta-cell autoimmunity in young children with genetic susceptibility to type 1 diabetes.

The first signs of beta-cell autoimmunity appear in infancy in genetically susceptible children from the general population: the Finnish Type 1 Diabetes Prediction and Prevention Study.

Little is known about the timing of the etiological events and the preclinical process of type 1 diabetes during the first years of life in the general population. In this population-based prospective birth cohort study, the appearance of diabetes-associated autoantibodies as a sign of beta-cell autoimmunity and the development of type 1 diabetes were monitored from birth. Of 25,983 newborn infants, 2,448 genetically susceptible children were monitored for islet cell antibodies (ICA) at 3- to 6-month intervals. If an infant seroconverted to ICA positivity, all his/her samples were also analyzed for insulin autoantibodies (IAA), antibodies to the 65-kDa isoform of glutamic acid decarboxylase, and antibodies to the protein tyrosine phosphatase-related IA-2 molecule. Fifteen children of those who carried the high-risk genotype (2.7%) and 23 of those who carried the moderate-risk genotype (1.2%; P = 0.019) tested positive for ICA at least once. Among those who showed positivity for at least 2 antibodies during the observation period (25 of 38), IAA appeared as the first or among the first antibodies in 22 children (88%) and emerged earlier than the other antibodies (P < 0.019 or less). The first autoantibodies appeared in the majority of the children in the fall and winter (30 of 38 vs. 8 of 38 in the spring and summer, P < 0.001). These observations suggest that young children in the general population with a strong human-leukocyte-antigen-DQ-defined genetic risk of type 1 diabetes show signs of beta-cell autoimmunity proportionally more often than those with a moderate genetic risk. IAA emerge as the first detectable antibody more commonly than any other antibody specificity, implying that insulin may be the primary antigen in most cases of human type 1 diabetes associated with the DR4-DQB1*0302 haplotype. The seasonal variation in the emergence of the first signs of beta-cell autoimmunity suggests that infectious agents may play a role in the induction of such autoimmunity.

Feasibility of genetic and immunological prediction of type I diabetes in a population-based birth cohort.

AIMS/HYPOTHESIS: Population-wide genetic screening of susceptibility to multifactorial diseases will become relevant as knowledge of the pathogenesis of these diseases increases and preventive interventions are identified. METHODS: Feasibility and acceptance of neonatal genetic screening for Type I (insulin-dependent) diabetes mellitus susceptibility and adherence of the at-risk children to frequent autoantibody follow-up were studied. Screening was offered to all families. The infants with HLA-DQB1 genotypes *02/*0302 and *0302/x (x not equal to *02, *0301, *0602) were invited to autoantibody follow-up. The children who developed signs of beta-cell autoimmunity were invited to a separate prevention trial. RESULTS: The parents of 31,526 babies born between November 1994 and April 1999 (94.4% of those eligible) agreed to genetic screening. We found that 4651 infants (14.8%) had increased genetic risk (2.5 to 15 times that of the general population) for Type I (insulin-dependent) diabetes mellitus, and 80% of them joined the autoantibody surveillance. At the age of 1, 2, 3 and 4 years, 74, 69, 68 and 76% of the at-risk children, respectively, attended the follow-up. A total of 17 of the 22 children (77%) who were born during the study period and have developed diabetes carry the risk genotypes we currently use for screening. CONCLUSIONS/INTERPRETATION: Population-based screening of genetic susceptibility for Type I diabetes, linked with a possibility to participate later in a prevention trial, is highly accepted in Finland and identifies about 75% of those developing diabetes at an early age. Families adhere well to the frequent measurement of signs of beta-cell autoimmunity in the children at-risk.

Enterovirus infection as a risk factor for beta-cell autoimmunity in a prospectively observed birth cohort: the Finnish Diabetes Prediction and Prevention Study.

Previous studies suggest that enterovirus infections may initiate and accelerate beta-cell damage years before the clinical manifestation of type 1 diabetes. We have now analyzed the role of enterovirus infections in the initiation of autoimmunity in children who have tested positive for diabetes-associated autoantibodies in a prospective study starting at birth (the Finnish Diabetes Prediction and Prevention Study). The frequency of enterovirus infections was studied using both serology and testing for the presence of enterovirus RNA in the sera of 21 children who developed and retained autoantibodies and in 104 control subjects chosen from the same study cohort and matched for the time of birth, sex, and HLA alleles determining genetic diabetes susceptibility. Sample intervals were taken as basic units of follow-up, to which the observed number of infections was adjusted. Enterovirus infections were detected in 26% of sample intervals in the case subjects and in 18% of the sample intervals in the control children (P = 0.03). A temporal relationship between enterovirus infections and the induction of autoimmunity was found; enterovirus infections were detected in 57% of the case subjects during a 6-month follow-up period preceding the first appearance of autoantibodies compared with 31% of the matched control children in the same age-group (odds ratio 3.7, 95% CI 1.2-11.4). The frequency of adenovirus infections did not differ between the patient and control groups. Our data imply that enterovirus infections are associated with the development of beta-cell autoimmunity and provide evidence for the role of enteroviruses in the initiation of beta-cell destruction.

Costs of predicting IDDM.

Programmes aiming at prediction and prevention of insulin-dependent diabetes mellitus (IDDM), a multifactorial autoimmune disease, have been launched or are in the planning phase in several countries. We hypothesized that the costs of finding the correct target subjects for preventive interventions are likely to vary markedly according to the prediction strategy chosen. Average direct costs accruing in the Finnish IDDM Prediction and Prevention Project (DIPP) were analysed from the health care provider's viewpoint. The genetically targeted strategy included costs of assessing genetic IDDM susceptibility followed by measurement of marker(s) of islet autoimmunity in the susceptibility restricted population at 3 to 6-month intervals. In the pure immunological strategy markers of autoimmunity were repeatedly analysed in the entire population. The data were finally exposed to sensitivity analysis. The genetically targeted prediction strategy is cost-saving in the first year if autoimmune markers are analysed as frequently as under the DIPP project, and in all circumstances later. The 10-year direct costs per child are US$ 245 (present value $ 217, 5% discount rate) if the genetically targeted approach is used and $ 733 (present value $ 619) if the pure immunological strategy is chosen. In sensitivity analysis the 10-year costs (present value) per child of the genetically targeted strategy and of the pure immunological strategy varied from $ 152 to $ 241 and from $ 430 to $ 788, respectively. The genetically targeted IDDM prediction strategy is remarkably cost-saving as compared with the pure immunological strategy mainly because fewer subjects will need retesting during the follow-up.

Longitudinal reproductive hormone profiles in infants: peak of inhibin B levels in infant boys exceeds levels in adult men.

The gonads are usually considered quiescent organs in infancy and childhood. However, during the first few postnatal months of life, levels of gonadotropins and sex hormones are elevated in humans. Recent epidemiological evidence suggests that environmental factors operating perinatally may influence male reproductive health in adulthood. The early postnatal activity of the Sertoli cell, a testicular cell type that is supposed to play a major role in sperm production in adulthood is largely unknown. Recently, the peptide hormone inhibin B was shown to be a marker of Sertoli cell function in the adult male. In the adult woman, inhibin B is secreted by the granulosa cells. Longitudinal serum levels of inhibin B were measured in healthy boys (n = 15) and girls (n = 15), in cord blood, and every third month during the first 2 yr of life. In addition, serum levels of FSH, LH, and testosterone (boys) were measured in the same group of children. In boys, inhibin B, FSH, LH, and testosterone levels were all elevated at 3 months of age. However, the peak of inhibin B was unexpectedly high, into the supraadult range (mean +/- SE, 378 +/- 23 pg/mL) and persisted much longer than the elevation of FSH, LH, and testosterone. Thus, although levels of FSH, LH, and testosterone decreased into the range observed later in childhood by the age of 6-9 months, serum inhibin B levels remained elevated up to at least the age of 15 months. In girls, the hormonal pattern was generally more complex, with a high interindividual variation in levels of inhibin B, FSH, and LH within each age. In conclusion, the sustained elevation of inhibin B to supraadult levels in infant boys indicates that the neonatal period may be a developmental window important for Sertoli cell proliferation and maturation. Thus, the gonads may be potentially vulnerable to exogenous endocrine interference, e.g. from environmental factors during this period of life. Measurement of serum levels of inhibin B in infants may give clinical clues about developmental deficiencies in the gonads that otherwise only become apparent around puberty or later in life.

Costs of insulin-dependent diabetes mellitus.

Insulin-dependent diabetes mellitus (IDDM) is a prevalent chronic disease that causes marked personal and financial costs for patients, their families and society. Accurate information on costs of the disease is scarce. In this article, we review studies on disease and disease stage-connected costs at the individual and societal levels, and discuss possibilities of decreasing or preventing costs attributable to IDDM. The 3 disease stages are the initial treatment, follow-up after the initial treatment and late treatment. Total costs of IDDM in a given country depend on the incidence of the disease and the efficiency (cost effectiveness) of treatment. Besides everyday treatment costs, the acute and long term complications of the disease cause major additional costs. The lifetime financial costs of IDDM and the amount of human suffering are always substantial. The costs of the 3 clinical stages of IDDM differ markedly. The initial and late periods induce cost peaks, but the costs of follow-up after initial treatment are small. During initial treatment, costs depend mostly on the possible length of hospitalisation. During the late treatment period, costs begin to accumulate rapidly because of long term complications such as diabetic nephropathy, retinopathy, neuropathy and macrovascular disease. Intensive ambulatory care, effective patient education that results in normoglycaemia or near-normoglycaemia in patients and, if needed, shortening of hospitalisations, are the only means to restrict or decrease the costs of IDDM until primary prevention is available. Postponing complications by any length of time will always decrease human suffering and lead to marked savings in healthcare resources.

Short-term and long-term initial stay in hospital of children with insulin-dependent diabetes: adjustment of families after two years.

A randomized prospective trial on the effect of the length of initial hospital stay (23 +/- 4 days and 9 +/- 3 days) in 61 consecutive children with newly diagnosed diabetes was carried out. Since the metabolic outcome was similar in the treatment groups for the first two years, we analyzed the adjustment and subjective well-being of families to the diabetes after a two-year follow-up period. A semi-structured interview by a psychologist who was blinded to the initial treatment length and medical history of the child showed that 74% of the families in the short-term and 58% in the long-term treatment groups had good overall psychosocial ability to function (ns); there were no unusual fears in 37% and 15% of the families (ns), respectively. After short-term treatment, families needed slightly but not significantly less time to be confident about the management of diabetes in the family. These findings show that the short-term initial hospital stay does not unfavorably affect the adjustment of the family to diabetes and should probably be preferred over the long-term initial hospital stay.

Serum insulin profiles in consecutive children 2 years after the diagnosis of IDDM.

We studied associations of 24-h serum insulin profiles with insulin dose, age, gender, haemoglobin A1c (HbA1c) and C-peptide values, as well as blood glucose profiles in 77 consecutive children-nine aged 2-4, 14 aged 5-8, 26 aged 9-12, and 28 aged 13-17 years--2 years after the onset of insulin-dependent diabetes mellitus (IDDM). Mean weight-based insulin doses in the four age groups were similar (0.7 +/- 0.2 U.kg-1.day-1 in all); body surface-area-based doses differed. Insulin doses correlated significantly with the 24-h mean and area-under-the-curve (AUC) values, and with mean values at 03.00 hours of serum insulin in the children aged 5-8 and 13-17 years. The mean insulin concentrations of the age groups (95% confidence intervals) increased with age [6.1 (3.8, 9.7), 7.6 (5.9, 9.8), 10.4 (8.6, 12.4), and 14.0 (11.6, 16.8) mU/l; p < 0.0002]. The 24-h mean of serum insulin together with HbA1c concentration predicted 32% of the variation of mean blood glucose concentrations. Of children aged less than 9 years, 50% had insulin values less than 5 mU/l (healthy subjects' lower reference limit), and 14% were of less than 2 mU/l (detection limit of the assay) at 03.00 hours. At 07.00 hours, 82% had insulin values of less than 5 mU/l, and 36% were of less than 2 mU/l, respectively. Some young children had night-time hypoglycaemia with simultaneous hypoinsulinaemia. Insulin profiles correlated poorly with the HbA1c and peak C-peptide values.(ABSTRACT TRUNCATED AT 250 WORDS)

The first two years of type 1 diabetes in children: length of the initial hospital stay affects costs but not effectiveness of care.

The long-term costs of care and the effects of the length of the initial hospital stay on costs and effectiveness of the care of children with Type 1 diabetes are largely unexplored. A randomized prospective study was carried out wherein we shortened the length of the initial hospital stay from 23 +/- 4 days to 9 +/- 3 days in half of 61 consecutive children with newly diagnosed Type 1 diabetes. Metabolic control, psychosocial adjustment, and direct and indirect costs of care were compared during a 2-year follow-up. Having confirmed similar metabolic and psychosocial outcomes, we now report the costs of the two treatment modes. The costs of care of a child with Type 1 diabetes totalled 10,834 pounds and 6928 pounds in the long-term and short-term alternatives, respectively, during the 2-year follow-up (p < 0.001, one-way ANOVA). Direct costs accounted for 83% of the expenses in the long-term and 82% of the expenses in the short-term group; 73% and 56% of the direct and 78% and 72% of the indirect costs were incurred during the first month in the two groups, respectively. The first month's expenses were twice as high in the long-term than in the short-term group. Consumed hospital days and the parents' lost work time were the largest cost items in both groups. There were no significant differences in the cost items during the following 23 months. We conclude that the greater part of both the direct and the indirect expenditures were associated with the initial hospital stay.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucose profiles in children two years after the onset of type 1 diabetes.

The relationship of 24-h glucose profiles to age, haemoglobin A1c (HbA1c), and C-peptide concentration was analysed in consecutive, unselected children who had developed Type 1 diabetes 2 years earlier. Seventy-seven children in four age groups (age 2-4 years, n = 9; 5-8 years, n = 14; 9-12 years, n = 26; and 13-17 years, n = 28) were studied. Each child was hospitalized for 2 days for the investigations. Mean blood glucose concentration was 9.7 +/- 4.1 (SD) mmol l-1 in children aged 2-4 years; 10.7 +/- 4.0 mmol l-1 in those aged 5-8 years; 11.3 +/- 3.4 mmol l-1 in those aged 9-12 years; and 9.8 +/- 3.3 mmol l-1 in those aged 13-17 years. Results were > 7.0 mmol l-1 in 69% (range 56-76%) and > 10 mmol l-1 in 49% (39-57%) of the measurements. Values decreased by 30% (21-43%) between 10 pm and 3 am. The nadir of the mean profiles of the groups was always at 3 am. Glucose concentration was mmol l-1 in 25% (14-50%), < 2.5 mmol l-1 in 9.6% (0-21%), and < 2.0 mmol l-1 in 2.7% (0-4.2%) of the children at 3 am; hypoglycaemia was most common in those aged 5-8 years. Of the four profile characteristics used, mean blood glucose predicted HbA1c (R2 = 24.7%, p < 0.00005, multiple linear regression analysis), and slightly more in combination with age (R2 = 32.0%, p < 0.00005).(ABSTRACT TRUNCATED AT 250 WORDS)

Randomised prospective study of short-term and long-term initial stay in hospital by children with diabetes mellitus.

To assess how an isolated change in the pattern of care influences outcome of care and hospital use, a randomised prospective 2-year study was done in which 31 of 61 consecutive children with newly diagnosed insulin-dependent diabetes mellitus (IDDM) were admitted to hospital at disease onset for about a week and compared with the other 30 children who were admitted for about 4 weeks. Insulin treatment and education about diabetes were similar in the two groups. Duration of initial stay in hospital had no effect on metabolic control during the 2 years but time since diagnosis was significant with respect to effect on haemoglobin A1 (p = 0.001), haemoglobin A1c (p = 0.004), and insulin dose (p less than 0.001). At 2 years, 45% of the children in the short-term group and 29% in the long-term group were C-peptide positive (p = NS); C-peptide positivity correlated with age. A change in the pattern of care of children with IDDM, led to a pronounced decrease in hospital use by this patient group. Irrespective of the length of initial stay in hospital, equally good metabolic control was obtained in both groups for 2 years.