Incidence of severe hypoglycemia in children with type 1 diabetes in the Nordic countries in the period 2008-2012: association with hemoglobin A 1c and treatment modality.

OBJECTIVE: Treatment of type 1 diabetes has been intensified aiming at normalizing blood glucose, which may increase the risk of severe hypoglycemia (SH). We aimed to compare the incidence of SH events in the four Nordic countries Denmark, Iceland, Norway and Sweden, and to assess the influence of hemoglobin A1c (HbA1c) and treatment modalities on the frequency of SH; particularly, to explore if a HbA1c target ≤6.7% (50 mmol/mol) is feasible. RESEARCH DESIGN AND METHODS: Data on children below 15 years with a diabetes duration more than 1 year, registered in the national childhood diabetes databases in the four Nordic countries from 2008 to 2012, were compiled. Data completeness was more than 95%. RESULTS: Totally 8806 (48% females) patients with 29 715 person years were included, mean age and diabetes duration were 11 years and 5.1 years, respectively. The overall rate of SH was 6.0 per 100 patient-years, and did not change during the study period. The Swedish population constantly had the lowest SH incidence while it decreased significantly in the Danish population. HbA1c decreased significantly over time (p<0.01), while the number of pump users increased (p<0.01). Stratifying for HbA1c levels showed the lowest risk of SH in patients with HbA1c ≤6.7% (≤50 mmol/mol), but in the statistical models adjusting for possible confounders the difference between the HbA1c groups disappeared. Pump users had the lowest SH risk, also after adjusting for possible confounders. CONCLUSIONS: Risk of SH differs between the Nordic countries with the lowest risk in Sweden. Pump therapy was associated with decreased risk of SH. The low HbA1c group had the same or a lower risk of SH compared with the highest HbA1c groups. A target HbA1c ≤6.7% (≤50 mmol/mol) seems achievable without increasing the risk of SH.

Early mortality in EURODIAB population-based cohorts of type 1 diabetes diagnosed in childhood since 1989.

AIMS/HYPOTHESIS: The aims of this study were to provide a contemporary picture of mortality and causes of death in Europe following a diagnosis of type 1 diabetes made before the 15th birthday, and to examine excess mortality by country for possible links to incidence level or national prosperity. METHODS: Thirteen population-based EURODIAB registers in 12 countries followed-up 28,887 children diagnosed since 1989, either by record linkage to population registers or through contact with doctors providing care. RESULTS: There were 141 deaths in the cohort during 219,061 person-years of follow-up compared with 69.1 deaths expected from national mortality rates, a standardised mortality ratio (SMR) of 2.0 (95% CI 1.7-2.4). The SMR varied from 0 to 4.7 between countries, but showed little relationship with the country's incidence rate or gross domestic product (US$ per capita). The SMR did not change significantly with attained age, calendar period or time since diagnosis. The female SMR (2.7; 95% CI 2.0-3.5) was greater than the male SMR (1.8; 95% CI 1.4-2.2), although absolute numbers of excess deaths were similar in the two sexes. One-third of deaths were classified as directly attributable to diabetes (many with mention of ketoacidosis) and half were unrelated to diabetes. There was a non-significant excess of accidental/violent deaths (48 observed vs 40.7 expected; SMR 1.2; 95% CI 0.9-1.6) but little excess in suicides (11 observed, 10.2 expected; SMR 1.1; 95% CI 0.5-1.9). CONCLUSIONS/INTERPRETATION: Before the onset of late complications, significant excess mortality existed following the diagnosis of type 1 diabetes in childhood, even in recent years. Variation between countries in this excess could not be explained.

Nordic consensus on treatment of undescended testes.

AIM: To reach consensus among specialists from the Nordic countries on the present state-of-the-art in treatment of undescended testicles. METHODS: A group of specialists in testicular physiology, paediatric surgery/urology, endocrinology, andrology, pathology and anaesthesiology from all the Nordic countries met for two days. Before the meeting, reviews of the literature had been prepared by the participants. RECOMMENDATIONS: The group came to the following unanimous conclusions: (1) In general, hormonal treatment is not recommended, considering the poor immediate results and the possible long term adverse effects on spermatogenesis. Thus, surgery is to be preferred. (2) Orchiopexy should be done between 6 and 12 months of age, or upon diagnosis, if that occurs later. (3) Orchiopexy before age one year should only be done at centres with both paediatric surgeons/urologists and paediatric anaesthesiologists. (4) If a testis is found to be undescended at any age after 6 months, the patient should be referred for surgery--to paediatric rather than general surgeons/urologists if the boy is less than one year old or if he has bilateral or non-palpable testes, or if he has got relapse of cryptorchidism.

Lower consumption of cow milk protein A1 beta-casein at 2 years of age, rather than consumption among 11- to 14-year-old adolescents, may explain the lower incidence of type 1 diabetes in Iceland than in Scandinavia.

AIM: To compare the consumption of the cow milk proteins A1 and B beta-casein among children and adolescents in Iceland and Scandinavia (Norway, Denmark, Sweden and Finland) as this might explain the lower incidence of type 1 diabetes (per 100,000/year, 0-14 years) in Iceland. METHODS: The consumption of A1 beta-casein in each country among 2- and 11- to 14-year-old children was calculated from results on food intake and on cow milk protein concentration. The consumption values were then compared and evaluated against the incidence of type 1 diabetes. RESULTS: There was a significant difference between the consumption of A1 (p = 0.034) as well as the sum of A1 and B (p = 0.021) beta-casein in Iceland and Scandinavia for 2-year-old children. In the same age group, consumption of A1 beta-casein correlated with the incidence of type 1 diabetes in the countries (r = 0.9; p = 0.037). No significant difference in consumption of A1 or the sum of A1 and B beta-casein was found for 11- to 14-year-old adolescents. CONCLUSION: This study supports that lower consumption of A1 beta-casein might be related to the lower incidence of type 1 diabetes in Iceland than in Scandinavia. Additionally it indicates that consumption in young childhood might be of more importance for the development of the disease incidence than consumption in adolescence.

Unchanged incidence of diabetic nephropathy in Type 1 diabetes: a nation-wide study in Iceland.

AIMS: Diabetic nephropathy is an uncommon cause of end-stage renal disease in Iceland in contrast to most industrialized countries. The aim of this study was to examine the incidence of diabetic nephropathy in Iceland. METHODS: All patients diagnosed with Type 1 diabetes in Iceland before 1992 were studied retrospectively. Patients diagnosed before age 30, who were insulin dependent from the onset, were defined as having Type 1 diabetes. Diabetic nephropathy was defined as persistent proteinuria measured with a dipstick test (Albustix) on three consecutive clinic visits at least 2 months apart. Patients were followed to the end of year 1998, to their last recorded outpatient visit, or until death. The cumulative incidence of diabetic nephropathy was calculated with the Kaplan-Meier method and presented according to the duration of diabetes divided into 5-year intervals. RESULTS: A total of 343 patients with Type 1 diabetes were identified. The mean follow-up period was 20.2 +/- 11.4 (mean +/- sd) years. Only 9.3% of patients were lost to follow-up. Sixty-five patients developed diabetic nephropathy. The cumulative incidence was 22.6% at 20 years and levelled off at 40.3% after approximately 35 years of diabetes duration. No significant changes in cumulative incidence were observed over time. Mean glycated haemoglobin was 8.4% in patients with proteinuria and 7.8% in a group of patients without proteinuria that was matched for age, gender and duration of diabetes (P = 0.04). CONCLUSIONS: The cumulative incidence of diabetic nephropathy in Iceland is comparable with previously reported cumulative incidence rates and has remained unchanged. Glycaemic control was significantly better in patients without proteinuria.

MODY in Iceland is associated with mutations in HNF-1alpha and a novel mutation in NeuroD1.

AIMS/HYPOTHESIS: Five different types of maturity-onset diabetes of the young (MODY) have been identified until now but mutation screening suggests that more MODY genes exist. Mutations in genes encoding transcription factors essential for normal development and function of pancreatic beta cells has recently become important in studying the genetics of Type II (non-insulin-dependent) diabetes mellitus. Patients with MODY and their families in Iceland were screened for mutations in the transcription factor genes. METHODS: Clinical and biochemical information on individuals with MODY was collected and their family trees constructed. Linkage analysis was carried out on chromosomal regions known to harbour genes previously shown to be associated with MODY. Mutations were identified by direct sequencing. RESULTS: Three families were identified. Two of these showed linkage to chromosome 12 and carried mutations in exon 4 of the HNF-1alpha gene (290fsdelC and R272C). However, the third family showed no linkage to the previously described MODY genes but shared a novel mutation in the NeuroD1 gene on chromosome 2q32. This mutation, a glutamate to lysine substitution at codon 110, resides in the basic domain of the protein. CONCLUSION/INTERPRETATION: Mutations in MODY subjects have been identified in the Icelandic population. In addition this study identified the NeuroD1 gene as the gene responsible for the sixth type of MODY.

Immunoglobulin class and subclass concentrations after treatment of childhood leukemia.

With greatly increased survival rates after childhood leukemia during the last 3 decades, the long-term effects of the treatment have become more evident. The disease and its treatment impair the immune system, but the duration of this impairment is unknown. The authors studied the serum concentrations of immunoglobulins and IgG subclasses in 20 Icelandic children cured of leukemia on average 8 years and 3 months after their treatment ended. Although no marked deviations were found in the concentrations of the main immunoglobulin classes IgA, IgM, IgG, and IgE, the IgG subclass levels were below reference values. The patients had on average 0.9 of age standardized reference values of IgG1, 0.5 of IgG2, 0.8 of IgG3, and 0.7 of IgG4. However, none had any autoimmune diseases or a markedly increased tendency for infections. The results indicate that although the immunoglobulin classes regain their normal values within a few years after cessation of treatment, recovery of the IgG subclasses, especially IgG2, is impaired.

Morphological, cytogenetic, and molecular evidence for introgressive hybridization in birch.

Extensive morphological variation of tetraploid birch (Betula pubescens) in Iceland is believed to be due to gene flow from diploid dwarf birch (B. nana) by means of introgressive hybridization. A combined morphological and cytogenetic approach was used to investigate this phenomenon in two geographically separated populations of natural birch woodland in Iceland. The results not only confirmed introgressive hybridization in birch, but also revealed bidirectional gene flow between the two species via triploid interspecific hybrids. The populations showed continuous morphological variation connecting the species, but karyotypically they consisted of only three types of plants: diploids, triploids, and tetraploids. No aneuploids were found. Some of the tetraploid plants had B. pubescens morphology as expected, but most of them had intermediate characters. Most of the diploid plants were B. nana, but some were intermediates and a few had B. pubescens morphology. The triploid plants were either intermediates or they resembled one of the two species. Similar introgressive variation was observed among the diploid and triploid progeny of open-pollinated B. nana in a garden. Birch samples including field plants and artificial hybrids were further examined using a molecular method based on genomic Southern hybridization. The experiments verified introgression at the DNA level.

Different beta-casein fractions in Icelandic versus Scandinavian cow's milk may influence diabetogenicity of cow's milk in infancy and explain low incidence of insulin-dependent diabetes mellitus in Iceland.

OBJECTIVES: To compare children with insulin-dependent diabetes mellitus (IDDM) with controls in Iceland regarding their consumption of cow's milk in infancy, and to investigate the beta-casein fractions in Scandinavian and Icelandic cow's milk. The A1 variant of beta-casein has been shown to be diabetogenic in animal studies, and suggestions have been made that the B variant of beta-casein acts similarly. Differences in the relative proportions of beta-casein fractions might explain the lower incidence of IDDM in Iceland than in Scandinavia. METHODS: A retrospective case-control study on IDDM patients and matching controls was performed in Iceland to compare their diets in infancy. Fifty-five children with IDDM born in Iceland over a 16-year period and randomly collected controls (n = 165) were recruited to the study. Mothers of the children answered questions on breastfeeding habits and on when cow's milk products were introduced. Samples of cow's milk from randomly selected milk batches from the largest consumption areas in Iceland and Scandinavia were collected. The milk samples were freeze-dried and their beta-casein fractions were analyzed using capillary electrophoresis. RESULTS: No significant difference was found between IDDM patients and controls in the frequency and duration of breastfeeding or the first introduction of cow's milk products. The analyses of milk samples showed that the percentage of the A1 and B variants of beta-casein in Icelandic milk was significantly lower than in the milk from the Scandinavian countries. CONCLUSIONS: Cow's milk consumption in infancy is not related to IDDM in Iceland. The lower fraction of A1 and B beta-caseins in Icelandic cow's milk may explain why there is a lower incidence of IDDM in Iceland than in Scandinavia.

[Puberty in Icelandic boys.].

In a crosssectional study, 2751 healthy Icelandic boys aged 6-16 years, were examined for physical signs of puberty. The study was performed in 1983-1987 and was a part of a larger crosssectional growth study of 5526 Icelandic children all of whom were examined by the authors. Testicular volume of 4 ml (T 4) was considered the first sign of puberty in boys. The mean age of Icelandic boys reaching T 4 was 11.89 years (SD 1.08). The mean time interval between T 4 and T 12 was 2.21 years. The first signs of pubic hair growth, Tanner stage 2 (PH 2), were found at 12.74 years (SD 1.37). The mean time interval between PH 2 and PH 5 was 2.43 years. Even though comparison with studies from other countries is difficult because of different methods and different study design, we find that the timing and tempo of puberty in Icelandic boys is similar to what has been reported from other Nordic countries and countries in Western-Europe. Key words: puberty, growth, Icelandic boys. Correspondence: Arni V. Thorsson. E-mail: arniv@shr.is.

[Height and weight of Icelandic children 6-20 years of age.].

INTRODUCTION: Monitoring growth rate in children reflects the state of health and nutrition of the individual as well as the state of health of a nation. Until now little information has been available about the growth pattern of Icelandic children. We report here the results of a nationwide cross-sectional study of growth in Icelandic children aged 6-20 years. MATERIAL AND METHODS: Height, standing and sitting and weight were measured in a total of 6500 schoolchildren, 3173 girls and 3327 boys. The measurements were performed 1983-1987. Children were randomly selected from The National Registry according to date of birth from both urban and rural areas of the whole country of Iceland. Stature was measured by a Harpenden stadiometer and the children were weighed in underwear only using a standardized scale. RESULTS: The mean values and standard deviations for height, standing and sitting and weight are presented in tables. Growth charts for height weigt and sitting height are presented. No difference in height and weight was found between children from rural and urban areas. The results show that the growth of Icelandic children is in all age groups almost identical to the growth of Norwegian children. Compaired to other Nordic and WHO growth standards, Icelandic children are tall, especially during early pubertal development. CONCLUSIONS: Icelandic children are tall and the growth of Icelandic and Norwegian children follows the same pattern wich supports the theory that the two nations are closely related. KEYWORDS: Icelandic children, growth, height, weight. Correspondance: Atli Dagbjartsson. E-mail: atlid@rsp.is Arni V. Thorsson. E-mail: arniv@shr.is.

[Kawasaki disease in Iceland 1979-1997.].

Kawasaki disease is a multisystem inflammatory disease most commonly affecting young children. The first patient documented with the disease in Iceland was diagnosed in 1979. In this retrospective study we describe our experience with the disease in Iceland over 19 years. From 1979 to 1997 40 children were diagnosed with Kawasaki disease, i.e. an annual incidence of 8.5 per 100,000 children younger than five years of age. Male-female ratio was 2:1. The number of patients each year varied from none to seven. Coronary aneurisms were revealed in four of 30 patients (13%) undergoing 2D echocardiography. One patient died (2.5%) of cardiac complication (heart failure). Twenty-seven of 30 patients diagnosed after 1987 were treated with intravenous immunoglobulins. The incidence of Kawasaki disease in Iceland is comparable to what has been reported in the other Nordic countries.

Screening for diabetic retinopathy. Initiation and frequency.

A screening program for diabetic eye disease was established in Iceland in 1980. Diabetics involved in the screening program have a low prevalence of blindness, 1% in type 1 and 1.6% in type 2. We examined ways to make the screening program more efficient by identifying subgroups at low risk of developing eye disease that require treatment and therefore need less frequent screening. We studied whether diabetic eye disease screening programs may be trimmed by excluding children and examining diabetics without retinopathy biannually. Our results indicate that diabetic children under the age of 12 years do not need regular screening for eye disease. Biannual examinations seem to suffice in type 1 and 2 diabetic patients without retinopathy. However, in a setting where the eye clinic is located apart from the diabetes clinics, biannual examinations present practical problems which could result in a less effective screening for diabetic eye disease.

[Congenital hypothyroidism in Iceland 1979-1993.].

A nationwide screening for congenital hypothyroidism (CHT) was initiated in Iceland on January 1st 1979. From the beginning the screening consisted of TSH measurements from blood samples obtained on the fifth day of life on filter paper. TSH was initially assayed by RIA but since 1990 DELFIA fluoroimmunoassay has been used. During the 15 year period 1979-1993, a total of 65,892 children were born in Iceland. Participation in the screening program was 99.5%. The diagnosis of CHT was established in 21 cases, eight boys and 13 girls or 1/3138. Elevated TSH was found in 33 infants in the initial screening program, but on recall, thyroid function proved to be normal in 12 infants. Two infants had transient hypothyroidism presumably caused by TSH blocking antibodies of maternal origin. In one infant CHT was diagnosed on the first day of life because of a large goiter. Goiter was found in six infants on diagnosis, ectopia in six and no uptake on thyroid scan in three infants. In six infants thvroid scan was not performed. The diagnosis was delayed for 71 and 131 days respectively in two infants. Both infants had severe neonatal problems needing intensive care. On follow-up, those two children have a mild developmental delay. In the remaining 19 children mental development has been normal as judged by school performance and developmental tests. Growth has been within normal limits in all cases, mean SDS for height is 0.3. The incidence of CHT in Iceland is comparable to the results published recently in most of the other Nordic countries.

Incidence and prevalence of type 1 (insulin-dependent) diabetes mellitus in Icelandic children 1970-1989.

Through use of primary and secondary data sources for registration and validation, the incidence and prevalence of Type 1 (insulin-dependent) diabetes mellitus in children aged 0-14 years in Iceland has been completely ascertained for the years 1970-1989. The age-adjusted mean annual incidence per 100,000 for the 20-year period was 9.4 (95% confidence interval 7.8-11.3); similar for boys (9.9; 7.7-12.7) and girls (8.8; 6.7-11.5). Between 1970-1979 the incidence was 8.0 (6.0-10.6) and between 1980-1989 it was comparable at 10.8 (8.4-13.8) (p greater than 0.10). By Poisson regression analysis the variation in incidence was related to age at diagnosis (p less than 0.001), while a linear trend for calendar year at diagnosis did not reach statistical significance (p = 0.07). A quadratic curve, however, better described the temporal variation in incidence (p less than 0.05). The total prevalence per 1,000 by the end of 1979 and 1989 was similar, 0.45 (0.30-0.65) and 0.57 (0.40-0.79), respectively. In conclusion, this study confirms that both the incidence and prevalence of childhood Type 1 diabetes in Iceland are low compared to the other Nordic countries. The findings may suggest a causative role for environmental factors that are not related to latitude or ambient temperature.

Expression of the insulin like growth factor-binding protein 3 (IGFBP-3) gene is increased in human renal carcinomas.

After we had established that the IGFBP-3 gene is expressed in normal human kidney we examined renal adenocarcinoma tissue for alterations of the expression of this gene. For this purpose we prepared poly(A)+ RNA from normal kidney tissue and adjacent renal adenocarcinoma of 18 adult patients and compared the levels of IGFBP-3 mRNA by Northern analysis in both samples. The mean content by densitometry was markedly increased in the carcinoma tissues; in 17 of 18 patients the carcinoma contained significantly more IGFBP-3 mRNA than the normal kidney sample. The highest mRNA levels were found in patients with N2 and N3 lymph node extensions. Comparative Southern analysis of paired samples of four of these patients did not reveal amplification of the gene as the cause of these increased mRNA levels. In one patient, however, we identified a restriction fragment length polymorphism (RFLP) present in normal and malignant cellular DNA. This suggests a participation of the IGFBP-3 gene in the development of human renal cell cancer.

Effects of eccentric and concentric resistance training on skeletal muscle substrates, enzyme activities and capillary supply.

This study compared the skeletal muscle metabolic adaptations in response to combined eccentric and concentric or concentric resistance training regimens. Twenty-six physically active males were assigned to either the combined eccentric and concentric group (n = 10), the concentric group (n = 10) or the control group (n = 6). The combined eccentric and concentric and the concentric groups performed four to five sets of maximal, voluntary bilateral quadriceps muscle actions at 1.05 rad s-1 using a speed-controlled dynamometer three times per week for 12 weeks. The concentric group performed 12 concentric actions per set, whereas the combined eccentric and concentric group performed six coupled eccentric and concentric actions per set. Bilateral percutaneous muscle biopsies were obtained from m. vastus lateralis at rest pre- and post-training. Tissue samples were analysed for contents of adenosine triphosphate, creatine phosphate and creatine and for enzyme activities of citrate synthase, lactate dehydrogenase, myokinase, phosphofructokinase, hexokinase and Mg2(+)-ATPase using fluorometric techniques. Histochemical staining procedures were employed to determine capillary supply. The overall increase (P less than 0.05) in muscle strength was greater (P less than 0.05) for the combined eccentric and concentric group than for the concentric group. Enzyme or substrate contents and capillary supply were unaltered after either type of training. It is suggested that substantial increases in muscle strength may occur in response to resistance training without enhancing or compromising metabolic function of skeletal muscle.

Enzyme activities of FT and ST muscle fibers in heavy-resistance trained athletes.

Tissue samples were obtained from the vastus lateralis muscle of elite olympic weight and power lifters (OL/PL, n = 6), bodybuilders (BB, n = 7), and sedentary men (n = 7). Enzyme activities of citrate synthase (CS), lactate dehydrogenase (LD), 3-OH-acyl-CoA-dehydrogenase (HAD), and myokinase (MK) were assayed on freeze-dried dissected pools of slow-twitch (ST) and fast-twitch (FT) fiber fragments by fluorometric means. Histochemical analyses were carried out to assess fiber type composition and fiber area. CS and HAD activities were lower (P less than 0.05), and LD and MK were higher (P less than 0.05) in FT than ST fibers in the entire subject pool (n = 20). CS of FT fibers and HAD of ST fibers were lower in athletes (P less than 0.05-0.01) compared with nonathletes, whereas LD of both fiber types was higher (P less than 0.05-0.001) in athletes. CS activity of ST fibers and MK activity of FT fibers were higher (P less than 0.05) in BB compared with OL/PL. FT and ST fiber area was greater (P less than 0.05) in athletes than in nonathletes. BB displayed greater (P less than 0.05) fiber size than OL/PL. FT/ST area was greater (P less than 0.05) in OL/PL than BB. It is suggested that long-term heavy-resistance training results in specific metabolic adaptations of FT and ST fiber types. These changes appear to be influenced by the type of resistance training.