Incidence of childhood type 1 diabetes mellitus in Yamanashi Prefecture, Japan, 1986-2018.

Introduction: Several studies have examined the incidence of childhood T1DM in Japan from the 1970s onwards, but none have been long-term studies using registration data. We estimate the incidence of childhood type 1 diabetes mellitus (T1DM) from 1986 to 2018 in Yamanashi Prefecture, Japan. Methods: We began a population-based, long-term study of childhood T1DM in 1986 involving every hospital paediatrics department in Yamanashi Prefecture. In the Prefecture, every child newly diagnosed with T1DM is referred to a hospital, and therefore, almost 100% of new patients aged <15 years are registered. We calculated the incidence of T1DM among children aged <15 years from 1986 to 2018. All cases met the Japan Diabetes Society diagnostic criteria and were tested for T1DM-related autoantibodies whenever possible. Results: Ninety-nine patients (44 boys and 55 girls) were newly diagnosed with T1DM. The annual incidence among 5- to 9-year-olds increased by 5.35% over the study period (95% confidence interval 2.34%-8.35%, p = .0005), and there was a trend towards increasing 3-year incidence (15.52% increase, p = .0516). There were also trends towards increasing annual and 3-year incidence among 0- to 14-year-olds. However, there were no changes over time in annual or 3-year incidence in the 0-4 year or 10-14 year age groups. Conclusions: The incidence of T1DM in Yamanashi Prefecture increased among children aged 0-14 years over the study period, with the most significant increase occurring among 5- to 9-year-olds. These data suggest that the number of children aged <15 years with T1DM is gradually increasing in one of the local prefectures in Japan, Yamanashi Prefecture and that the age of onset is decreasing.

Carotid intima media thickness in a girl with sitosterolemia carrying a homozygous mutation in the ABCG5 gene.

BACKGROUND: Sitosterolemia is a rare lipid metabolism disorder that involves storage of plant sterols. This disease is associated with atherosclerosis, but detailed vascular endothelial assessment is difficult. CASE PRESENTATION: We report a 5-year-old girl with sitosterolemia who presented with xanthomas at 23 months of age. Her total cholesterol was 868 mg/dL, and her plasma sitosterol level was 9.48 mg/dL. Direct sequencing detected a homozygous mutation in gene ABCG5 (p.Arg389His). Echocardiographic examination revealed that the carotid artery intima media thickness (cIMT) was 0.4 mm with heterogenous hyperechogenicity inside the arterial wall. She was treated using dietary therapy and ezetimibe, which effectively lowered her sitosterol levels. After 3 years of treatment, her cIMT was stable in diameter and arterial wall echogenicity had improved. CONCLUSIONS: Sitosterolemia is a unique disorder in which it is difficult to avoid premature atherosclerosis because of high sitosterol levels. cIMT measurement with arterial wall assessment may improve management.

The ratio of glycated albumin to hemoglobin A1c measured in IFCC units accurately represents the glycation gap.

The glycation gap (G-gap: difference between measured hemoglobin A1c [A1C] and the value predicted by its regression on the fructosamine level) is stable and associated with diabetic complications. Measuring A1C level in International Federation of Clinical Chemistry (IFCC) units (A1C-SI; mmol/mol) and National Glycohemoglobin Standardization Program units (A1C-NGSP; %) and using glycated albumin (GA) level instead of fructosamine level for calculating the G-gap, we investigated whether the G-gap is better represented by GA/A1C ratio if expressed in SI units (GA/A1C-SI ratio) rather than in NGSP units (GA/A1C-% ratio). We examined 749 Japanese children with type 1 diabetes using simultaneous GA and A1C measurements. Of these, 369 patients were examined more than five times to assess the consistency of the G-gap and the GA/A1C ratio within individuals. The relationship of GA/A1C-% ratio to the corresponding A1C-NGSP was stronger than that of GA/A1C-SI ratio to A1C-IFCC. At enrollment, the inverse relationship between the GA/A1C-SI ratio and G-gap was highly significant (R(2) = 0.95) compared with that between the GA/A1C-% ratio and G-gap (R(2) = 0.69). A highly significant inverse relationship was also observed between the mean GA/A1C-SI ratio and the mean G-gaps obtained individually over time (R(2) = 0.95) compared with that using the corresponding A1C-NGSP (R(2) = 0.67). We conclude that the G-gap is better represented by the GA/A1C-SI ratio. We propose the use of mean GA/A1C-SI ratios easily obtained individually over time as reference values in Japanese children with type 1 diabetes (6.75 ± 0.60 [means ± SD]).

Severe hypothalamopituitary dysfunction accompanied by influenza-associated encephalopathy: report of two pediatric cases.

Severe influenza infection may lead to neurological damage, such as encephalopathy. This may, in turn, cause acquired hypothalamopituitary dysfunction, which can result in severe morbidity and even death. We herein report two pediatric patients who developed influenza-associated hypopituitarism and were subsequently diagnosed with encephalopathy. They were diagnosed with acute necrotizing encephalopathy and postresuscitation encephalopathy, respectively. Both showed evidence of endocrine dysfunction, and hormone replacement therapy of adrenal, thyroid, and antidiuretic hormones are resulting in continued cardiac activity and resulted in prolonged survival. Screening for endocrine function is important in patients with severe central nervous system dysfunction.

HLA-class II and class I genotypes among Japanese children with Type 1A diabetes and their families.

OBJECTIVE: To determine the HLA-DRB1, DQB1, DPB1, A, C, and B genotypes among Japanese children with autoimmune type 1 diabetes. METHODS: Four hundred and thirty patients who were GADAb and/or IA-2Ab-positive (Type 1A) were recruited from 37 medical centers as part of a nationwide multicenter collaborative study. DNA samples from 83 siblings of the children with Type 1A diabetes and 149 parent-child trios were also analyzed. A case-control study and a transmission disequilibrium test (TDT) were then performed. RESULTS: The susceptible and protective DRB1 and DQB1 alleles and haplotypes were confirmed. DPB1 alleles unique to the Japanese population and those common to multiple ethnic groups were also present. A linkage disequilibrium (LD) analysis showed both susceptible and protective haplotypes. The TDT did not reveal any alleles that were transmitted preferentially from the mother or father to children with Type 1A. Homozygosity for DRB1-09:01-DQB1-03:03 and heterozygosity for DRB1-04:05-DQB1-04:01 and DRB1-08:02-DQB1-03:02 were associated with an extremely high risk of Type 1A. A comparison of children with Type 1A and their parents and siblings suggested a dose effect of susceptible DRB1-DQB1 haplotypes and an effect of protective alleles on immunological pathogenesis. DRB1-09:01 appeared to be strongly associated with an early onset in preschool children with Type 1A diabetes. CONCLUSIONS: This study demonstrated the characteristic association of HLA-class II and class I genes with Type 1A diabetes among Japanese children. A TDT did not reveal the genomic imprinting of HLA-class II and class I genes in Type 1A diabetes.

Role of counterregulatory hormones for glucose metabolism in children and adolescents with type 1 diabetes.

To elucidate the mechanism of insulin resistance due to insulin counterregulatory hormones (ICRHs) and evaluate ICRH secretion kinetics, ICRH concentrations were measured and correlated with blood glucose levels in 28 type 1 diabetic patients. Blood glucose was measured before bedtime. Early morning urine samples were collected the next morning before insulin injection and breakfast. Fasting blood glucose, cortisol, glucagon and HbA1c levels were measured. Growth hormone (GH), adrenaline, cortisol and C-peptide levels in morning urine samples were measured; SD scores were calculated for urine GH. The laboratory values (mean ± SD) were as follows; HbA1c of 8.1% ± 1.4%; pre-bedtime glucose of 203 ± 105 mg/dl; fasting blood glucose of 145 ± 87 mg/dl; serum cortisol of 21.6 ± 5.5 µg/dl; plasma glucagon of 98 ± 41 pg/ml; urinary GH, 27.2 ± 13.0 ng/gCr; urinary cortisol of 238 ± 197 ng/gCr; and urinary Adrenaline of 22.9 ± 21.0 ng/gCr. The mean urinary GH SD score was increased (+1.01 ± 0.70; p=0.000); the mean plasma glucagon lebel (98 ± 41 pg/ml) was not. Fasting blood glucose was positively correlated with plasma glucagon (R=0.378, p=0.0471) and negatively correlated with urinary cortisol (R=-0.476, p=0.010). Urinary adrenaline correlated positively with urinary GH (R=0.470, p=0.013) and urinary cortisol (R=0.522, p=0.004). In type 1 diabetes, GH, glucagon and cortisol hypersecretion may contribute to insulin resistance, but the mechanism remains unclear.

Late-onset circulatory dysfunction after thyroid hormone treatment in an extremely low birth weight infant.

Late-onset circulatory dysfunction (LCD) is a phenomenon specific to premature infants and is characterized by sudden onset of hyponatremia, hypotension, oliguria and non-physiological weight gain, without an obvious cause, in premature infants after stabilization of circulation and respiration. The cause of LCD is not clear, but adrenal insufficiency in premature infants is a severe syndrome because steroid replacement therapy is often essential to treat the symptoms. We report a rare case of a premature infant who developed an LCD crisis the day after thyroxine replacement therapy. The female infant was born at 25 weeks of gestational age, weighing 672 g, and appeared to have hypothyroidism, with free T4 of 0.19 ng/dl and elevated TSH levels of 26.3 microIU/ml at Day 14. She developed an LCD crisis the day after starting thyroxine treatment. She received steroid replacement therapy for 4 weeks and her adrenal function progressively recovered. She also needed thyroxine supplementation for 13 weeks, which maintained her thyroid function as euthyroid. Because she exhibited cortisol insufficiency and thyroid hormone insufficiency, the antecedent thyroid hormone replacement may be responsible for the onset of LCD. We must consider monitoring adrenal function when starting thyroxine therapy in premature infants with hypothyroxinemia.

A case report of dysosteosclerosis observed from the prenatal period.

Dysosteosclerosis is a sclerosing bone dysplasia with skeletal changes resembling those of osteopetrosis. The disorder is associated with dental anomalies and occasionally mental retardation. Because of the rarity and phenotypic diversity of dysosteosclerosis, it remains unsolved whether or not the disorder is heterogeneous. We report here on an affected boy associated with brain calcification and epilepsy with developmental delay. Prenatal ultrasound revealed ventriculomegaly, and brain CT in the neonatal period showed periventricular calcifications. At 13 mo of age, he presented with generalized convulsion with developmental delay. Metaphyseal sclerosis, metaphyseal undermodeling, and oval-shaped vertebral bodies on skeletal survey warranted a diagnosis of dysosteosclerosis. Retrospective review of radiographs as a neonate showed metaphyseal radiolucency, but not metaphyseal sclerosis. Since then, neither the bone changes nor neurological symptom has progressively worsened up to 4 yr of age. Thus, it is thought that the clinical and radiological manifestations of the sclerotic disorder become obvious during infancy. Brain calcification of prenatal onset may be an essential syndromic constituent of the disorder.

Expression of stanniocalcin-1 in gastrointestinal tracts of neonatal and mature rats.

Stanniocalcin-1 (STC-1) produced by ovaries endocrinologically targets to mammary glands and is secreted into milk during lactation. The decline of mother's serum level by STC-1 antiserum administration reduced the milk fat content and the pups' body fat content. Nevertheless, the pups' fecal fat content was increased, suggesting that milk-derived STC-1 could influence intestinal fat absorption. We investigated the STC-1 expression in rat gastrointestinal tissues using immunocytochemistry and in situ hybridization. STC-1 was widely expressed in the chief cells of gastric pits and the cells of intestinal glands. Goblet cells in the small intestine contained STC-1 protein in their mucus. The distribution shows that this peptide is secreted exocrinologically into the gastrointestinal lumen. Quantitative RT-PCR analysis revealed that the expression ratio was higher in the periods of heavy nutritional demand, such as growing and lactation. The endogenous STC-1, similar to milk-derived STC-1, may be involved in digestion and/or absorption in gastrointestinal organs.

Subtractive hybridisation screen identifies genes regulated by glucose deprivation in human neuroblastoma cells.

Glucose is the major source of energy for the brain and inadequate glucose supply causes damage of neuronal cells. In this study we employed the human neuroblastoma cell line SH-SY5Y, as an in vitro model for neuronal cells, to identify genes regulated by glucose deprivation. Using subtractive hybridisation screen, validated by Northern analysis, we identify for the first time specific targets of the glucopenic response. These genes are involved in key cellular process including gene transcription, protein synthesis, mitochondrial metabolism, neuronal development, neuroprotection and neuronal apoptosis. Our findings suggest that the fate of neuronal cells undergoing glucose starvation relies on complex gene interactions. Modulation of the expression of these genes in vivo will enable determination of the precise role of each gene and possibly identify key elements and potential therapeutic targets of the glucopenic response.

Association of the CTLA-4 gene 49 A/G polymorphism with type 1 diabetes and autoimmune thyroid disease in Japanese children.

OBJECTIVE: To clarify the role of the T-lymphocyte-associated-4 (CTLA-4) polymorphism in the susceptibility to child-onset type 1 diabetes with regard to its clinical characteristics and complications with autoimmune thyroid disease (AITD) in the Japanese population. RESEARCH DESIGN AND METHODS: The CTLA-4 49 A/G polymorphism was detected by the PCR-restriction fragment-length polymorphism (RFLP) method in 97 type 1 diabetic subjects and 20 patients with Graves' disease, a cohort which included 4 patients who also had type 1 diabetes. RESULTS: The genotypes and allele frequencies of this polymorphism did not differ between the type 1 diabetic subjects and the control subjects. The G allele frequency was 63.9% in the type 1 diabetic subjects. The G allele frequency in the subgroup of patients with a high titer of autoantibodies to the GAD antibody (Ab) was 72.9% (P = 0.0499 vs. control subjects); in the subgroup of patients without HLA DRB1*0405, it was 72.6% (P = 0.0271 vs. control subjects); and in the subgroup of patients with a residual beta-cell function, it was 78.6% (P = 0.0391 vs. control subjects). The G allele frequency in the patients with Graves' disease was also significantly higher at 78.1% (P = 0.0405 vs. control subjects). Furthermore, the frequency in our diabetic subjects complicated with Graves' disease was even higher (87.5%). CONCLUSIONS: We have demonstrated that a distinct association exists between the G allele of CTLA-4 and high values of GAD Ab, residual beta-cell function, and the absence of HLA-DRB1*0405.

The association of Ala45Thr polymorphism in NeuroD with child-onset Type 1a diabetes in Japanese.

Recently Iwata et al. reported that the polymorphism in NeuroD exon 2(Ala45Thr) was associated with adult-onset Type 1 diabetes in Japanese. Furthermore, the mutations in the NeuroD as a regulator of insulin transcription have been reported to result in Type 2 diabetes. We, therefore, aimed to clarify the role of this Ala45Thr polymorphism in the susceptibility to Type 1a, immune-mediated, diabetes of child-onset Japanese patients. Eighty patients with child-onset Type 1 diabetes were examined along with 121 non-diabetic subjects as the controls. The polymorphism in Ala45Thr was defined using the PCR-RFLP method. The GAD Ab, IA-2 Ab, HLA-DRB1 genotypes and residual beta-cell function at 3 years from onset were evaluated in relation to the difference in this polymorphism. The frequency of the Ala45Thr heterozygotes was significantly higher in the Type 1 diabetic patients than in the controls (21.3 versus 9.9%, P=0.0252). The frequency of loss of beta-cell function was higher in heterozygotes patients than in wild type homozygotes patients (P=0.0112). Type 1 diabetic patients with DRB1*0901 allele showed a significantly higher frequency, 27.9%, of the Ala45Thr variant than the controls (P=0.0041). In conclusion, the Ala45Thr polymorphism contributes to the risk of development of, and to the early deterioration of beta-cell function, in Type 1a diabetes among the Japanese population.