Satomi Koyama

Adiposity Rebound and the Development of Metabolic Syndrome

OBJECTIVE: The age of adiposity rebound (AR) is defined as the time at which BMI starts to rise after infancy and is thought to be a marker of later obesity. To determine whether this age is related to future occurrence of metabolic syndrome, we investigated the relationship of the timing of AR with metabolic consequences at 12 years of age. METHODS: A total of 271 children (147 boys and 124 girls) born in 1995 and 1996 were enrolled in the study. Serial measurements of BMI were conducted at the ages of 4 and 8 months and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 years, based on which age of AR was calculated. Plasma lipids and blood pressure were measured at 12 years of age. RESULTS: An earlier AR (<4 years of age) was associated with a higher BMI (≥20) and a lipoprotein phenotype representative of insulin resistance. This phenotype consists of elevated triglycerides, apolipoprotein B, and atherogenic index and decreased high-density lipoprotein cholesterol in boys and elevated apolipoprotein B in girls at 12 years of age. The earlier AR was also related to elevated blood pressure in boys. CONCLUSIONS: This longitudinal population-based study indicates that children who exhibit AR at a younger age are predisposed to future development of metabolic syndrome. Therefore, monitoring of AR may be an effective method for the early identification of children at risk for metabolic syndrome.

Association between Timing of Adiposity Rebound and Body Weight Gain during Infancy

OBJECTIVE To investigate whether increments of weight gain in early infancy are related to the timing of adiposity rebound (AR). STUDY DESIGN A total of 271 children (147 boys and 124 girls) in 1 community were enrolled in the study. Serial measurements of body mass index were carried out at the ages of 4, 8, and 12 months and 1.5, 2, 3, 4, 5, 6, 7, 8, 9, and 10 years, based on which the age of AR was determined. We also calculated body weight increments in 3 separate periods: birth to 4 months, 4-8 months, and 8-12 months. RESULTS There was no significant relationship between weight gain in any period of infancy and the age of AR. Weight gain between birth and 4 months was positively correlated only with body mass index at 7 years of age. CONCLUSIONS We could not find an association between body weight gain during infancy and the timing of AR. This suggests that infantile weight gain is not related to childhood obesity through AR.

Increase of body mass index (BMI) from 1.5 to 3 years of age augments the degree of insulin resistance corresponding to BMI at 12 years of age

Abstract: To elucidate the effect of early growth patterns on the metabolic sensitivity to adiposity, we examined the relationship between the homeostatic model assessment of insulin resistance (HOMA-IR) and body mass index (BMI) levels at 12 years of age in 101 boys and 91 girls in a birth cohort. Children with an increase in BMI from the ages of 1.5 to 3 years exhibited a greater increase of HOMA-IR per BMI increase at 12 years of age compared to those with a decrease in BMI or stable BMI from 1.5 to 3 years. This suggests that children who show an increase in BMI from 1.5 to 3 years, a period normally characterized by a decreased or stable BMI, are more prone to developing insulin resistance at 12 years of age.

Relation between low-density lipoprotein particle size and insulin and diabetes mellitus

To the Editor: We read the review by Maahs et al with much interest. There have only been a few studies on low-density lipoprotein (LDL) particle size and number in children with diabetes mellitus, and in this context, we would very much like to present our data here. All LDL particles are atherogenic, but smaller dense LDL particles are recognized to be more atherogenic. LDL particle sizes are also known to be correlated with insulin resistance. We have measured LDL particle sizes in children with gradient gel electrophoresis. The average LDL particle size in a control group of 508 healthy male and female children (10 to 13 years old) was 26.7 0.45 nm, compared with 26.4 0.54 nm (range, 25.6-27.2 nm) in children with type 1 diabetes mellitus (T1DM; n = 18, 2-19 years old) and 26.0 1.14 nm (range, 23.3-27.1 nm) in children with type 2 diabetes mellitus (T2DM; n = 7, 12-20 years old). The mean hemoglobin A1c levels of the 2 groups were 9.5% 2.6% and 9.2% 2.7%. The mean LDL particle size in patients with T1DM and T2DM was significantly smaller than that in healthy children (P < .05 and P < .01), but there was no difference between the patients with T1DM and the patients with T2DM. A significant negative correlation was observed between LDL particle sizes and hemoglobin A1c levels in the T1DM group (r =–0.55, P < .05), but not in the T2DM group (r = –0.13, P value not significant). The frequencies of small dense LDL particles (<25.5 nm in diameter) was 30 of 508 (5.9%) in the healthy control group, 4 of 18 (28.5%) in the T1DM group, and 2 of 7 (28.5%) in the T2DM group. Poor glycemic control may contribute to an increase in atherogenic small dense LDL particle size in both types of diabetes mellitus in children and adolescents, as also is evident in our data. The negative correlation between hemoglobin A1c levels and LDL particle sizes noted in T1DM is interesting and deserves further examination. The number of subjects with T2DM was too small to make a statement about this issue, and a larger study is warranted. Assessment of abnormalities in LDL particle number in addition to LDL particle size is important for qualitative evaluation of atherogenicity caused by LDL particles. LDL particle numbers cannot be directly assessed with gel electrophoresis, the method used in our study, in contrast to direct analysis of the lipoprotein subclass with nuclear magnetic resonance. However, determination of whole plasma apolipoprotein B (ApoB) can be considered as a surrogate measurement of LDL particle number because each LDL particle carries 1 apolipoprotein B-100 molecule. In our subjects, the mean concentrations of LDL cholesterol were 113 42 mg/dL, 117 44 mg/dL, and 94 21 mg/dL in the T1DM, T2DM, and control groups, respectively, and the mean ApoB concentrations were 85 25 mg/dL, 111 19 mg/dL, and 70 21 mg/dL, respectively.

Incidence rate and characteristics of symptomatic vitamin D deficiency in children: a nationwide survey in Japan

There is concern that vitamin D deficiency is prevalent among children in Japan as well as worldwide. We conducted a nationwide epidemiologic survey of symptomatic vitamin D deficiency to observe its incidence rate among Japanese children. A questionnaire inquiring the number of new patients with vitamin D deficiency rickets and/or hypocalcemia for 3 years was sent to 855 randomly selected hospitals with a pediatrics department in Japan. In this survey, we found that 250 children were diagnosed with symptomatic vitamin D deficiency. The estimated number of patients with symptomatic vitamin D deficiency per year was 183 (95% confidence interval (CI): 145-222). The overall annual incidence rate among children under 15 years of age was 1.1 per 100,000 population (95% CI: 0.9-1.4). The second survey has provided detailed information on 89 patients with symptomatic vitamin D deficiency under 5 years of age in hospitals in the current research group. The nationwide and second surveys estimated the overall annual incidence rate of symptomatic vitamin D deficiency in children under 5 years of age to be 3.5 (2.7-4.2) per 100,000 population. The second survey revealed 83% had bowed legs, 88% had exclusive breastfeeding, 49% had a restricted and/or unbalanced diet and 31% had insufficient sun exposure among the 89 patients. This is the first nationwide survey on definitive clinical vitamin D deficiency in children in Japan. Elucidating the frequency and characteristics of symptomatic vitamin D deficiency among children is useful to develop preventative public health strategies.

Early Adiposity Rebound and Small Dense Low-Density Lipoprotein in Childhood Obesity

Aim: The adiposity rebound (AR) corresponds to the second rise in the body mass index (BMI) curve that occurs between ages 5 and 7 years. The goal of this study was to determine whether age at AR is related to the presence at 12 years old of small dense low-density lipoprotein (SDLDL), an atherogenic lipoprotein produced as a metabolic consequence of AR. Methods: A longitudinal population-based prospective study was performed in 215 children. Serial measurements of BMI were conducted at ages 1, 1.5, 2 and yearly thereafter until 12, based on which age at AR was calculated. The subjects were divided into 5 groups according to age at AR of ≤4, 5, 6, 7 and ≥8 years. Plasma lipids and SDLDL were measured at 12 years of age. SDLDL (LDL particle size <25.5 nm) was determined by nondenaturing 2-16% gradient gel electrophoresis. Results: The prevalences of SDLDL were 15.0% in children with age at AR ≤4 y, 8.1% in those with age at AR 5 y, and 0% in all other groups (AR at ≥6 years). An earlier AR was significantly associated with higher BMI, increased plasma triglyceride (p < 0.05), increased atherogenic index (p < 0.05), and decreased HDL-cholesterol (p < 0.05) at 12 years of age. Conclusion: Children with AR before 4 years old showed a high prevalence of atherogenic SDLDL, indicating a predisposition for future cardiovascular disease.

Estimation of LDL Particle Size Using Lipid Indices: A Population-Based Study of 1578 Schoolchildren

BACKGROUND Low-density lipoprotein (LDL) is atherogenic and LDL particles are reduced in diameter in the presence of insulin resistance, forming small, dense LDL. This study was conducted to assess the relationship between commonly used lipid indices and LDL particle size and furthermore to clarify the best surrogate lipid markers that could conveniently be used to estimate LDL particle size in children. METHODS We determined LDL particle diameter by gradient gel electrophoresis in 1578 children aged 10-12 years. At the fasting state, the relationships between measured LDL particle size and lipid variables [total cholesterol (TC), triglycerides (TG), LDL-cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), atherogenic index [(TC-HDL-C)/HDL-C, TG/HDL-C, LDL-C/HDL-C, and LDL-C/apolipoprotein B (Apo B) and non-HDL-C (TC-HDL-C)] were analyzed. RESULTS The LDL particle diameter was 26.64 (mean) ± 0.48 (SD) nm in boys (n = 820) and 26.66 ± 0.49 nm in girls (n = 758); there was not a statistically significant difference. There were statistically significant correlations between LDL particle size and TG or HDL-C concentrations (r = 0.28∼0.37), but the correlations with LDL-C and ApoB were very weak. The combined lipid measures, such as atherogenic index, TC/HDL-C, TG/HDL-C, and LDL-C/HDL-C showed moderate correlations (r = 0.33∼0.38) with LDL particle size; however, the correlation of non-HDL-C with LDL particle size was weak (r = 0.18∼0.19). Simple HDL-C measure appeared to be of comparable value to combined lipid measures. CONCLUSIONS Our data indicate that various lipid indices are not superior to HDL-C levels alone as a clinical tool for estimating LDL particle size. Non-HDL-C was less valuable in this aspect.

Body mass index increase before 3 years‐of‐age augments the degree of insulin resistance corresponding to body mass index in adolescent girls

In a recent study of insulin resistance (IR), insulin deficiency and their relationship with obesity in children using homeostasis model assessment (HOMA) values in a population-based setting, Nishimura et al. showed that increased body mass index (BMI) was significantly correlated with increased IR in boys, but not in girls. The authors concluded that increases in BMI could have far more diverse implications for girls than for boys, and suggested that it should be assumed that there are girls in whom IR can easily increase without an apparent increase in obesity. We have recently observed similar findings with regard to a sex difference in the development of IR from a different perspective. An association between BMI increase in early childhood (adiposity rebound) and future cardiometabolic risk is of increasing interest, as identifying growth patterns harmful to cardiometabolic health might provide opportunities for early interventions. Therefore, to examine the effect of early growth patterns on IR corresponding to adiposity, we examined the relationship between the HOMA of insulin resistance (HOMA-R) and BMI in children aged 12 years in groups based on an increase or decrease in BMI from age 1.5–3 years (101 boys and 91 girls in a birth cohort). Routine health checks of children are carried out at 1.5 and 3 years by the Ministry of Health, Labor and Welfare in Japan, and data from these health checks were used to evaluate growth. In statistical analysis, the augmented degree of log-transformed HOMA-R per log-transformed BMI was significantly higher in girls who had a BMI increase from 1.5 to 3 years compared with those who showed a decrease in BMI or stable BMI (Z-score for BMI increase within 0.5 standard deviation). This means that girls with an increase of BMI from 1.5 to 3 years showed a greater increase of HOMA-IR per BMI increase at 12 years old, compared to those with a decrease of BMI from 1.5 to 3 years. These results suggest that girls who show an increase of BMI from 1.5 to 3 years, a period normally characterized by a decreased BMI, are more prone to developing insulin resistance at 12 yearsof-age. In general, females are slightly more insulin resistant and have a higher body fat percentage than males from early childhood through to old age. Therefore, changes of body composition (increase in adiposity) during early growth periods might be of long-term relevance for altered insulin sensitivity to adiposity, particularly in girls. The present data might provide one possible explanation of the observation made by Nishimura et al.

Central hypothyroidism in a pediatric case of primary acute monoblastic leukemia with central nervous system infiltration: A case report

Rationale: Central nervous system (CNS) leukemia is a frequent diagnosis in pediatric acute myeloblastic leukemia (AML) and includes neural symptoms. However, CNS leukemia is rarely associated with central hypsothyroidism. Patient concerns and diagnoses: A 2-year-old female with AML with MLL rearrangement presented with CNS infiltration. Laboratory tests suggested the presence of central hypothyroidism (thyroid-stimulating hormone [TSH]: 0.48 mIU/ml, normal range 0.7–6.4 mIU/ml; serum free thyroxine [FT4]: 0.62 ng/dl, normal range 0.8–2.2 ng/dl; free triiodothyronine: 1.57 pg/ml, normal range 2.7–5.6 pg/ml). Magnetic resonance imaging detected no lesions in the hypothalamus, pituitary, or thyroid. Interventions and outcomes: Levothyroxine (2.5 mg/kg/day) was administered together with chemotherapy and intrathecal injection of methotrexate, cytarabine, and hydrocortisone into the cerebrospinal fluid. The FT4 concentration increased after levothyroxine treatment, but later decreased after relapse of CNS leukemia. The TSH concentrations remained low. After remission of CNS leukemia, the TSH and FT4 concentrations quickly recovered to their normal ranges. Lessons: We believe that the CNS leukemia directly affected TSH and thyroid hormone secretion in our patient.

A case of congenital combined pituitary hormone deficiency who showed respiratory distress and hypoglycemia soon after birth

Congenital combined pituitary hormone deficiency (CCPHD) is a rare disease, presenting with respiratory distress, hypoglycemia and jaundice soon after birth. It is caused by .pituitary aplasia or hypoplasia or abnormality of transcription factor which related to pituitary development. We describe a Japanese patient with CCPHD, who presented with respiratory distress, hypoglycemia and jaundice soon after birth. The patient is now 13 months old Japanese girl. She was born by cesarean section because of fetal distress with 39 weeks and 4 days gestation after an uneventful pregnancy. Her parents were unrelated. Birth length and weight were 43.8cm (-2.2SD) and 2,100g and Apgar scores were 8 at both of 1 and 5 min. She had showed tachypnea and cyanosis since soon after birth and taken nasal-CPAP. However respiratory distress had not improved. She had also showed jaundice and hypoglycemia and was treated with phototherapy and infusion therapy. At 6 days old, we found her FT4 level was 0.4 pg/ml and TSH level was below 0.01 μIU/ml. She was suspected CPHD and anterior pituitary hormone levels were assessed. All of anterior pituitary hormones were undetectable. Anterior pituitary was not visible, posterior pituitary was detected at normal position and there were no other abnormality on brain magnetic resonance imaging. We diagnosed her as CCPHD and hydrocortisone was started since 6 days old and levothyroxine since 8 days old. After that respiratory distress and jaundice had improved rapidly. But hypoglycemia had appeared again after interrupting infusion therapy. GH level after arginine stimulation was also undetectable. She had also started growth hormone therapy since 25 days old and she has had no hypoglycemic episodes after that. Her length and weight were 70.3cm (-1.2SD) and 8,485g at 1 year old. GH replacement therapy that was started soon after diagnosis was able to prevent the severe growth retardation. She has no gene abnormalities of transcription factors, HESX1, LHX4 and OTX2, that involves pituitary development. Further studies are needed for investigating genetic basis of this patient. Careful and prompt clinical, endocrinological and neuroradiological assessment are needed for diagnosis of hypopituitarism in patients who show prolonged respiratory distress, hypoglycemia or jaundice soon after birth. Written informed consent was obtained from the patients parent or guardian for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.