Kisho Kobayashi

Pathogenic factors of glucose intolerance in obese Japanese adolescents with type 2 diabetes.

We attempted to identify the pathogenic factors involved in the progression to type 2 diabetes in obese Japanese adolescents. Subjects included 18 nondiabetic obese adolescents, 12 obese adolescents with type 2 diabetes on diet therapy, 10 obese adolescents with type 2 diabetes manifesting ketosis at onset or with a history of treatment with hypoglycemic agents, and 26 non-obese adolescent control subjects. The first-phase insulin response (FPIR), glucose disappearance constant (Kg), glucose effectiveness (Sg), and insulin sensitivity (S(I)) were obtained using an insulin-modified frequently sampled intravenous glucose tolerance test (FSIGT) and a minimal model analysis. The disposition index (DI, by FPIR x S(I)) was determined to assess any endogenous insulin effect. The results showed that Kg was decreased significantly (P = .0006) with the progression to severe diabetes in the obese groups. Although S(I) and Sg did not differ significantly among the 3 obese groups, both parameters were significantly lower in each obese group versus the non-obese controls. As a result of the significant decrease in FPIR (P < .0001), the DI decreased (P = .0006) with the progression to severe diabetes in the obese groups. In conclusion, an early manifestation of type 2 diabetes with occasional ketosis at onset may result from beta-cell dysfunction to glucose stimulation. This finding is demonstrated by the relatively low FPIR to decreased S(I) in obese Japanese adolescents, as well as the low Sg as a synergic role in glucose intolerance. The present findings from a Japanese population for pathogenic factors aside from obesity may help us to gain a better understanding of the progression to adolescent, early-onset, obese type 2 diabetes and its severity.

Role of IGF binding protein-1 in the dawn phenomenon and glycemic control in children and adolescents with IDDM

OBJECTIVE To clarify the involvement of IGF binding protein (IGFBP)-1 in the dawn rise in plasma glucose and in the overall glycemic control in patients with IDDM. RESEARCH DESIGN AND METHODS Seventy patients with IDDM were divided into three groups according to pubertal development. Blood samples were obtained for measuring plasma glucose, IGFBP-1, and free insulin at 2200, 0500, and 0700 over a 2-day period. Levels of HbA1c, IGF-1, and IGFBP-3 were determined at 0700. Urinary growth hormone (GH) was collected overnight. To examine its frequency, the dawn phenomenon was defined on the basis of the following: 1) change in plasma glucose from 0500 to 0700, 2) plasma glucose level at 0700, and 3) no antecedent hypoglycemia. RESULTS There was a statistically significant link between the dawn changes in plasma glucose and IGFBP-1 (r = 0.37, P < 0.01). The former was not related to the change in free insulin or to the overnight urinary GH level. In stepwise regression analyses, plasma glucose at 0700 = 0.03 IGFBP-1 (P < 0.01) + 0.525 HbA1c (P < 0.01) + 3.696 (R2 = 51%). Approximately half of the patients in each group exhibited the dawn phenomenon; 38% of patients with HbA1c < 8% also showed the dawn phenomenon. CONCLUSIONS We have demonstrated a statistically significant link between the morningrisk in IGFBP-1 and plasma glucose. The free fraction of IGF-1 modulated by acute changes in IGFBP-1 may play a direct role. The dawn phenomenon may occur regardless of pubertal stage or glycemic control in children and adolescents with IDDM.

Association of angiotensin-converting enzyme gene polymorphism with lipid profiles in children and adolescents with insulin-dependent diabetes mellitus.

We attempted to clarify the association between angiotensin-converting enzyme (ACE) gene polymorphism and the other predictive factors for macroangiopathy in children and adolescents with uncomplicated insulin-dependent diabetes mellitus (IDDM). Sixty-three patients were divided into 3 groups according to the ACE genotypes. The lipid profiles were evaluated according to ACE genotypes. The level of lipoprotein(a) (Lp(a)) in the II genotype was significantly lower than that in groups with the D allele. Lp(a) significantly correlated with apo B/apo A-I (p < 0.001, r = 0.63) and atherogenic index (AI = (total cholesterol – high-density lipoprotein cholesterol)/high-density lipoprotein cholesterol; p = 0.004, r = 0.36). We suggest that the D allele may affect the level of Lp(a) and the other lipid profiles in IDDM.

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

Sugihara S, Ogata T, Kawamura T, Urakami T, Takemoto K, Kikuchi N, Takubo N, Tsubouchi K, Horikawa R, Kobayashi K, Kasahara Y, Kikuchi T, Koike A, Mochizuki T, Minamitani K, Takaya R, Mochizuki H, Nishii A, Yokota I, Kizaki Z, Mori T, Shimura N, Mukai T, Matsuura N, Fujisawa T, Ihara K, Kosaka K, Kizu R, Takahashi T, Matsuo S, Hanaki K, Igarashi Y, Sasaki G, Soneda S, Teno S, Kanzaki S, Saji H, Tokunaga K, Amemiya S, and The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT). HLA‐class II and class I genotypes among Japanese children with Type 1A diabetes and their families.

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.

Decreased activity of plasma cholesteryl ester transfer protein in children and adolescents with insulin-dependent diabetes mellitus

The aims of the present study were to determine whether the activity of cholesteryl ester transfer protein (CETP) is altered in the plasma of children and adolescents with insulin‐dependent diabetes mellitus (IDDM), and whether high‐density lipoprotein‐cholesterol (HDL‐C) levels reflect CETP activity. Plasma CETP activity was measured by a micromethod for radioisotopic assay, using exogenous lipoproteins as donor and acceptors. The study subjects were 22 Japanese children and adolescents with IDDM (8M, 14F) with a mean age of 13.0 y. They were non‐obese and did not suffer from any significant nephropathy. The age‐matched control group consisted of 20 children (10M, 10F) with a mean age of 12.7 y. Serum triglycerides were significantly decreased, while the levels of HDL‐C and apolipoprotein (apo) A1 were markedly increased, in the IDDM patients. Plasma CETP activity was significantly lower in the IDDM patients than in the control children. None of the anthropometric indices nor the biochemical data correlated significantly with CETP activity in the IDDM patients. Suppression of CETP along with the putative activation of lipoprotein lipase due to peripheral hyperinsulinism appears to induce synergistically the increase in HDL‐C in IDDM children.

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.

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

Abstract 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.

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

Abstract 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.