Haruhisa Yamashita

Variation of the Fatty Acid Binding Protein 2 Gene Is Not Associated With Obesity and Insulin Resistance in Japanese Subjects

An alanine to threonine substitution at codon 54 of the fatty acid binding protein 2 (FABP2) gene has been associated with insulin resistance in Pima Indians and with obesity in aboriginal Canadians. We investigated whether this polymorphism contributes to obesity and insulin resistance in 258 Japanese subjects. Thirty-six subjects (13.9%) were homozygous for the Thr54 allele, 106 (41.1%) were heterozygous for the Ala54/Thr54 allele, and 116 (45.0%) were homozygous for the Ala54 allele. The frequency of the Thr54 allele was 0.34 and did not differ significantly between men and women. The incidence of non-insulin-dependent diabetes mellitus (NIDDM) was not different among the three genotypes. The variation at codon 54 of the FABP2 gene was not associated with obesity, hypertension, dyslipidemia, hyperuricemia, or hyperinsulinemia. These results suggest that the polymorphism at codon 54 of the FABP2 gene is not a major contributing factor to obesity and insulin resistance in Japanese subjects.

Pioglitazone prevents mice from multiple low-dose streptozotocin-induced insulitis and diabetes.

Macrophage infiltration into pancreatic islets is thought to be an initial event inducing insulitis in the development of type 1 diabetes. Thiazolidinedione is a direct ligand for peroxisome proliferator-activated receptor-gamma, recently reported to inhibit macrophage activation, including cytokine production and type 2 nitric oxide synthase expression. We investigated the effect of pioglitazone, a thiazolidinedione compound, on the development of multiple low-dose streptozotocin (MLDS)-induced autoimmune diabetes in mice. CD-1 mice intraperitoneally injected with five daily sub-diabetogenic doses (30 or 40 mg/kg body weight) of streptozotocin developed mononuclear cell infiltration in and around islets, followed by hyperglycemia. Oral administration of pioglitazone (0.01% food admixture) from 7 days before the first streptozotocin injection prevented or delayed the development of diabetes induced by MLDS. Histologically, pioglitazone blocked the infiltration of mononuclear cells into islets in MLDS mice. Peritoneal macrophages from MLDS mice at day-7 produced significantly large amount of nitric oxide compared with those from control mice. Such activation of peritoneal macrophages was not observed in pioglitazone-treated MLDS mice. These findings suggest that pioglitazone blocks the autoimmune process in the development of MLDS diabetes, partly by inhibiting the macrophage activation.

Phenotypic characterization of the β3-adrenergic receptor mutation and the uncoupling protein 1 polymorphism in Japanese men

The Trp64Arg mutation of the beta3-adrenergic receptor (beta3AR) gene and A to G polymorphism of the uncoupling protein 1 (UCP1) gene are reported to be associated with weight gain, and both have been shown to have an additive effect on weight gain in Caucasians. Racial differences have also been noted in the beta3AR mutation; however, the effect of UCP1 polymorphism on body weight is not obvious in the Japanese. Thus, we investigated the association of genetic variations in beta3AR and UCP1 genes and the additive effects of these two genes in 214 Japanese men. The frequency of the Trp64Arg allele was 0.19, and serum triglyceride was significantly higher in Arg64 homozygotes versus Trp64 homozygotes. The frequency of the G allele was 0.51, and the body mass index (BMI) was significantly higher in subjects with the G allele (GG homozygotes and AG heterozygotes) versus those without it (AA homozygotes). The beta3AR mutation and UCP1 polymorphism were not found to have additive effects, and they were not related to glucose tolerance patterns and insulin resistance. Our results suggest that the beta3AR mutation is associated with hypertriglyceridemia and the UCP1 polymorphism may be a weak contributing factor to obesity in Japanese men.

A New Procedure for Construction of Oxocane and Oxonane Derivatives Based on Alkyne–Co2(CO)6 Complexes

Abstract Treatment of 2-(3-hydroxy-5-phenylpent-4-yn-1-yl)-2-(trimethylsilylmethyl)tetrahydrofuran (18) with Co2(CO)8 gave the corresponding cobalt complex, which was subsequently exposed to methanesulfonyl chloride and triethylamine in methylene chloride at refluxing temperature to provide the oxocane derivative 20 in 72% yield. This method was found to be applicable for construction of the oxonane framework.

Elevated serum levels of soluble vascular cell adhesion molecule-1 in NIDDM patients with proliferative diabetic retinopathy

We studied 68 Japanese NIDDM patients (38 men and 30 women), aged 56.9+/-1.2 years (range 33-75 years), with a BMI of 23.1+/-0.5 kg/m2 without hypertension, dyslipidemia, and diabetic macroangiopathy for evaluating the relationship between serum soluble vascular cell adhesion molecule-1 (sVCAM-1) levels and the severity of diabetic retinopathy. Fundus examination was performed by an ophthalmologist using an ophthalmoscope, and the findings were graded as: (1) no signs of diabetic retinopathy (NDR), (2) background diabetic retinopathy (BDR), or (3) proliferative diabetic retinopathy (PDR). Serum sVCAM-1 levels were measured in duplicate by enzyme-linked immunosorbent assay using the soluble VCAM-1 KIT (R&D Systems Ltd., Ablingdon, Oxfordshire, UK). There was no difference in serum sVCAM-1 levels between patients with BDR (n = 17) and patients with NDR (n = 40) (1035.3+/-104.4 and 978.8+/-48.9 ng/ml, respectively, P = 0.8), but patients with PDR (n = 11) showed a significant increase of serum sVCAM-1 levels compared with patients with NDR (1281.8+/-166.3 and 978.8+/-48.9 ng/ml, respectively, P = 0.02). Although serum sVCAM-1 levels were correlated, not only with age but also with the known diabetic duration (r = 0.39, P = 0.001, and r = 0.40, P = 0.0007, respectively), age-adjusted sVCAM-1 levels were still significantly higher in the PDR group than in the NDR group. In contrast. serum sVCAM-1 levels were not related to the presence of diabetic nephropathy or HbA1c levels. Our results suggest that sVCAM-1 might be implicated in the development of the diabetic retinopathy, and measurement of serum sVCAM-1 levels in NIDDM patients maybe clinically useful for assessing the severity and possibly the activity of diabetic retinopathy.

Synthesis of oxaspiro[m.n] skeletons based on the Nicholas reaction

Abstract Treatment of alkyne–Co 2 (CO) 6 complexes possessing a methylidene moiety as well as a terminal hydroxy functionality with SnCl 4 at 0°C effected tandem ring-closure reactions resulting in the formation of 1-oxaspiro[4.4]nonane, 1-oxaspiro[4.5]decane, 6-oxaspiro[4.5]decane, and 1-oxaspiro[5.5]undecane frameworks in high yields.

Extramedullary plasmacytoma in the adrenal incidentaloma

High‐resolution imaging has led to the increasingly frequent discovery of adrenal incidentalomas. Most are nonfunctioning tumours and adenomas, but it is difficult to distinguish benign from malignant tumours using only morphological and laboratory data, and the diagnosis often remains uncertain without histological examination. Here we report the case of a 52‐year‐old Japanese man who had a right adrenal incidentaloma 4 cm in diameter. The tumour was removed by laparoscopic adrenalectomy. The pathology specimen revealed the typical histology of plasmacytoma. Extramedullary plasmacytoma is a very rare type of plasma cell proliferative disorder. This is the first documented case of an extramedullary plasmacytoma in the adrenal gland.

Adrenocorticotropin-independent unilateral adrenocortical hyperplasia with Cushing's syndrome: Immunohistochemical studies of steroidogenic enzymes, ultrastructural examination and a review of the literature

A 60‐year‐old woman presented with a history of palpitations, headaches and severe hypertension, which was resistant to hypotensive agents. She had a 2‐year history of obesity and a moon face. Her plasma adrenocorticotropic hormone level was below the limits of detection and did not respond to corticotropin‐releasing hormone. Urinary‐free cortisol was elevated and the circadian rhythm of serum cortisol level had completely disappeared. Imaging analysis demonstrated a unilaterally functioning mass in the left adrenal gland. Serum cortisol level in the left adrenal vein was elevated. The resected adrenal mass measured 4 × 3.5 × 2.5 cm, and ranged from yellow to tan in color. The adrenal cortex adjacent to the nodule did not demonstrate cortical atrophy. The mass was well circumscribed but not encapsulated, and consisted of multiple cortical nodules. These nodules were composed predominantly of clear cortical cells, and partly of compact cortical cells. Immunoreactivity of steroidogenic enzymes including cholesterol side‐chain‐cleavage P450, 3β‐hydroxysteroid dehydrogenase, 21‐hydroxylase cytochrome P450, 11β‐hydroxylase cytochrome P450 and 17α‐hydroxylase cytochrome P450 was marked in cortical nodules, but minimal in non‐nodular cortex. Ultrastructural examination of nodular cortical cells also demonstrated well‐developed mitochondria and smooth endoplasmic reticulum, consistent with elevated steroidogenesis in these cells.

S20G mutation of the amylin gene in Japanese patients with type 2 diabetes.

Amylin is a major protein component of islet amyloid, and thought to be a pancreatic islet hormone that plays a role similar to insulin and glucagon in the maintenance of glucose homeostasis [1]. Recently, Sakagashira et al. [2] reported that a serine to glycine missense mutation at position 20 of the amylin molecule (S20G) was found in 4.1% of Japanese patients with type 2 diabetes and 10% of those with early-onset type 2 diabetes, whereas the mutation was not found in non-diabetic subjects and type 1 diabetic patients. Racial differences have been noted in the frequency and role of the S20G mutation in association with the development of diabetes. No mutation was found in Caucasians [3–5]. The mutation was found in Chinese and Taiwanese subjects, but an association with diabetes was only established among the former [6,7]. In contrast to the findings of Sakagashira et al., Yamada et al. [8] reported that the frequency of the mutation was not statistically different between Japanese type 2 diabetic patients and subjects with normal glucose tolerance (NGT). To help clarify this apparent inconsistency in the role of the S20G mutation in the development of diabetes in Japanese subjects, we investigated the mutation in 308 Japanese patients with type 2 diabetes aged from 20 to 89 years (60.9912.2 years, mean9SD), and 149 NGT subjects with no family histories of diabetes aged from 40 to 67 years (50.996.3 years, mean9SD). Type 2 diabetes and NGT were defined by the World Health Organization (WHO) criteria. In the type 2 diabetic patients (a total of 175 men and 133 women), 150 subjects had family histories of dia* Corresponding author. Tel.: +81-76-2652234; fax: +8176-2344250.