Showing papers by "Kazuo Hara published in 2007"

Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions.

Abstract: Adiponectin plays a central role as an antidiabetic and antiatherogenic adipokine. AdipoR1 and AdipoR2 serve as receptors for adiponectin in vitro, and their reduction in obesity seems to be correlated with reduced adiponectin sensitivity. Here we show that adenovirus-mediated expression of AdipoR1 and R2 in the liver of Lepr(-/-) mice increased AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor (PPAR)-alpha signaling pathways, respectively. Activation of AMPK reduced gluconeogenesis, whereas expression of the receptors in both cases increased fatty acid oxidation and lead to an amelioration of diabetes. Alternatively, targeted disruption of AdipoR1 resulted in the abrogation of adiponectin-induced AMPK activation, whereas that of AdipoR2 resulted in decreased activity of PPAR-alpha signaling pathways. Simultaneous disruption of both AdipoR1 and R2 abolished adiponectin binding and actions, resulting in increased tissue triglyceride content, inflammation and oxidative stress, and thus leading to insulin resistance and marked glucose intolerance. Therefore, AdipoR1 and R2 serve as the predominant receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress in vivo.

Variations in the HHEX gene are associated with increased risk of type 2 diabetes in the Japanese population.

Abstract: Recently, several groups have carried out whole-genome association studies in European and European-origin populations and found novel type 2 diabetes-susceptibility genes, fat mass and obesity associated (FTO), solute carrier family 30 (zinc transporter), member 8 (SLC30A8), haematopoietically expressed homeobox (HHEX), exostoses (multiple) 2 (EXT2), CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1), cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4) (CDKN2B) and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), which had not been in the list of functional candidates. The aim of this study was to determine the association between single nucleotide polymorphisms (SNPs) in these genes and type 2 diabetes in participants from the Japanese population. Sixteen previously reported SNPs were genotyped in 864 Japanese type 2 diabetes individuals (535 men and 329 women; age 63.1 ± 9.5 years (mean±SD), BMI 24.3 ± 3.9 kg/m2) and 864 Japanese control individuals (386 men and 478 women; age 69.5 ± 6.8 years, BMI 23.8 ± 3.7 kg/m2). The SNPs rs5015480 [odds ratio (OR) = 1.46 (95% CI 1.20–1.77), p = 2.0 × 10−4], rs7923837 [OR = 1.40 (95% CI 1.17–1.68), p = 2.0 × 10−4] and rs1111875 [OR = 1.30 (95% CI 1.11–1.52), p = 0.0013] in HHEX were significantly associated with type 2 diabetes with the same direction as previously reported. SNP rs8050136 in FTO was nominally associated with type 2 diabetes [OR = 1.22 (95% CI 1.03–1.46), p = 0.025]. SNPs in other genes such as rs7756992 in CDKAL1, rs10811661 in CDKN2B and rs13266634 in SLC30A8 showed nominal association with type 2 diabetes. rs7756992 in CDKAL1 and rs10811661 in CDKN2B were correlated with impaired pancreatic beta cell function as estimated by the homeostasis model assessment beta index (p = 0.023, p = 0.0083, respectively). HHEX is a common type 2 diabetes-susceptibility gene across different ethnic groups.

A genetic variation of the transcription factor 7-like 2 gene is associated with risk of type 2 diabetes in the Japanese population.

Abstract: Aims/hypothesis It has been suggested that transcription factor 7-like 2 protein (TCF7L2) plays an important role in glucose metabolism by regulating the production level of glucagon-like peptide-1, a hormone which modifies glucose-dependent insulin secretion. Recently, variants of TCF7L2 gene were reported to confer an increased risk of type 2 diabetes in three different samples from European and European-origin populations. We studied whether the single nucleotide polymorphisms (SNPs) in TCF7L2 were associated with type 2 diabetes in samples from a Japanese population.

Improved ELISA for Selective Measurement of Adiponectin Multimers and Identification of Adiponectin in Human Cerebrospinal Fluid

Abstract: Background: Human serum adiponectin exists in 3 multimer forms: high molecular weight (HMW), middle molecular weight, and low molecular weight (LMW), with some of the latter bound to albumin (Alb)-LMW. Some studies have suggested that adiponectin crosses the blood–brain barrier and plays a central role in energy homeostasis. Methods: To determine cerebrospinal fluid (CSF) adiponectin at extremely low concentrations, we modified the protocol of the ELISA system used to assay serum adiponectin. The 3 multimers of adiponectin were measured separately by pretreating CSF with 2 proteases. We measured the CSF adiponectin concentrations in anonymous human samples (n = 19). The molecular sizes of adiponectin in CSF pretreated with proteases or untreated were determined by use of native PAGE and immunoblotting. Results: The ELISA system measured adiponectin in the range of 1.0–167 μg/L. The between-assay imprecision estimates (CVs) were 6%–17% for the 3 forms. The mean total CSF adiponectin concentration (7.2 μg/L) was ∼1/1000 of the mean concentration in serum. Unlike serum adiponectin, the LMW and Alb-LMW forms predominated in all of the CSF samples. Immunoblotting analysis revealed that most LMW forms were bound to Alb, although the HMW form was detected in some samples. Conclusions: The modified ELISA system measures the 3 multimers separately and is sufficiently sensitive to measure adiponectin in CSF.

Adiponectin and adiponectin receptors in obesity-linked insulin resistance.

Abstract: Adiponectin is an abundantly expressed adipokine in adipose tissue and has direct insulin sensitizing activity. We have proposed the following adiponectin hypothesis. Interactions of genetic factors such as single nucleotide polymorphisms (SNPs) in the Adiponectin gene and environmental factors causing obesity result in hypoadiponectinaemia, which appears to play an important causal role in obesity-linked insulin resistance, type 2 diabetes and the metabolic syndrome. We have cloned the adiponectin receptors, AdipoR1 and AdipoR2, which mediate the antidiabetic metabolic actions of adiponectin. AdipoR1 and AdipoR2 are down-regulated in obesity-linked insulin resistance. Up-regulation of adiponectin or adiponectin receptors may represent potential versatile therapeutic targets to combat obesity-linked diseases characterized by insulin resistance.

Reduced adiponectin level is associated with severity of coronary artery disease.

Abstract: Adipocyte-derived adiponectin has an antiatherosclerotic effect that acts independently of its antidiabetic effect. Plasma adiponectin levels are generally low in subjects with coronary artery disease. In this study, the relationship between the plasma adiponectin level and the severity of coronary artery disease, as assessed using the Gensini score, an index for the severity of coronary artery stenosis, was investigated. The subjects of the study were 104 patients (72 men and 32 women; BMI, 23.5 +/- 3.3 kg/m(2); age, 63.6 +/- 10.1 years) admitted to Tokyo University Hospital for coronary angiography. Plasma adiponectin levels were inversely correlated with the insulin resistance index HOMA-IR (P = 0.0127). The plasma adiponectin level was significantly associated with the Gensini score (P = 0.0332). After adjustment for conventional risk factors for cardiovascular diseases, the plasma adiponectin level tended to be inversely correlated with the Gensini score (P = 0.087). The measurement of plasma adiponectin levels may be useful for predicting the severity of coronary artery stenosis.

Frequency of the G/G genotype of resistin single nucleotide polymorphism at -420 appears to be increased in younger-onset type 2 diabetes.

Abstract: Objective: Resistin is an adipocyte-secreted hormone associated with insulin resistance in mice. We reported that the G/G genotype of a resistin single nucleotide polymorphism (SNP) at -420 increases type 2 diabetes (T2DM) susceptibility by enhancing its promoter activity. Research Design and Methods: To determine the relevance of SNP-420 in a large number of subjects, we examined 2610 T2DM cases and 2502 controls. The relation between SNP-420 and the age of T2DM onset was further analyzed by adding 237 T2DM subjects with the age of onset 40 or younger. Results: When analyzed without considering subject age, the SNP-420 genotype was not associated with T2DM. Since we reported that the onset of T2DM was earlier in G/G genotype, we analyzed the data using trend test for age intervals of 10 years. The frequency of G/G genotype differed among age grades in T2DM ( P =0.037), and appeard to be higher in younger grades. In T2DM, G/G genotype was more frequent in subjects younger than 40 years than in those who were 40 or older (G/G vs C/C, P =0.003). In a total of 2430 T2DM subjects with the age of onset younger than 60, the trend test showed that the G/G genotype had an increasing linear trend as the age grade of T2DM onset became younger ( P =0.0379). In controls, the frequency of C/G genotype showed an increasing linear trend with increasing age ( P =0.010). Conclusions: The G/G genotype frequency of resistin SNP-420 appears to be increased in younger onset T2DM subjects.

Education and imaging. Gastrointestinal: diphyllobothriasis.

Abstract: A 34-year-old Japanese man whose favorite food was salmon sushi was referred for evaluation because of abdominal discomfort. Colonoscopy was performed. Surprisingly, we identified a long, noodle-like, mobile worm extending from the terminal ileum to the anus (Figs 1,2). The worm had a pale color and fragments were removed from the colon by gentle traction with a retrieval basket. The worm was identified as Diphyllobothrium latum. The patient was treated with 600 mg of praziquantel. D. latum is the longest tapeworm in humans and is usually located in the lower jejunum or upper ileum. A typical worm is 4–15 m in length and 10–20 mm in width. It has an elongated scolex with two sucking grooves, a thin neck and 3000–4000 proglottids. The latter produce up to 1 million eggs each day that are excreted into the intestinal lumen and passed in feces. The life-cycle is relatively complex and involves larval stages that develop in water and in two intermediate hosts, fresh water crustaceans and fish. Humans are infected by eating raw fish. As the developing larvae have particular ecologic requirements, human infections are largely restricted to Northern Europe, Canada and Alaska. Tapeworms can be single or multiple and may result in symptoms such as fatigue, weakness, parasthesia, diarrhea and craving for salt. A minority of patients (2%) develop vitamin B12 deficiency, apparently because of vitamin B12 absorption by the adult worms as well as interference with the ileal absorption of cobalamins. The diagnosis of D. latum is usually made by the detection of eggs in feces and patients can be treated with a variety of drugs including praziquantel. The detection of adult worms at the time of colonoscopy appears to be unusual. The infective larval forms in fish (plerocercoids), can be readily killed by cooking fish at 55°C for 5 min or by freezing for 8–72 h.

Recent advances and future perspective of eus in the diagnosis of pancreatic disorders

Abstract: 膵疾患診断における超音波内視鏡（EUS）の有用性は既に確立されており，必須の検査法であるといえる．基本となるB-mode画像において，電子走査方式EUSはメカニカルラジアル走査方式に比して同等以上の画質が得られることが証明されたことで，EUSの主流がメカニカルラジアル走査方式から電子走査方式（電子ラジアル型，電子コンベックス型）に変化することは必然的なものとなる．電子走査方式になることで，ティッシュハーモニックイメージング法，カラードプラ断層法·パワードプラ断層法，造影ハーモニックイメージング法，三次元画像，real time tissue elastography®などすでに体外式超音波検査（US）では広く臨床応用されている技術がEUSで行えるようになった．このように多方面からのtissue characterizationが可能になったことは膵疾患診断に関する有用性がさらに向上したことを意味する．今後はさらに症例を蓄積し明確な臨床的有用性を証明してゆく必要がある．本稿では，電子走査型EUSで可能になった種々の画像診断法に関して概説する．