Kazuhiro Nomura

Role of S6K1 in regulation of SREBP1c expression in the liver.

The transcription factor sterol regulatory element-binding protein 1c (SREBP1c) plays an important role in the control of fatty acid metabolism in the liver. Evidence suggests that mammalian target of rapamycin (mTOR) complex 1 (mTORC1) contributes to the regulation of SREBP1c expression, but signaling downstream of mTORC1 remains unclear. We have now shown that medium rich in branched-chain amino acids stimulates expression of the SREBP1c gene in cultured hepatocytes in a manner sensitive both to rapamycin, a pharmacological inhibitor of mTORC1, and to a short hairpin RNA (shRNA) specific for S6 kinase 1 (S6K1), a downstream effector of mTORC1. The phosphorylation of S6K1 was increased in the liver of obese db/db mice. Furthermore, depletion of hepatic S6K1 in db/db mice with the use of an adenovirus vector encoding S6K1 shRNA resulted in down-regulation of SREBP1c gene expression in the liver as well as a reduced hepatic triglyceride content and serum triglyceride concentration. These results thus suggest that S6K1 regulates SREBP1c expression both in cultured hepatocytes and in mouse liver, and that increased hepatic activity of S6K1 contributes at least in part to the pathogenesis of obesity-induced hepatic steatosis and hypertriglyceridemia.

Relationship Between Carotid Intima-Media Thickness and Silent Cerebral Infarction in Japanese Subjects With Type 2 Diabetes

OBJECTIVE We examined the relationship between intima-media thickness of common carotid artery (CCA-IMT) and silent cerebral infarction (SCI) with the magnetic resonance imaging (MRI) study in Japanese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS The brain MRI study and the carotid ultrasonography were performed in a total of 217 consecutive Japanese subjects with type 2 diabetes. Various risk factors for SCI were examined using multiple logistic analyses. RESULTS The SCI was found in 60.4% of the diabetic subjects. In the diabetic subjects, age, systolic blood pressure (SBP), pulse wave velocity, and CCA-IMT were significantly higher in the subjects with SCI than in those without it. Multiple logistic analyses indicated that age, SBP, and CCA-IMT were significant and independent risk factors of SCI in the diabetic subjects. CONCLUSIONS CCA-IMT, but not pulse wave velocity, was independently associated with SCI in Japanese subjects with type 2 diabetes.

Identification of a Novel Domain of Ras and Rap1 That Directs Their Differential Subcellular Localizations

The small GTPase Ha-Ras and Rap1A exhibit high mutual sequence homology and share various target proteins. However, they exert distinct biological functions and exhibit differential subcellular localizations; Rap1A is predominantly localized in the perinuclear region including the Golgi apparatus and endosomes, whereas Ha-Ras is predominantly localized in the plasma membrane. Here, we have identified a small region in Rap1A that is crucial for its perinuclear localization. Analysis of a series of Ha-Ras-Rap1A chimeras shows that Ha-Ras carrying a replacement of amino acids 46-101 with that of Rap1 exhibits the perinuclear localization. Subsequent mutational studies indicate that Rap1A-type substitutions within five amino acids at positions 85-89 of Ha-Ras, such as NNTKS85-89TAQST, NN85-86TA, and TKS87-89QST, are sufficient to induce the perinuclear localization of Ha-Ras. In contrast, substitutions of residues surrounding this region, such as FAI82-84YSI and FEDI90-93FNDL, have no effect on the plasma membrane localization of Ha-Ras. A chimeric construct consisting of amino acids 1-134 of Rap1A and 134-189 of Ha-Ras, which harbors both the palmitoylation and farnesylation sites of Ha-Ras, exhibits the perinuclear localization like Rap1A. Introduction of a Ha-Ras-type substitution into amino acids 85-89 (TAQST85-89NNTKS) of this chimeric construct causes alteration of its predominant subcellular localization site from the perinuclear region to the plasma membrane. These results indicate that a previously uncharacterized domain spanning amino acids 85-89 of Rap1A plays a pivotal role in its perinuclear localization. Moreover, this domain acts dominantly over COOH-terminal lipid modification of Ha-Ras, which has been considered to be essential and sufficient for the plasma membrane localization.

Usefulness of serum cystatin C in Japanese patients with type 2 diabetes mellitus and nephropathy

We examined usefulness of serum cystatin C to detect chronic kidney disease (CKD) stage >or=3, which was defined by Modification of Diet in Renal Disease formula. Serum cystatin C could detect CKD stage >or=3 with high efficacy in 289 Japanese patients with type 2 diabetes and nephropathy.

A case of lymphocytic panhypophysitis (LPH) during pregnancy

A 37-year-old pregnant woman developed continuous headache in the 10th week of pregnancy, followed by bilateral visual field defect and general malaise in the 24th week. The brain magnetic resonance imaging showed a pituitary mass. In laboratory examination, plasma concentration of free thyroxine, thyroid stimulating hormone (TSH), cortisol, and adrenocorticotropic hormone (ACTH) was low. General malaise vanished shortly after the replacement therapy of glucocorticoid and thyroid hormone, but partial central diabetes insipidus (CDI) appeared, which could be treated with desmopressin acetate (DDAVP). The visual field defect having enlarged, transsphenoidal surgery was performed in the 31st week of pregnancy. Adenohypophysis could be resected, and it showed infiltration of mature lymphocytes. After the surgery, the visual defect had improved, but hormone replacement was still necessary. She delivered a baby in the 38th week without any trouble. Provocative tests after delivery revealed a low response in TSH, prolactin (PRL), and follicle stimulating hormone (FSH). Hormone replacement and DDAVP administration was necessary in the same doses after delivery. The diagnosis was lymphocytic panhypophysitis (LPH). In the case of pregnant woman, LPH should be included in the differential diagnosis of pituitary mass for the fetomaternal safety.

Relationship between telmisartan dose and glycaemic control in Japanese patients with type 2 diabetes mellitus and hypertension: a retrospective study.

BACKGROUND AND OBJECTIVES Telmisartan has been reported to have beneficial effects on insulin resistance and lipid profiles by acting as a peroxisome proliferator-activated receptor-γ (PPARγ) agonist. In this study we investigated the relationship between telmisartan dose and glycaemic control in Japanese subjects with type 2 diabetes mellitus and hypertension. METHODS Patients (n = 263) who were prescribed telmisartan 20, 40 or 80 mg/day at our clinic were retrospectively identified from our clinical database. Only patients without changes in their treatments for diabetes and hypertension for 6 months after starting telmisartan were included in this study. Glycosylated haemoglobin A(1c) (HbA(1c)) levels were measured at 0, 3 and 6 months after starting telmisartan. RESULTS At 3 and 6 months after starting telmisartan, HbA(1c) levels were significantly decreased in patients treated with telmisartan 40 or 80 mg/day but not in patients treated with telmisartan 20 mg/day (mean ± standard error change at 6 months: -0.29 ± 0.10%, p < 0.001; -0.48 ± 0.15%, p < 0.001; and -0.03 ± 0.10%, p = 0.33; respectively). When patients were classified into two groups by telmisartan dose (20 vs ≥40 mg/day), there was no significant correlation between baseline HbA(1c) and change in HbA(1c) levels over time in the 20 mg/day group. However, in patients treated with ≥40 mg/day of telmisartan, baseline HbA(1c) was negatively correlated with the change in HbA(1c) at 6 months. Multiple regression analysis confirmed that baseline HbA(1c) and telmisartan dose were the predictive factors. CONCLUSION Our results suggest that telmisartan influences glycaemic control in a dose-dependent manner; doses ≥40 mg/day may be needed to improve glycaemic control. Our data also suggest that patients with higher baseline HbA(1c) may experience greater improvements in glycaemic control with telmisartan.

Relationship between Telmisartan Dose and Glycaemic Control in Japanese Patients with Type 2 Diabetes Mellitus and Hypertension

AbstractBackground and Objectives: Telmisartan has been reported to have beneficial effects on insulin resistance and lipid profiles by acting as a peroxisome proliferator-activated receptor-γ (PPARγ) agonist. In this study we investigated the relationship between telmisartan dose and glycaemic control in Japanese subjects with type 2 diabetes mellitus and hypertension. Methods: Patients (n = 263) who were prescribed telmisartan 20, 40 or 80 mg/day at our clinic were retrospectively identified from our clinical database. Only patients without changes in their treatments for diabetes and hypertension for 6 months after starting telmisartan were included in this study. Glycosylated haemoglobin A1c (HbA1c) levels were measured at 0, 3 and 6 months after starting telmisartan. Results: At 3 and 6 months after starting telmisartan, HbA1c levels were significantly decreased in patients treated with telmisartan 40 or 80 mg/day but not in patients treated with telmisartan 20 mg/day (mean ± standard error change at 6 months: −0.29 ± 0.10%, p<0.001; −0.48 ± 0.15%, p<0.001; and −0.03 ± 0.10%, p = 0.33; respectively). When patients were classified into two groups by telmisartan dose (20 vs ≥40 mg/day), there was no significant correlation between baseline HbA1c and change in HbA1c levels over time in the 20 mg/day group. However, in patients treated with ≥40 mg/day of telmisartan, baseline HbA1c was negatively correlated with the change in HbA1c at 6 months. Multiple regression analysis confirmed that baseline HbA1c and telmisartan dose were the predictive factors. Conclusion: Our results suggest that telmisartan influences glycaemic control in a dose-dependent manner; doses ≥40 mg/day may be needed to improve glycaemic control. Our data also suggest that patients with higher baseline HbA1c may experience greater improvements in glycaemic control with telmisartan.

Efficacy and Safety of Miglitol: Switching Study from Voglibose in Japanese Patients with Type 2 Diabetes

We investigated the efficacy and safety of miglitol, a new alpha-glucosidase inhibitor, by switching from voglibose in Japanese patients with type 2 diabetes. Subjects included those who had previously been administered with voglibose (n=90, 0.6mg/day). After voglibose was changed into miglitol (150mg/day), HbA1C level, body weight and abdominal symptoms were evaluated six months later. HbA1C level was significantly decreased from 7.8±1.2 to 7.3±1.0% (P<0.01). Body weight showed a small but significant decrease after 6 months (62.5±11.0 to 62.1±12.3kg, P<0.01). There was no significant difference between frequencies of side effects before and after switching from voglibose to miglitol. This study suggests the efficacy and safety of miglitol to improve glycemic control in Japanese patients with type 2 diabetes, who had previously been treated with voglibose. Several recent studies have suggested that the clinical significance of postprandial hyperglycemia in relation to the risk of microvascular and macrovascular complications (1). In 2007, International Diabetes Federation has announced the guideline which claimed that postprandial glucose should be less than 140mg/dl (2). Miglitol is a new alpha-glucosidase inhibitor ( -GI), which has recently been approved for clinical use in Japan. A distinctive feature of miglitol is that it is partially absorbed from the upper portion of the small intestine, thereby making it possible to administer in large doses. Although there have been several preliminary reports about the effects of miglitol on glycemic control (3), there has been no study which compares the clinical effects of miglitol and other  -GIs. In the present study, we investigated the efficacy and safety of miglitol by switching from voglibose, another  - GI, which has broadly been used in Japanese patients with type 2 diabetes. Subjects included a total of 90 Japanese patients with type 2 diabetes (54 men and 36 women, mean age 66.5±SD10.9 years), who had previously been administered with voglibose (0.6mg/day). In all subjects, voglibose was changed into miglitol (150mg/day). Serum HbA1C level, plasma postprandial C-peptide level (2 h after the meal), body weight and abdominal symptoms were evaluated before and 6 months after switching from voglibose to miglitol. The data was expressed as mean±SD. Statistical analysis was performed with Students t test between the two groups. Differences were defined as significant at P < 0.05.

In silico and in vitro analyses of the pathological relevance of the R258H mutation of hepatocyte nuclear factor 4α identified in MODY1

Mutations of the hepatocyte nuclear factor 4α (HNF4α) gene give rise to maturity‐onset diabetes of the young type 1. Although many such mutations have been identified in affected individuals, part of these mutations has been characterized with regard to their pathological relevance. We here identified a missense mutation (c.773G>A, p.R258H) of HNF4A in a mother and daughter with early‐onset diabetes and impaired insulin secretion. In silico simulation and in vitro luciferase reporter analyses showed that the mutation impairs the stability of self‐dimerization and the transactivation activity of HNF4α. Although arginine‐258 does not appear to participate directly in dimerization, its mutation alters the electrostatic surface potential of the dimer interface. Our results thus suggest that this mutation impairs the function of HNF4α and thereby contributes to the pathogenesis of maturity‐onset diabetes of the young type 1.

Clinical heterogeneity of adult Japanese diabetes depending on titers of glutamic acid decarboxylase autoantibodies.

Aims/Introduction:  We examined whether levels of glutamic acid decarboxylase autoantibodies (GADAb) might show the clinical heterogeneity of adult Japanese diabetes.