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ABSTRACT: Glucose-induced insulin secretion from pancreatic ß-cells depends critically on activity of ATP-sensitive K+ channels (KATP channel). We previously generated mice lacking Kir6.2, the pore subunit of the ß-cell KATP channel (Kir6.2-/-), that show almost no insulin secretion in response to glucose in vitro. In the present study, we compared insulin secretion by voluntary feeding (self-motivated, oral nutrient ingestion) and by forced feeding (intra-gastric nutrient injection via gavage) in wild-type (Kir6.2+/+) and Kir6.2-/- mice. Under ad libitum feeding or during voluntary feeding of standard chow, blood glucose levels and plasma insulin levels were similar in Kir6.2+/+ and Kir6.2-/- mice. By voluntary feeding of carbohydrate alone, insulin secretion was induced significantly in Kir6.2-/- mice, but was markedly attenuated compared to that in Kir6.2+/+ mice. On forced feeding of standard chow or carbohydrate alone, the insulin secretory response was markedly impaired or completely absent in Kir6.2-/- mice. Pre-treatment of a muscarine receptor antagonist, atropine methyl nitrate, which does not cross the blood-brain barrier, almost completely blocked insulin secretion induced by voluntary feeding of standard chow or carbohydrate in Kir6.2-/- mice. Substantial glucose-induced insulin secretion was induced in pancreas perfusion study of Kir6.2-/- mice only in the presence of carbamylcholine. These results suggest that a KATP channel-independent mechanism mediated by the vagal nerve plays a critical role in insulin secretion in response to nutrients in vivo.
Journal of Endocrinology 04/2013; · 3.55 Impact Factor
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ABSTRACT: OBJECTIVE: Alpha-glucosidase inhibitors (α-GIs) show various anti-diabetic or anti-obesity effects in addition to the suppression of postprandial hyperglycemia. Based on recent observations that bile acids (BAs) are involved in glucose and energy homeostasis, we examined the ability of miglitol, an α-GI, to influence BA metabolism and ameliorate insulin resistance and obesity. MATERIALS/METHODS: NSY mice, representing an obese type 2 diabetic model, were fed with a high-fat diet and treated with miglitol for 4 or 12weeks. BAs were quantified in feces, blood from the portal vein or the vena cava and in the liver. The gene expression of type 2 iodothyronine deiodinase (D2) in brown adipose tissues, gluconeogenetic enzymes in the liver and adipokines in epididymal fat was measured, and portal blood glucagon-like peptide-1 (GLP-1) levels, body weight changes, glucose tolerance along with insulin sensitivity were evaluated. RESULTS: Miglitol significantly increased BAs in both feces and portal blood while the hepatic BA level was reduced. The drug clearly enhanced active GLP-1 secretion into the portal blood and there was a good positive correlation between the active GLP-1 levels and portal blood BA concentrations. D2 expression in brown adipose tended to increase in association with the elevated BA concentrations. Miglitol ameliorated body weight gain, glucose intolerance, insulin resistance and inflammatory adipokine upregulation that were induced by a high-fat diet. CONCLUSIONS: Collectively, miglitol substantially affects BA regulation in mice and this novel finding may explain in part the known favourable effects of the drug on diabetes and obesity.
Metabolism: clinical and experimental 11/2012; · 2.59 Impact Factor
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Ayako Fukami, Yusuke Seino,
Nobuaki Ozaki,
Michiyo Yamamoto,
Chisato Sugiyama,
Eriko Sakamoto-Miura,
Tatsuhito Himeno,
Yoshiko Takagishi,
Shin Tsunekawa,
Safina Ali,
Daniel J Drucker,
Yoshiharu Murata,
Yutaka Seino,
Yutaka Oiso,
Yoshitaka Hayashi
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ABSTRACT: Glucagon and glucagon-like peptide-1 (GLP-1) are produced in pancreatic α-cells and enteroendocrine L-cells, respectively, in a tissue-specific manner from the same precursor, proglucagon, that is encoded by glucagon gene (Gcg), and play critical roles in glucose homeostasis. Here, we studied glucose homeostasis and β-cell function of Gcg-deficient mice that are homozygous for a Gcg-GFP knock-in allele (Gcg(gfp/gfp)). The Gcg(gfp/gfp) mice displayed improved glucose tolerance and enhanced insulin secretion, as assessed by both oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT). Responses of glucose-dependent insulinotropic polypeptide (GIP) to both oral and intraperitoneal glucose loads were unexpectedly enhanced in Gcg(gfp/gfp) mice, and immunohistochemistry localized GIP to pancreatic β-cells of Gcg(gfp/gfp) mice. Furthermore, secretion of GIP in response to glucose was detected in isolated islets of Gcg(gfp/gfp) mice. Blockade of GIP action in vitro and in vivo by cAMP antagonism and genetic deletion of the GIP receptor, respectively, almost completely abrogated enhanced insulin secretion in Gcg(gfp/gfp) mice. These results indicate that ectopic GIP expression in β-cells maintains insulin secretion in the absence of proglucagon-derived peptides (PGDPs), revealing a novel compensatory mechanism for sustaining incretin hormone action in islets.
Diabetes 10/2012; · 8.29 Impact Factor
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Tetsuji Okawa,
Hideki Kamiya,
Tatsuhito Himeno,
Jiro Kato, Yusuke Seino,
Atsushi Fujiya,
Masaki Kondo,
Shin Tsunekawa,
Keiko Naruse,
Yoji Hamada,
Nobuaki Ozaki,
Zhao Cheng,
Tetsutaro Kito,
Hirohiko Suzuki,
Sachiko Ito,
Yutaka Oiso,
Jiro Nakamura,
Ken-Ichi Isobe
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ABSTRACT: Impaired vascularity and nerve degeneration are the most important pathophysiological abnormalities of diabetic polyneuropathy (DPN). Therefore, regeneration of both vascular and nervous systems is required for the treatment of DPN. The neural crest (NC) is a transient embryonic structure in vertebrates that differentiates into a vast range of cells, including peripheral neurons, Schwann cells and vascular smooth muscle cells. In this study, we investigated the ability of transplantation of NC like (NCL) cells derived from aged mouse induced pluripotent stem (iPS) cells in the treatment of DPN. iPS cells were induced to differentiate into neural cells by stromal cell-derived inducing activity (SDIA) and subsequently supplemented with bone morphogenetic protein 4 to promote a differentiation of NC lineage. After the induction, p75 neurotrophin receptor positive NCL cells were purified using magnetic-activated cell sorting. Sorted NCL cells differentiated to peripheral neurons, glial cells and smooth muscle cells by additional SDIA. NCL cells were transplanted into hind limb skeletal muscles of 16-week streptozotocin-diabetic mice. Nerve conduction velocity, current perception threshold, intraepidermal nerve fiber density, sensitivity to thermal stimuli, sciatic nerve blood flow, plantar skin blood flow and capillary number-to-muscle fiber ratio were evaluated. Four-weeks after the transplantation, transplanted cells engrafted with producing growth factors; nerve growth factor, neurotrophin 3, vascular endothelial growth factor and basic fibroblast growth factor. It was also confirmed that some engrafted cells differentiated into vascular smooth muscle cells or Schwann cell like cells at each intrinsic site. The transplantation improved the impaired nerve and vascular functions. These results suggest that transplantation of NCL cells derived from iPS cells could have therapeutic effects on DPN through paracrine actions of growth factors and differentiation into Schwann cell like cells and vascular smooth muscle cells.
Cell Transplantation 10/2012; · 5.13 Impact Factor
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Chika Watanabe, Yusuke Seino,
Hiroki Miyahira,
Michiyo Yamamoto,
Ayako Fukami,
Nobuaki Ozaki,
Yoshiko Takagishi,
Jun Sato,
Tsutomu Fukuwatari,
Katsumi Shibata,
Yutaka Oiso,
Yoshiharu Murata,
Yoshitaka Hayashi
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ABSTRACT: Glucagon is believed to be one of the most important peptides for upregulating blood glucose levels. However, homozygous glucagon-green fluorescent protein (gfp) knock-in mice (Gcg(gfp/gfp): GCGKO) are normoglycemic despite the absence of proglucagon-derived peptides, including glucagon. To characterize metabolism in the GCGKO mice, we analyzed gene expression and metabolome in the liver. The expression of genes encoding rate-limiting enzymes for gluconeogenesis was only marginally altered. On the other hand, genes encoding enzymes involved in conversion of amino acids to metabolites available for the tricarboxylic acid cycle and/or gluconeogenesis showed lower expression in the GCGKO liver. The expression of genes involved in the metabolism of fatty acids and nicotinamide was also altered. Concentrations of the metabolites in the GCGKO liver were altered in manners concordant with alteration in the gene expression patterns, and the plasma concentrations of amino acids were elevated in the GCGKO mice. The insulin concentration in serum and phosphorylation of Akt protein kinase in liver were reduced in GCGKO mice. These results indicated that proglucagon-derived peptides should play important roles in regulating various metabolic pathways, especially that of amino acids. Serum insulin concentration is lowered to compensate the impacts of absent proglucagon-derived peptide on glucose metabolism. On the other hand, impacts on other metabolic pathways are only partially compensated by reduced insulin action.
Diabetes 01/2012; 61(1):74-84. · 8.29 Impact Factor
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Tatsuhito Himeno,
Hideki Kamiya,
Keiko Naruse,
Norio Harada,
Nobuaki Ozaki, Yusuke Seino,
Taiga Shibata,
Masaki Kondo,
Jiro Kato,
Tetsuji Okawa,
Ayako Fukami,
Yoji Hamada,
Nobuya Inagaki,
Yutaka Seino,
Daniel J Drucker,
Yutaka Oiso,
Jiro Nakamura
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ABSTRACT: The therapeutic potential of exendin-4, an agonist of the glucagon-like peptide-1 receptor (GLP-1R), on diabetic polyneuropathy (DPN) in streptozotocin (STZ)-induced diabetic mice was investigated.
The presence of the GLP-1R in lumbar dorsal root ganglion (DRG) was evaluated by immunohistochemical analyses. DRG neurons were dissected from C57BL6/J mice and cultured with or without Schwann cell-conditioned media in the presence or absence of GLP-1 (7-37) or exendin-4. Then neurite outgrowth was determined. In animal-model experiments, mice were made diabetic by STZ administration, and after 12 weeks of diabetes, exendin-4 (10 nmol/kg) was intraperitoneally administered once daily for 4 weeks. Peripheral nerve function was determined by the current perception threshold and motor and sensory nerve conduction velocity (MNCV and SNCV, respectively). Sciatic nerve blood flow (SNBF) and intraepidermal nerve fiber densities (IENFDs) also were evaluated.
The expression of the GLP-1R in DRG neurons was confirmed. GLP-1 (7-37) and exendin-4 significantly promoted neurite outgrowth of DRG neurons. Both GLP-1R agonists accelerated the impaired neurite outgrowth of DRG neurons cultured with Schwann cell-conditioned media that mimicked the diabetic condition. At the doses used, exendin-4 had no effect on blood glucose or HbA(1c) levels. Hypoalgesia and delayed MNCV and SNCV in diabetic mice were improved by exendin-4 without affecting the reduced SNBF. The decreased IENFDs in sole skins of diabetic mice were ameliorated by exendin-4.
Our findings indicate that exendin-4 ameliorates the severity of DPN, which may be achieved by its direct actions on DRG neurons and their axons.
Diabetes 08/2011; 60(9):2397-406. · 8.29 Impact Factor
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Yusuke Seino,
Takeshi Kawarabayashi,
Yasuhito Wakasaya,
Mitsunori Watanabe,
Ayumi Takamura,
Yukiko Yamamoto-Watanabe,
Tomoko Kurata,
Koji Abe,
Masaki Ikeda,
David Westaway,
Tetsuro Murakami,
Peter St George Hyslop,
Etsuro Matsubara,
Mikio Shoji
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ABSTRACT: In Alzheimer's disease, Aβ deposits are considered the initial cardinal events that induce tauopathy secondarily. However, the relationship between Aβ amyloidosis and tauopathy has not been determined in detail. We produced double transgenic mice, 2×TgTau(+/-) APP(+/-) , by mating Tg2576 mice that exhibit Aβ amyloidosis and TgTauP301L mice that show tauopathy, and statistically analyzed the effect of Aβ accumulation on tauopathy. There was no significant difference in theprogression of Aβ accumulation among 2×TgTau(+/-) APP(+/-) and 1×TgTau(-/-) APP(+/-) , and tau accumulation among 2×TgTau(+/-) APP(+/-) and 1×Tg Tau(+/-) APP(-/-) . The appearance rates of phosphorylated tau developing in neurons and processes were significantly accelerated in 2×TgTau(+/-) APP(+/-) mice compared with those in 1×TgTau(+/-) APP(-/-) mice at 23 months of age. Accumulation of phosphorylated and confomationally altered tau and GSK3β in neuronal processes was accelerated in the white matter in 2×TgTau(+/-) APP(+/-) . The level of phosphorylated tau in the sarkosyl-insoluble fraction was increased in 2×TgTau(+/-) APP(+/-) brains compared with that in 1×TgTau(+/-) APP(-/-) brains. Thus, Aβ amyloid partially enhances tauopathy through accumulation of insoluble, phosphorylated, and conformationally changed tau in neuronal cytoplasm and processes in the late stage.
Journal of Neuroscience Research 10/2010; 88(16):3547-54. · 2.74 Impact Factor
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Yasuhito Wakasaya,
Mitsunori Watanabe,
Masahiko Tomiyama,
Chieko Suzuki,
Mandy Jackson,
Masahiro Fujimuro,
Tamaki Kimura, Yusuke Seino,
Takeshi Kawarabayashi,
Yukiko Yamamoto-Watanabe,
Etsuro Matsubara,
Ikumi Shirahama,
Ayumi Takamura,
Naoko Nakahata,
Mikio Shoji
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ABSTRACT: A 55-year-old man underwent radiation therapy due to malignant lymphoma of the neck. Eight years after the therapy he developed tetanus. It appears that the radiation therapy resulted in mandibular necrosis, and that this lesion may have been the infectious focus of tetanus. Treatment with penicillin G was very effective in the acute stage, and chronic administration of metronidazole prevented relapse of the disease. However in spite of injections of tetanus toxoid, symptoms of tetanus returned when the administration of metronidazole was discontinued because the infectious focus could not be completely removed. This is the first report of chronic relapsing tetanus associated with radiation-induced mandibular osteomyelitis, and demonstrates that tetanus can occur due to mandibular focus but the chronic administration of metronidazole can prevent relapse.
Internal Medicine 02/2009; 48(15):1311-3. · 0.94 Impact Factor
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Chieko Suzuki,
Mitsunori Watanabe,
Masahiko Tomiyama,
Kazuhiro Sugimoto,
Eiji Nanba,
Mandy Jackson,
Tamaki Kimura, Yusuke Seino,
Yasuhito Wakasaya,
Takeshi Kawarabayashi,
Yasuo Miki,
Yukiko Yamamoto-Watanabe,
Mikio Shoji
European Neurology 11/2008; 60(6):310-1. · 1.81 Impact Factor
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Yusuke Seino,
Takashi Miki,
Hiroshi Kiyonari,
Takaya Abe,
Wakako Fujimoto,
Keita Kimura,
Ayako Takeuchi,
Yoshihisa Takahashi,
Yutaka Oiso,
Toshihiko Iwanaga,
Susumu Seino
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ABSTRACT: Isx (intestine specific homeobox) is an intestine-specific transcription factor. To elucidate its physiological function, we generated Isx-deficient mice by knocking in the beta-galactosidase gene (LacZ) in the Isx locus (IsxLacZ/LacZ mice). LacZ staining of heterozygous (IsxLacZ/+) mice revealed that Isx was expressed abundantly in intestinal epithelial cells from duodenum to proximal colon. Quantitative mRNA expression profiling of duodenum and jejunum showed that beta-carotene 15,15'-monooxygenase (EC1.14.99.36 Bcmo1) and the class B type I scavenger receptor, which are involved in vitamin A synthesis and carotenoid uptake, respectively, were drastically increased in IsxLacZ/LacZ mice. Although mild vitamin A deficiency decreased Isx expression in duodenum of wild-type (Isx+/+) mice, severe vitamin A deficiency decreased Isx mRNA expression in both duodenum and jejunum of Isx+/+ mice. On the other hand, vitamin A deficiency increased Bcmo1 expression in both duodenum and jejunum of Isx+/+ mice. However, Bcmo1 expression was not increased in duodenum of IsxLacZ/LacZ mice by mild vitamin A deficiency. These data suggest that Isx participates in the maintenance of vitamin A metabolism by regulating Bcmo1 expression in the intestine.
Journal of Biological Chemistry 03/2008; 283(8):4905-11. · 4.77 Impact Factor
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Mitsunori Watanabe,
Natsuki Monai,
Mandy Jackson,
Yukiko Yamamoto-Watanabe,
Yoshio Ikeda,
Chieko Suzuki,
Masahiko Tomiyama,
Takeshi Kawarabayashi,
Tamaki Kimura, Yusuke Seino,
Yasuhito Wakasaya,
Yasuo Miki,
Etsuro Matsubara,
Mikio Shoji
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ABSTRACT: A Japanese woman developed gait disturbances at 25 years of age, and subsequently underwent gradual changes in her personality. By the age of 42, she showed clear signs of dementia and cerebellar ataxia, and displayed behavioral abnormalities, choreic movements and hyperreflexia. The findings of MRI not only showed cerebellar and cerebral atrophy, but also revealed putaminal rim hyperintensity on T2-weighted images. We identified a heterozygously expanded CAG/CAA repeat (45/36) within the TATA-binding protein gene, leading to a diagnosis of SCA17. These results show that a 45 CAG/CAA repeat is pathological, giving rise to early-onset SCA17.
Internal Medicine 02/2008; 47(24):2179-82. · 0.94 Impact Factor
