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ABSTRACT: Recent studies have shown colestimide, a bile acid-binding resin, to also exert a glucose-lowering effect via amelioration of insulin resistance. To evaluate the effects of colestimide on glucose metabolism and to elucidate the underlying mechanism, we conducted a 6-month, open-label pilot study on 43 type 2 diabetic patients with obesity (BMI ≥ 25). The subjects were randomized to either treatment with colestimide 4g/day (T group, n=23) or continuation of their current therapy (C group, n=20). In the T group patients, mean HbA1c and fasting glucose improved markedly (from 7.71 ± 0.32% to 6.97 ± 0.20%; from 147.4 ± 7.3mg/dL to 127.0 ± 5.0mg/dL, respectively), while obesity-related parameters, i.e. body weight, waist circumference, and visceral fat and subcutaneous fat as determined by umbilical slice abdominal CT, showed no significant changes. Fractionation analyses of serum bile acids revealed significantly increased cholic acids (CA) and decreased chenodeoxycholic acids (CDCA) in the T group patients. However, no correlation was observed between these changes and ΔHbA1c. According to logistic regression analysis, baseline HbA1c was the only variable predicting the decrease of HbA1c (>0.5%) among sex, age, BMI, total cholesterol, ΔCA and ΔCDCA. The index of insulin resistance, i.e. HOMA-R, did not improve, and the index of β cell function, i.e. HOMA-β, actually increased significantly. These results suggests that, in obese patients with type 2 diabetes, the mechanism underlying improved glycemic control with colestimide treatment involves enhanced β cell activity rather than improved insulin resistance.
Endocrine Journal 01/2012; 59(3):239-46. · 2.03 Impact Factor
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Tsutomu Inoue,
Eito Kozawa,
Hirokazu Okada, Kouichi Inukai,
Shinichi Watanabe,
Tomohiro Kikuta,
Yusuke Watanabe,
Tsuneo Takenaka,
Shigehiro Katayama,
Junji Tanaka,
Hiromichi Suzuki
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ABSTRACT: Interstitial fibrosis and hypoxia accelerate the progression of CKD, but clinical tools to quantitate these factors in patients are lacking. Here, we evaluated the use of two magnetic resonance imaging (MRI) techniques, diffusion-weighted (DW)-MRI and blood oxygen level-dependent (BOLD)-MRI, to assess kidney fibrosis and hypoxia of the cortex in 142 patients with either diabetic nephropathy (n = 43), CKD without diabetes (n = 76), or acute kidney injury (AKI) (n = 23). Apparent diffusion coefficient (ADC) values of DW-MRI correlated with estimated glomerular filtration rates (eGFR) in the diabetic nephropathy and CKD groups (r(2) = 0.56 and r(2) = 0.46, respectively). Although the T2* values of BOLD-MRI and eGFR displayed good correlation in the CKD group (r(2) = 0.38), we did not observe a significant correlation between these values in the diabetic nephropathy group, suggesting that factors other than tubulointerstitial alteration determine the degree of hypoxia in the renal cortex. In the AKI group, neither the T2* nor ADC values correlated with eGFR. Renal biopsies from patients with CKD demonstrated that the T2* and ADC MRI values correlated with renal pathology. Taken together, ADC and T2* values appear to serve as accurate indices for evaluating renal tubulointerstitial alterations and parenchymal hypoxia, respectively, in the cortex. Functional MRI can thus contribute to multilateral, noninvasive, in vivo assessment of kidney function.
Journal of the American Society of Nephrology 08/2011; 22(8):1429-34. · 9.66 Impact Factor
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ABSTRACT: PPARgamma agonists are widely used in type 2 diabetic patients to reduce insulin resistance. Recently, telmisartan, an AT1 receptor antagonist, was reported to function as a partial agonist of PPARgamma based on in vitro experiments. The aim of the present study was to investigate whether the PPARgamma enhancing activity of telmisartan is exerted clinically in diabetic patients.
We compared the effects of telmisartan with those of candesartan, on insulin sensitivity, the serum levels of various adipocytokines and oxidative stress.
In total, 85 Japanese type 2 diabetic patients with hypertension, maintained on 8 mg per day of candesartan, were randomly assigned to the TM group (candesartan switched to 40 mg of telmisartan, n=38) or the CD group (no treatment change, n=47).
After 3 months, oxidized lipids were significantly decreased only in the TM group. Although the homeostasis assessment model of insulin resistance (HOMA-R) tended to be improved and serum concentrations of HDL-cholesterol and HMW adiponectin tended to be increased only in the TM group, these alterations were too small to be significant by unpaired t-test. Interestingly, in subgroup analysis, the alterations of HOMA-R, serum concentrations of oxidized lipids, and HMW adiponectin were more apparent in obese TM group subjects and the changes reached statistical significance.
Switching from candesartan to telmisartan in obese subjects increases serum adiponectin and improves both insulin resistance and oxidative stress, while these effects were not statistically apparent in the total patient population. These results support the idea that telmisartan exerts its PPARgamma enhancing activity clinically in obese type 2 diabetic patients.
Internal Medicine 01/2010; 49(17):1843-7. · 0.94 Impact Factor
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ABSTRACT: Adiponectin is an adipocyte-derived protein that acts to reduce insulin resistance in the liver and muscle and also inhibits atherosclerosis. Although adiponectin reportedly enhances AMP-activated protein kinase and inhibits tumor necrosis factor-alpha action downstream from the adiponectin signal, the precise physiological mechanisms by which adiponectin acts on skeletal muscles remain unknown.
We treated murine primary skeletal muscle cells with recombinant full-length human adiponectin for 12 h and searched, using two-dimensional electrophoresis, for proteins upregulated more than threefold by adiponectin compared with untreated cells.
We found one protein that was increased 6.3-fold with adiponectin incubation. MALDI-TOF (matrix-assisted laser desorption/ionization-top of flight) mass spectrometric analysis identified this protein as ferritin heavy chain (FHC). When murine primary skeletal muscle cells were treated with adiponectin, IkappaB-alpha phosphorylation was observed, suggesting that adiponectin stimulates nuclear factor (NF)-kappaB activity. In addition, FHC upregulation by adiponectin was inhibited by NF-kappaB inhibitors. These results suggest NF-kappaB activation to be involved in FHC upregulation by adiponectin. Other NF-kappaB target genes, manganese superoxide dismutase (MnSOD) and inducible nitric oxide synthase (iNOS), were also increased by adiponectin treatment. We performed a reactive oxygen species (ROS) assay using CM-H(2)DCFDA fluorescence and found that ROS-reducing effects of adiponectin were abrogated by FHC or MnSOD small-interfering RNA induction.
We have demonstrated that adiponectin upregulates FHC in murine skeletal muscle tissues, suggesting that FHC elevation might partially explain how adiponectin protects against oxidative stress in skeletal muscles.
Diabetes 11/2008; 58(1):61-70. · 8.29 Impact Factor
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ABSTRACT: To investigate the association between serum adiponectin levels and 2-hour post-75-g oral glucose load glycemia, we conducted 75-g oral glucose tolerance tests in 50 subjects who had been diagnosed as having impaired glucose tolerance (IGT) within the prior 3 years. When adjusted for age, body mass index, and sex, serum adiponectin levels in the IGT and diabetes mellitus groups were significantly lower than those in the normal glucose tolerance and impaired fasting glucose groups (P < .0001). To determine which variables had significant impacts on 2-hour post-oral glucose glycemia, we performed multiple regression analyses. In stepwise analysis, serum adiponectin levels showed the highest F value (F = 6.43), suggesting the adiponectin level to be an independent predictor of 2-hour post-oral glucose glycemia. Thus, our clinical data suggest the involvement of low adiponectin levels in IGT and diabetes mellitus. To further assess this possibility, we prepared mice fed a high-fat diet for 2 months as an IGT model. Afterward, we compared the 2-hour postglucose glycemia in the IGT mice overexpressing recombinant adiponectin with that in control IGT mice. Mice overexpressing adiponectin showed significantly blunted 2-hour postglucose glycemia (5.66 +/- 0.39 mmol/L) as compared with control mice (8.52 +/- 0.67 mmol/L), whereas fasting glycemia was not significantly altered by adiponectin overexpression. Taken together, our results reveal the plasma glucose level in response to a glucose load to be negatively associated with serum adiponectin levels, suggesting low adiponectin levels to be one of the predictors of abnormal glucose homeostasis in IGT.
Metabolism: clinical and experimental 11/2008; 57(10):1350-4. · 2.59 Impact Factor
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Kanou Kojima,
Hiroyuki Motoshima,
Atsuyuki Tsutsumi,
Motoyuki Igata,
Takeshi Matsumura,
Tatsuya Kondo,
Junji Kawashima,
Kenshi Ichinose,
Noboru Furukawa, Kouichi Inukai,
Shigehiro Katayama,
Barry J Goldstein,
Takeshi Nishikawa,
Kaku Tsuruzoe,
Eiichi Araki
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ABSTRACT: AMP-activated protein kinase (AMPK) is a cellular energy sensor involved in multiple cell signaling pathways that has become an attractive therapeutic target for vascular diseases. It is not clear whether rottlerin, an inhibitor of protein kinase Cdelta, activates AMPK in vascular cells and tissues. In the present study, we have examined the effect of rottlerin on AMPK in vascular smooth muscle cells (VSMCs) and isolated rabbit aorta. Rottlerin reduced cellular ATP and activated AMPK in VSMCs and rabbit aorta; however, inhibition of PKCdelta by three different methods did not activate AMPK. Both VSMCs and rabbit aorta expressed the upstream AMPK kinase LKB1 protein, and rottlerin-induced AMPK activation was decreased in VSMCs by overexpression of dominant-negative LKB1, suggesting that LKB1 is involved in the upstream regulation of AMPK stimulated by rottlerin. These data suggest for the first time that LKB1 mediates rottlerin-induced activation of AMPK in vascular cells and tissues.
Biochemical and Biophysical Research Communications 10/2008; 376(2):434-8. · 2.48 Impact Factor
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ABSTRACT: Class IA phosphatidylinositol 3-kinase (PI 3-kinase), which is composed of a 110kDa catalytic subunit and a regulatory subunit, plays a key role in most insulin dependent cellular responses. To date, five mammalian regulatory subunit isoforms have been identified, including two 85kDa proteins (p85alpha and p85beta), two 55kDa proteins (p55gamma and p55alpha), and one 50kDa protein (p50alpha). In the present study, we overexpressed these recombinant proteins, tagged with green fluorescent proteins (GFP), in CHO-IR cells and investigated intracellular localizations in both the presence and the absence of insulin stimulation. Interestingly, in response to insulin, only p85alpha and p85beta redistributed to isolated foci in the cells, while both were present throughout the cytoplasm in quiescent cells. In contrast, p55s accumulated in the perinuclear region irrespective of insulin stimulation, while p50alpha behaved similarly to control GFP. Immunofluorescent antibodies against endogenous IRS-1 revealed IRS-1 to be co-localized in the p85 foci in response to insulin. As both insulin receptors and p110alpha catalytic subunits were absent from these foci on immunofluorescence study, only p85 and IRS-1 were suggested to form a sequestration complex in response to insulin. To determine the domain responsible for IRS-1 complex formation, we prepared and overexpressed the SH3 domain deletion mutant of p85alpha in CHO-IR cells. This mutant failed to form foci, suggesting the SH3 domain of regulatory subunits to be responsible for formation of the p85-IRS-1 sequestration complex. In conclusion, our study revealed the SH3 domain of PI 3-kinase to play a critical role in intracellular localizations, including formation of foci with IRS-1 in response to insulin.
Biochemical and Biophysical Research Communications 02/2008; 365(3):433-8. · 2.48 Impact Factor
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ABSTRACT: Two adiponectin receptors were recently identified, AdipoR1 and R2. AdipoR1 expression was increased approximately 2.5-fold in muscle tissues from insulin-deficient diabetic mice, but normalized with insulin administration. AdipoR1 expression was decreased by 44% in insulin-resistant obese, as compared to lean, mice. These results indicate AdipoR1 expression to correlate inversely with plasma insulin levels. Insulin treatment for 24 h decreased AdipoR1 expression by approximately 60% in C2C12 myocytes. In addition, this effect was mediated by the phosphatidylinositol-3 kinase/Foxo 1 dependent pathway. In contrast, AdipoR2 expression was not significantly altered in diabetic states. Our results indicate that regulation of AdipoR1, but not AdipoR2, may be involved in glucose and lipid metabolism in diabetic states.
Nippon rinsho. Japanese journal of clinical medicine 12/2007; 65(11):2125-30.
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Hiroyuki Iizuka,
Takuya Awata,
Masataka Osaki,
Tamotsu Neda,
Susumu Kurihara,
Kiyoaki Inoue, Kouichi Inukai,
Sho Kabasawa,
Keisuke Mori,
Shin Yoneya,
Shigehiro Katayama
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ABSTRACT: Pigment epithelium-derived factor (PEDF or SERPINF1), a neuroprotective and anti-angiogenic factor, may play an important role in the pathogenesis of diabetic retinopathy (DR). In 416 patients with type 2 diabetes, four polymorphisms in the PEDF SNPs were identified, rs12150053 and rs12948385 in the promoter region, rs9913583 in the 5'-untranslated region, and rs1136287 (Met72Thr) in exon 3. Based on case-control studies, rs12150053 and rs12948385, but not rs9913583 and rs1136287, were significantly associated with DR. A logistic regression analysis revealed that the TC or CC genotype of rs12150053 was a significant risk factor for DR (odds ratio 2.40, p=0.0004). The GA or AA genotype of rs12948385 was also a significant risk factor for DR. In addition, a significant interaction between the vascular endothelial growth factor (VEGF) and PEDF SNPs in the susceptibility to DR was found. These results demonstrate that the PEDF gene, in cooperation with the VEGF gene, may contribute to the development of DR.
Biochemical and Biophysical Research Communications 10/2007; 361(2):421-6. · 2.48 Impact Factor
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ABSTRACT: To explore the effects of various antihypertensive regimes on microalbuminuria, an angiotensin II receptor blocker (ARB), valsartan, was substituted for or added to treatment with a calcium channel blocker (CCB). After a 6-month CCB baseline period, 28 Japanese hypertensive patients with incipient diabetic nephropathy (defined as a urinary albumin excretion [UAE] of 30-300 mg/g creatinine), were assigned to two groups according to their blood pressure (BP) levels: in patients with a BP of more than 130/85 mmHg (n=17), valsartan was added to the CCB (Group A), while in patients with a BP <130/85 mmHg, valsartan alone was given (Group B: n=11) for 12 months. UAE was determined before and at 3, 6 and 12 months after the initiation of ARB. Although the initial BP was significantly higher in Group A (150/83 mmHg) than Group B (127/77 mmHg), BP was decreased to 141/78 mmHg in Group A and slightly, but not significantly, increased to 130/82 mmHg in Group B. In both groups, UAE was significantly decreased after ARB treatment (to 89% of the basal value in Group A and to 40.5% of the basal value in Group B) and did not differ each other and the amount of decrease did not differ significantly between the two groups. These results suggest that combination therapy with an ARB and CCB is very effective in lowering BP and UAE in cases in which BP is not well controlled, while, even in patients with a sufficient BP control of <130/85 mmHg, the use of ARB singly resulted in a significant decrease in UAE without a further decrease in BP, implying that the ARB had a renoprotective action independent of changes in BP.
Hypertension Research 06/2007; 30(6):529-33. · 2.58 Impact Factor
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ABSTRACT: LKB1 is a 50 kDa serine/threonine kinase that phosphorylates and activates the catalytic subunit of AMPK at its T-loop residue Thr 172. We prepared adenoviruses expressing the constitutive active (wild-type) form (CA) or dominant negative (kinase inactive, D194A mutant) form (DN) of LKB1 and overexpressed these proteins in cultured myotubes (C2C12 cells) and rat hepatoma cells (FAO cells). When analyzed by immunoblotting with the antibody against Thr172-phosphorylated AMPK, the phosphorylation of AMPK was increased (2.5-fold) and decreased (0.4-fold) in cells expressing CA and DN LKB1, respectively, as compared with Lac-Z expressing control cells. Immunoprecipitation experiments, using isoform-specific antibody, revealed these alterations of AMPK phosphorylation to be attributable to altered phosphorylation of AMPK alpha2, but not alpha1 catalytic subunits, strongly suggesting the alpha2 catalytic subunit to be the major substrate for LKB1 in mammalian cells. In addition, adiponectin or AICAR-stimulated AMPK phosphorylation was inhibited by overexpression of DN LKB1, while phenformin-stimulated phosphorylation was unaffected. These results may explain the difference in AMPK activation mechanisms between AMP and phenformin, and also indicate that AMPK phosphorylation by LKB1 is involved in AMP-stimulated AMPK activation. As a downstream target for AMPK, AICAR-induced glucose uptake and ACCbeta phosphorylation were found to be significantly reduced in DN LKB1 expressing C2C12 cells. The expression of key enzymes for gluconeogenesis, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, was also dependent on LKB1 activities in FAO cells. These results demonstrate that LKB1 is a crucial regulator of AMPK activation in muscle and liver cells and, therefore, that LKB1 activity is potentially of importance to our understanding of glucose and lipid metabolism.
Biochemical and Biophysical Research Communications 01/2007; 351(3):595-601. · 2.48 Impact Factor
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Kenji Uno,
Hideki Katagiri,
Tetsuya Yamada,
Yasushi Ishigaki,
Takehide Ogihara,
Junta Imai,
Yutaka Hasegawa,
Junhong Gao,
Keizo Kaneko,
Hiroko Iwasaki,
Hisamitsu Ishihara,
Hironobu Sasano, Kouichi Inukai,
Hiroyuki Mizuguchi,
Tomoichiro Asano,
Masakazu Shiota,
Masamitsu Nakazato,
Yoshitomo Oka
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ABSTRACT: Coordinated control of energy metabolism and glucose homeostasis requires communication between organs and tissues. We identified a neuronal pathway that participates in the cross talk between the liver and adipose tissue. By studying a mouse model, we showed that adenovirus-mediated expression of peroxisome proliferator-activated receptor (PPAR)-g2 in the liver induces acute hepatic steatosis while markedly decreasing peripheral adiposity. These changes were accompanied by increased energy expenditure and improved systemic insulin sensitivity. Hepatic vagotomy and selective afferent blockage of the hepatic vagus revealed that the effects on peripheral tissues involve the afferent vagal nerve. Furthermore, an antidiabetic thiazolidinedione, a PPARg agonist, enhanced this pathway. This neuronal pathway from the liver may function to protect against metabolic perturbation induced by excessive energy storage.
Science 07/2006; 312(5780):1656-9. · 31.20 Impact Factor
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Akifumi Kushiyama,
Nobuhiro Shojima,
Takehide Ogihara, Kouichi Inukai,
Hideyuki Sakoda,
Midori Fujishiro,
Yasushi Fukushima,
Motonobu Anai,
Hiraku Ono,
Nanao Horike,
Amelia Y I Viana,
Yasunobu Uchijima,
Koichi Nishiyama,
Tatsuo Shimosawa,
Toshiro Fujita,
Hideki Katagiri,
Yoshitomo Oka,
Hiroki Kurihara,
Tomoichiro Asano
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ABSTRACT: Resistin and resistin-like molecules (RELMs) are a family of proteins reportedly related to insulin resistance and inflammation. Because the serum concentration and intestinal expression level of RELMbeta were elevated in insulin-resistant rodent models, in this study we investigated the effect of RELMbeta on insulin signaling and metabolism using transgenic mice and primary cultured hepatocytes. First, transgenic mice with hepatic RELMbeta overexpression were shown to exhibit significant hyperglycemia, hyperlipidemia, fatty liver, and pancreatic islet enlargement when fed a high fat diet. Hyperinsulinemic glucose clamp showed a decreased glucose infusion rate due to increased hepatic glucose production. In addition, the expression levels of IRS-1 and IRS-2 proteins as well as the degrees of insulin-induced phosphatidylinositol 3-kinase and Akt activations were attenuated in RELMbeta transgenic mice. Similar down-regulations of IRS-1 and IRS-2 proteins were observed in primary cultured hepatocytes chronically treated (for 24 h) with RELMbeta, suggesting the insulin resistance-inducing effect of RELMbeta to be direct. Furthermore, it was shown that RELMbeta acutely and markedly activates ERK and p38, while weakly activating JNK, in primary cultured hepatocytes. This increased basal p38 phosphorylation level was also observed in the livers of RELMbeta transgenic mice. In conclusion, RELMbeta, a gut-derived hormone, impairs insulin signaling probably via the activations of classic MAPKs, and increased expression of RELMbeta may be involved in the pathogenesis of glucose intolerance and hyperlipidemia in some insulin-resistant models. Thus, RELMbeta is a potentially useful marker for assessing insulin resistance and may also be a target for future novel anti-diabetic agents.
Journal of Biological Chemistry 01/2006; 280(51):42016-25. · 4.77 Impact Factor
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Akifumi Kushiyama,
Nobuhiro Shojima,
Takehide Ogihara, Kouichi Inukai,
Hideyuki Sakoda,
Midori Fujishiro,
Yasushi Fukushima,
Motonobu Anai,
Hiraku Ono,
Nanao Horike,
Amelia Y. I. Viana,
Yasunobu Uchijima,
Koichi Nishiyama,
Tatsuo Shimosawa,
Toshiro Fujita,
Hideki Katagiri,
Yoshitomo Oka,
Hiroki Kurihara,
Tomoichiro Asano
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ABSTRACT: Resistin and resistin-like molecules (RELMs) are a family of proteins reportedly related to insulin resistance and inflammation.
Because the serum concentration and intestinal expression level of RELMβ were elevated in insulin-resistant rodent models,
in this study we investigated the effect of RELMβ on insulin signaling and metabolism using transgenic mice and primary cultured
hepatocytes. First, transgenic mice with hepatic RELMβ overexpression were shown to exhibit significant hyperglycemia, hyperlipidemia,
fatty liver, and pancreatic islet enlargement when fed a high fat diet. Hyperinsulinemic glucose clamp showed a decreased
glucose infusion rate due to increased hepatic glucose production. In addition, the expression levels of IRS-1 and IRS-2 proteins
as well as the degrees of insulin-induced phosphatidylinositol 3-kinase and Akt activations were attenuated in RELMβ transgenic
mice. Similar down-regulations of IRS-1 and IRS-2 proteins were observed in primary cultured hepatocytes chronically treated
(for 24 h) with RELMβ, suggesting the insulin resistance-inducing effect of RELMβ to be direct. Furthermore, it was shown
that RELMβ acutely and markedly activates ERK and p38, while weakly activating JNK, in primary cultured hepatocytes. This
increased basal p38 phosphorylation level was also observed in the livers of RELMβ transgenic mice. In conclusion, RELMβ,
a gut-derived hormone, impairs insulin signaling probably via the activations of classic MAPKs, and increased expression of
RELMβ may be involved in the pathogenesis of glucose intolerance and hyperlipidemia in some insulin-resistant models. Thus,
RELMβ is a potentially useful marker for assessing insulin resistance and may also be a target for future novel anti-diabetic
agents.
Journal of Biological Chemistry 12/2005; 280(51):42016-42025. · 4.77 Impact Factor
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Takuya Awata,
Susumu Kurihara,
Nobuki Takata,
Tamotsu Neda,
Hiroyuki Iizuka,
Tomoko Ohkubo,
Masataka Osaki,
Masaki Watanabe,
Youhei Nakashima, Kouichi Inukai,
Ikuo Inoue,
Izumi Kawasaki,
Keisuke Mori,
Shin Yoneya,
Shigehiro Katayama
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ABSTRACT: Since vascular endothelial growth factor (VEGF) has a strong effect on induction of vascular permeability, VEGF is an attractive candidate gene for development of diabetic macular edema (ME). Among the 378 patients with type 2 diabetes studied, 203 patients had no retinopathy, 93 had non-proliferative diabetic retinopathy (NPDR), and 82 had proliferative diabetic retinopathy (PDR). ME was present in 16 patients with NPDR and 47 patients with PDR. We genotyped three VEGF polymorphisms: C-2,578A, G-1,154A, and C-634G. Genotype and allele distribution of C-634G, but not C-2,578A or G-1,154A, were significantly different between patients with and without diabetic retinopathy. Logistic regression analysis revealed that the C-634G genotype was a risk factor for DR (p = 0.002), and furthermore for ME (p = 0.047), independently from severity of DR, with the -634C allele increasing the risk. Macular thickness measured by optical coherence tomography was correlated with the C-634G genotype, with the trend increasing with the presence of more -634C alleles (p = 0.006). Stepwise regression analysis showed that duration of diabetes and presence of the C-634G genotype were independent predictors of macular thickness. In addition, basic transcriptional activity levels associated with the -634C allele were greater compared to those seen with the -634G allele in human glioma and lymphoblastic T-lymphocyte cells. These results demonstrate that the VEGF C-634G polymorphism is a genetic risk factor for ME as well as DR.
Biochemical and Biophysical Research Communications 09/2005; 333(3):679-85. · 2.48 Impact Factor
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ABSTRACT: Wolfram syndrome (WFS) is an autosomal recessive disorder characterized by early onset diabetes mellitus, progressive optic atrophy, sensorineural deafness and diabetes insipidus. Affected individuals may also have renal tract abnormalities as well as neurogical and psychiatric syndromes. WFS1 encoding a transmembrane protein was identified as the gene responsible for WFS. We report herein a Japanese family, of which two members had this syndrome. In the WFS1 gene of these patients, we identified a novel mutation, a nine nucleotide insertion (AFF344-345ins). In addition, one of these patients had preclinical hypopituitarism, which is an unusual feature of WFS. As only the two family members homozygous for the mutation showed WFS, these data support the notion that this mutation is the cause of WFS.
Diabetes Research and Clinical Practice 09/2005; 69(2):136-41. · 2.75 Impact Factor
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Kouichi Inukai,
Masaki Watanabe,
Youhei Nakashima,
Takahiro Sawa,
Nobuki Takata,
Masahiko Tanaka,
Hideyuki Kashiwabara,
Kensuke Yokota,
Masao Suzuki,
Susumu Kurihara,
Takuya Awata,
Shigehiro Katayama
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ABSTRACT: We investigated the efficacy of glimepiride, a third-generation sulfonylurea (SU), in Japanese type 2 diabetic patients in whom glycemic control had been inadequate with a conventional SU, gliclazide or glibenclamide. A total of 172 Japanese type 2 diabetic patients (HbA1C > or = 7.0%), maintained on a conventional SU, were randomly assigned to the 3rd SU group (SU treatments switched to glimepiride) or the 2nd SU group (treatments not changed). The conventional SU was switched to the indicated doses of glimepiride (gliclazide 40 mg = glimepiride 1 mg, glibenclamide 2.5 mg = glimepiride 2 mg). After 6 months, glycemic control (HbA1C and fasting plasma glucose) had not changed significantly in either the 2nd or the 3rd SU group. The homeostasis assessment model of insulin resistance (HOMA-IR) in the 3rd SU group was decreased by more than 10% (p = 0.015), whereas no change was observed in the 2nd SU group. The triglyceride level was decreased by approximately 10% in the 3rd SU group, not a significant change (p = 0.080). Patients who had been treated with only SU, or treated with SU for a short time (less than 5 years), and who were also obese (BMI > or = 25) or had a high HOMA-IR (HOMA-IR > or = 3), showed significantly reduced insulin resistance. According to logistic regression analysis, high BMI ( > or = 25) was the only variable predicting that glimepiride would more effectively improve HbA1C than conventional SU treatment. In conclusion, switching conventional SUs to glimepiride reduced insulin resistance without improving glycemic control. A notable finding of this study is that glimepiride was more beneficial in obese than in non-obese Japanese type 2 diabetic patients.
Diabetes Research and Clinical Practice 06/2005; 68(3):250-7. · 2.75 Impact Factor
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ABSTRACT: Adiponectin is an adipocyte-derived factor that plays pivotal roles in lipid and glucose metabolism in muscle and liver. The following two adiponectin receptor types were recently identified: AdipoR1 is abundantly expressed in muscle, whereas AdipoR2 is predominantly expressed in the liver. To clarify the regulation of adiponectin receptor gene expression in diabetic states, we examined mRNA levels of AdipoR1 in the muscles of diabetic animals by Northern blotting. The level of AdipoR1 mRNA was increased approximately 2.5-fold in muscle of streptozotocin (STZ) diabetic mice, but the normal level was restored by insulin administration, indicating that insulin has an inhibitory effect on AdipoR1 expression. To confirm this inhibitory effect of insulin, we performed in vitro experiments using C2C12 skeletal muscle cells. Insulin treatment for 24 h decreased AdipoR1 expression by approximately 60% in C2C12 cells. In addition, this effect was mediated by the phosphatidylinositol 3-kinase-dependent pathway rather than the mitogen-activated protein kinase pathway. AdipoR1 expression in insulin-resistant diabetic mice was also investigated. AdipoR1 expression was decreased by 36% in type 2 diabetic obese db/db mice compared with lean mice. In contrast, hepatic AdipoR2 expression was not significantly changed in either STZ mice or genetically obese mice. Our results indicate that regulation of AdipoR1, but not that of AdipoR2, may be involved in glucose and lipid metabolism in diabetic states.
AJP Endocrinology and Metabolism 06/2005; 288(5):E876-82. · 4.75 Impact Factor
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ABSTRACT: Glimepiride, a third-generation sulfonylurea (SU), exerts its effects mainly by stimulating insulin secretion but has also been shown to have pleiotropic effects. Recent clinical studies showed glimepiride to enhance insulin sensitivity. In the present study, to clarify the mechanism by which insulin resistance is improved, we investigated the effects of glimepiride on AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma (PPAR gamma) activity, using cultured adipocytes and muscle cells. When we treated fully differentiated 3T3-L1 adipocytes with 1 microM glimepiride, endogenous PPAR gamma transcriptional activity was significantly elevated, while AICAR-induced phosphorylation of AMPK was not affected in differentiated C2C12 myoblasts. The maximum PPAR gamma activity enhancing effect of glimepiride is approximately 20% that of 1 microM pioglitazone. In contrast, this mild PPAR gamma-stimulatory effect was not observed under the same conditions with a 2nd generation SU, glibenclamide. Furthermore, with glimepiride treatment, transcriptional levels of aP2, the adipogenic marker gene, were increased 2.4- and 3.7-fold in 3T3-L1 adipocytes and fibroblasts, respectively. Analysis of triglyceride contents revealed glimepiride to promote differentiation of 3T3-L1 adipocytes. These results indicate that glimepiride has the potential to induce PPAR gamma activity, thereby improving insulin resistance.
Biochemical and Biophysical Research Communications 04/2005; 328(2):484-90. · 2.48 Impact Factor
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ABSTRACT: Peroxisome proliferator-activated receptor gamma (PPAR gamma) has been shown to play an important role in adipocyte differentiation. A Pro12Ala substitution in PPAR gamma 2 has been reported to decrease receptor activity in vitro and to be associated with a decreased risk of type 2 diabetes in the general population. Recently, a PPAR response element (PPRE) was identified in the adiponectin promoter, suggesting that decreased PPAR gamma activity may lead to lower adiponectin levels. In the present study, serum adiponectin concentrations and the PPAR gamma Pro12Ala polymorphism were analyzed to determine whether this polymorphism is associated with lower serum adiponectin concentrations in young healthy Japanese subjects. Serum adiponectin concentrations were significantly lower in men with than in those without the Ala12 allele, whereas body mass index (BMI), homeostasis model assessment (HOMA)-beta, HOMA-IR, the insulin sensitivity index during oral glucose tolerance test (ISI [composite]), and serum leptin did not differ significantly between subjects with and without the Ala12 allele. Stepwise regression demonstrated BMI and the Ala12 allele to be independent predictors of serum adiponectin concentrations in men. In conclusion, the Pro12Ala substitution in PPAR gamma 2 may reduce serum adiponectin concentrations in young Japanese men.
Metabolism 01/2005; 53(12):1548-51. · 2.66 Impact Factor
