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C57BL/KsJ-db/db-ApcMin/+ Mice Exhibit an Increased Incidence of Intestinal Neoplasms  [PDF]
Kazuya Hata,Masaya Kubota,Masahito Shimizu,Hisataka Moriwaki,Toshiya Kuno,Takuji Tanaka,Akira Hara,Yoshinobu Hirose
International Journal of Molecular Sciences , 2011, DOI: 10.3390/ijms12118133
Abstract: The numbers of obese people and diabetic patients are ever increasing. Obesity and diabetes are high-risk conditions for chronic diseases, including certain types of cancer, such as colorectal cancer (CRC). The aim of this study was to develop a novel animal model in order to clarify the pathobiology of CRC development in obese and diabetic patients. We developed an animal model of obesity and colorectal cancer by breeding the C57BL/KsJ- db /db (db/db) mouse, an animal model of obesity and type II diabetes, and the C57BL/6J- ApcMin/+ (Min/+) mouse, a model of familial adenomatous polyposis. At 15 weeks of age, the N9 backcross generation of C57BL/KsJ- db /db- ApcMin/+ (db/db-Min/+) mice developed an increased incidence and multiplicity of adenomas in the intestinal tract when compared to the db/m-Min/+ and m/m-Min/+ mice. Blood biochemical profile showed significant increases in insulin (8.3-fold to 11.7-fold), cholesterol (1.2-fold to 1.7-fold), and triglyceride (1.2-fold to 1.3-fold) in the db/db-Min/+ mice, when compared to those of the db/m-Min/+ and m/m-Min/+ mice. Increases (1.4-fold to 2.6-fold) in RNA levels of insulin-like growth factor (IGF)-1, IRF-1R, and IGF-2 were also observed in the db/db-Min/+ mice. These results suggested that the IGFs, as well as hyperlipidemia and hyperinsulinemia, promoted adenoma formation in the db/db-Min/+ mice. Our results thus suggested that the db/db-Min/+ mice should be invaluable for studies on the pathogenesis of CRC in obese and diabetes patients and the therapy and prevention of CRC in these patients.
No Association between Glycemia and Wound Healing in an Experimental db/db Mouse Model  [PDF]
Margrete Berdal,Trond Jenssen
ISRN Endocrinology , 2013, DOI: 10.1155/2013/307925
Abstract: Impaired wound healing is a frequent problem in diabetes. Hyperglycemia may be an operative mechanism, but a link between glycemic control and wound healing has never been established. Wounds in db/db mice have been extensively studied. This study was undertaken to see if plasma glucose was a predictor of wound healing. An excisional wound was made (149 db/db mice). Wound closure was studied versus metabolic variables. The animals were weeks (mean ± standard error of the mean), obese ( ?g), and hyperglycemic (fasting plasma glucose ?mmol/L). Wound closure at day 13 was . In linear mixed model analyses neither fasting plasma glucose nor its change from start to end of experiment was a significant predictor of wound closure ( , , 95% CI: ?0.01 to 0.31 and , , 95% CI: ?0.11 to 0.23, resp.). However, increase in body weight significantly and independently predicted wound closure (for weight change, , , 95% CI: 0.06 to 0.38). This study strongly suggests that wound healing in db/db mice is independent of prevailing glycemia but dependent on anabolic changes such as weight gain over time. 1. Introduction Impaired wound healing—a well-known problem in diabetes—has been extensively studied in animals [1, 2]. One model, which has been explored for this purpose, is the genetically leptin receptor deficient, diabetic db/db mouse with characteristics such as obesity, transient hyperinsulinemia, insulin resistance, severe hyperglycemia, and impaired wound healing [2–8]. Hyperglycemia is one factor that may be implicated in impaired wound repair. Clinical guidelines advocate optimization of metabolic control to facilitate wound healing [9]. A retrospective study in humans suggested that glycated hemoglobin (A1C) predicted healing rates in diabetic wounds [10]. However, as far as we know, direct evidence of a link between glycemic control and healing is lacking [11]. In the db/db mouse model, a few studies have addressed the possible impact of hyperglycemia on wound healing [6, 12, 13]. They included up to 31?db/db mice from one or two age groups, and baseline body weight but not weight change was assessed. No significant associations between metabolic parameters and wound healing were observed [6]. In the present study we included 149?db/db mice, aged 6–16 weeks, with the aim of testing whether fasting plasma glucose at baseline, the change in fasting plasma glucose, or other metabolic parameters, including weight change, were associated with wound closure. 2. Materials and Methods 2.1. Animals Diabetic C57BL/KsBom-db/db mice were studied. All animals were purchased
The db/db Mouse: A Useful Model for the Study of Diabetic Retinal Neurodegeneration  [PDF]
Patricia Bogdanov, Lidia Corraliza, Josep A. Villena, Andrea R. Carvalho, José Garcia-Arumí, David Ramos, Jesús Ruberte, Rafael Simó, Cristina Hernández
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0097302
Abstract: Background To characterize the sequential events that are taking place in retinal neurodegeneration in a murine model of spontaneous type 2 diabetes (db/db mouse). Methods C57BLKsJ-db/db mice were used as spontaneous type 2 diabetic animal model, and C57BLKsJ-db/+ mice served as the control group. To assess the chronological sequence of the abnormalities the analysis was performed at different ages (8, 16 and 24 weeks). The retinas were evaluated in terms of morphological and functional abnormalities [electroretinography (ERG)]. Histological markers of neurodegeneration (glial activation and apoptosis) were evaluated by immunohistochemistry. In addition glutamate levels and glutamate/aspartate transporter (GLAST) expression were assessed. Furthermore, to define gene expression changes associated with early diabetic retinopathy a transcriptome analyses was performed at 8 week. Furthermore, an additional interventional study to lower blood glucose levels was performed. Results Glial activation was higher in diabetic than in non diabetic mice in all the stages (p<0.01). In addition, a progressive loss of ganglion cells and a significant reduction of neuroretinal thickness were also observed in diabetic mice. All these histological hallmarks of neurodegeneration were less pronounced at week 8 than at week 16 and 24. Significant ERG abnormalities were present in diabetic mice at weeks 16 and 24 but not at week 8. Moreover, we observed a progressive accumulation of glutamate in diabetic mice associated with an early downregulation of GLAST. Morphological and ERG abnormalities were abrogated by lowering blood glucose levels. Finally, a dysregulation of several genes related to neurotransmission and oxidative stress such as UCP2 were found at week 8. Conclusions Our results suggest that db/db mouse reproduce the features of the neurodegenerative process that occurs in the human diabetic eye. Therefore, it seems an appropriate model for investigating the underlying mechanisms of diabetes-induced retinal neurodegeneration and for testing neuroprotective drugs.
Effects of Gametophytes of Ecklonia Kurome on the Levels of Glucose and Triacylglycerol in db/db, Prediabetic C57BL/6J and IFN-γ KO Mice  [cached]
Febriza Dwiranti,Takahiro Taguchi,Akira Tominaga,Masanori Hiraoka
International Journal of Biomedical Science , 2012,
Abstract: We have studied edible algae that have the potential to down-regulate blood glucose. In Japan, Ecklonia species have been believed to improve the circulation of blood. In this study, we used leptin receptor deficient type 2 diabetes model mice (db/db) and prediabetic C57BL/6J mice. We also focused on the role of IFN-γ in the control of blood levels of triacylglycerol and glucose, because it is reportedly engaged in the regulation of energy consumption together with leptin. We report that gametophytes of Ecklonia kurome down-regulate the blood level of glucose and serum level of triacylglycerol in db/db. We also report that gametophytes of Ecklonia kurome down-regulate the level of glucose but not the level of triacylglycerol in prediabetic C57BL/6J mice induced by a high fat diet. They increased the level of triacylglycerol compared to that of control group in C57BL/6J, but not in IFN-γ KO mice. Gametophytes of Ecklonia kurome were administered orally to prediabetic C57BL/6J and IFN-γ KO mice and oral glucose tolerance tests were performed to evaluate the effects of algae. During the administration of the normal diet, we found a higher level of blood glucose in a glucose tolerance test of IFN-γ KO mice compared with that of C57BL/6J. Although a high fat diet induced a higher level of blood glucose compared with a normal diet group in a glucose tolerance test of C57BL/6J mice, this effect of high fat diet was not observed clearly at first but appeared three hours after glucose administration in IFN-γ KO mice. Gametophytes of Ecklonia kurome down-regulated the level of blood glucose in both C57BL/6J and IFN-γ KO mice, when administered a normal diet after making them prediabetic. These results suggest that Ecklonia kurome are effective to down-regulate the blood glucose and IFN-γ is involved in the regulation of blood glucose and triacylglycerol.
Urinary corticosterone and normetanephrine levels after voluntary wheel and forced treadmill running in the db/db mouse  [PDF]
Cassandra R. Parrott, Priya Ghosh, Jamie Tedeschi, Gayan Gunasekara, Tom L. Broderick
Journal of Diabetes Mellitus (JDM) , 2011, DOI: 10.4236/jdm.2011.14011
Abstract: Exercise is recommended for the treatment of type 2 diabetes because of its benefits on body weight and glycemic control. Our recent work using the db/db mouse, a model that mimics the phenotype of type 2 diabetes, demonstrated that forced treadmill training exerted detrimental effects on obesity, hyperglycemia and insulin resistance. We investigated whether this response is explained by increased corticosterone and norepinephrine secretion, measured as urinary byproducts, since these hormones are known to alter glucose homeostasis. Male db/db mice and lean littermates serving as controls, were assigned to sedentary, voluntary wheel, and forced treadmill training groups for a period of 5 weeks. After 5 weeks of treadmill running, db/db mice remained hyperglycemic compared to sedentary db/db mice and were hyperinsulinemic compared to db/db voluntary runners. Urine glucose and corticosterone levels were also highest in db/db treadmill runners compared to all groups. Urine normetanephrine levels, although lower in db/db mice compared to control mice, were increased after treadmill running. Our results indicate that treadmill running leads to perturbations in plasma levels of hormones associated with glucose homeostasis. A greater stress response may be invoked by treadmill training, worsening glycemic control in this model of type 2 diabetes.
Diet supplementation with green tea extract epigallocatechin gallate prevents progression to glucose intolerance in db/db mice
Henrik Orts?ter, Nina Grankvist, Swen Wolfram, Nicolas Kuehn, ?ke Sj?holm
Nutrition & Metabolism , 2012, DOI: 10.1186/1743-7075-9-11
Abstract: Young (7 week-old) db/db mice were randomized and assigned to receive diets supplemented with or without EGCG or rosiglitazone for 10 weeks. Fasting blood glucose, body weight and food intake was measured along the treatment. Glucose and insulin levels were determined during an oral glucose tolerance test after 10 weeks of treatment. Pancreata were sampled at the end of the study for blinded histomorphometric analysis. Islets were isolated and their mRNA expression analyzed by quantitative RT-PCR.The results show that, in db/db mice, EGCG improves glucose tolerance and increases glucose-stimulated insulin secretion. EGCG supplementation reduces the number of pathologically changed islets of Langerhans, increases the number and the size of islets, and heightens pancreatic endocrine area. These effects occurred in parallel with a reduction in islet endoplasmic reticulum stress markers, possibly linked to the antioxidative capacity of EGCG.This study shows that the green tea extract EGCG markedly preserves islet structure and enhances glucose tolerance in genetically diabetic mice. Dietary supplementation with EGCG could potentially contribute to nutritional strategies for the prevention and treatment of type 2 diabetes.The WHO and CDC (U.S. Center for Disease Control) predict that by today some 26 million people in the U.S. only are afflicted by diabetes (http://www.cdc.gov/diabetes/ webcite). Previously viewed as a disease of the elderly, type 2 diabetes is now seen in ever-younger age groups. In the U.S. about one third of all newly diagnosed diabetes in children and adolescents (age 10-19 years) now is type 2, an alarming scenario considering the magnitude of premature cardiovascular and cerebrovascular morbidity in these individuals. Recent estimates by the CDC indicate that the life-time risk of getting diabetes is not less than 40% for people born in 2000 in the U.S., with certain ethnic groups being significantly overrepresented (http://www.cdc.gov/diabetes web
Downregulation in GATA4 and Downstream Structural and Contractile Genes in the db/db Mouse Heart  [PDF]
Tom L. Broderick,Marek Jankowski,Donghao Wang,Bogdan A. Danalache,Cassandra R. Parrott,Jolanta Gutkowska
ISRN Endocrinology , 2012, DOI: 10.5402/2012/736860
Abstract: Reduced expression of GATA4, a transcriptional factor for structural and cardioprotective genes, has been proposed as a factor contributing to the development of cardiomyopathy. We investigated whether the reduction of cardiac GATA4 expression reported in diabetes alters the expression of downstream genes, namely, atrial natriuretic peptide (ANP), B-type natriuretic, peptide (BNP), and α- and β-myosin heavy chain (MHC). db/db mice, a model of type 2 diabetes, with lean littermates serving as controls, were studied. db/db mice exhibited obesity, hyperglycemia, and reduced protein expression of cardiac GLUT4 and IRAP (insulin-regulated aminopeptidase), the structural protein cosecreted with GLUT4. Hearts from db/db mice had reduced protein expression of GATA4 (~35%) with accompanying reductions in mRNA expression of ANP (~40%), BNP (~85%), and α-MHC mRNA (~50%) whereas expression of β-MHC mRNA was increased by ~60%. Low GATA4 was not explained by an increased ligase or atrogin1 expression. CHIP protein content was modestly downregulated (27%) in db/db mice whereas mRNA and protein expression of the CHIP cochaperone HSP70 was significantly decreased in db/db hearts. Our results indicate that low GATA4 in db/db mouse heart is accompanied by reduced expression of GATA4-regulated cardioprotective and structural genes, which may explain the development of cardiomyopathy in diabetes. 1. Introduction Diabetes is a major risk factor in the development of cardiovascular disease [1]. Impairment of left ventricular function is frequent in patients with type 2 diabetes even in the absence of ischemic, hypertensive, and valvular heart disease [2, 3]. Type 2 diabetes is associated with increased adverse outcomes following ischemic events, reflected by a heightened mortality rate [4]. Although disturbances in energy metabolism and vascular endothelial function play a role in the development of left ventricular dysfunction, altered transcription of genes encoding for contractile and structural proteins also contribute to the cardiovascular risk of diabetic patients [5–8]. GATA4 is a zinc finger-containing transcription factor that belongs to the GATA superfamily [9]. GATA4 is highly expressed in cardiomyocytes where it regulates the transcription of α- and β-myosin heavy chain (MHC) composition, atrial natriuretic (ANP), and B-type natriuretic (BNP) peptides, which are important in cardiac function, blood pressure regulation, and cardioprotection [9, 10]. Accordingly, GATA4 is essential for important adaptive responses such as cardiomyocyte survival, hypertrophy in
Pitavastatin suppresses diethylnitrosamine-induced liver preneoplasms in male C57BL/KsJ-db/db obese mice
Masahito Shimizu, Yoichi Yasuda, Hiroyasu Sakai, Masaya Kubota, Daishi Terakura, Atsushi Baba, Tomohiko Ohno, Takahiro Kochi, Hisashi Tsurumi, Takuji Tanaka, Hisataka Moriwaki
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-281
Abstract: Male db/db mice were administered tap water containing 40 ppm DEN for 2 weeks and were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 14 weeks.At sacrifice, feeding with 10 ppm pitavastatin significantly inhibited the development of hepatic premalignant lesions, foci of cellular alteration, as compared to that in the untreated group by inducing apoptosis, but inhibiting cell proliferation. Pitavastatin improved liver steatosis and activated the AMPK-α protein in the liver. It also decreased free fatty acid and aminotransferases levels, while increasing adiponectin levels in the serum. The serum levels of tumor necrosis factor (TNF)-α and the expression of TNF-α and interleukin-6 mRNAs in the liver were decreased by pitavastatin treatment, suggesting attenuation of the chronic inflammation induced by excess fat deposition.Pitavastatin is effective in inhibiting the early phase of obesity-related liver tumorigenesis and, therefore, may be useful in the chemoprevention of liver cancer in obese individuals.Hepatocellular carcinoma (HCC) is a serious healthcare problem worldwide because of its increasing morbidity and high mortality. Chronic inflammation of the liver and subsequent cirrhosis, which are highly correlated with hepatitis B and hepatitis C viruses infection and alcoholic liver disease, are the strongest risk factors for HCC development. Recent evidence also indicates that obesity and related metabolic abnormalities, especially diabetes mellitus and insulin resistance, raise the risk of HCC [1-4]. In obese individuals, high levels of free fatty acid (FFA) flux into the liver from excess adipose tissue. This in turn promotes hepatic steatosis and inflammation through the production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, and is closely associated with liver carcinogenesis [5-7]. Aberrant lipogenesis in the liver, which is closely linked to obesity and metabolic syndrome, is also a domina
白藜芦醇调节c57bl/ksj-db/db糖尿病小鼠糖脂代谢的作用与机制  [PDF]
南方医科大学学报 , 2014,
Abstract: 目的研究白藜芦醇对c57bl/ksj-db/db(db/db)糖尿病小鼠糖脂代谢的作用与机制。方法随机将db/db糖尿病小鼠分为模型组、白藜芦醇组(200mg/kg)和吡格列酮组(5mg/kg),每组8只,给予相应的药物治疗8周。实验结束后比较各组空腹血糖、糖化血清蛋白、糖化血红蛋白、血清总胆固醇、甘油三脂等糖脂代谢指标,比较各组血清胰岛素浓度及胰岛素抵抗指数、胰岛素敏感指数、超氧化物歧化酶活性、丙二醛含量等指标的变化。采用real-timepcr技术和westernblot检查肝脏组织中低密度脂蛋白受体基因和蛋白的表达。结果与模型组比较,白藜芦醇组能显著降低小鼠空腹血糖、糖化血清蛋白、糖化血红蛋白、血清总胆固醇、甘油三脂等指标的升高(p<0.05),明显改善血清胰岛素水平及胰岛素抵抗指数、胰岛素敏感指数,超氧化物歧化酶活性、丙二醛等指标的异常(p<0.05);显著提高肝脏中肝糖原含量和低密度脂蛋白受体的表达(p<0.05)。结论白藜芦醇具有明显改善糖脂代谢紊乱的作用,其作用机制与其改善胰岛素抵抗、提高抗氧化应激能力以及增加低密度脂蛋白受体的表达等密切相关。
Inbred mouse strains C57BL/6J and DBA/2J vary in sensitivity to a subset of bitter stimuli
John D Boughter, Sandeep Raghow, Theodore M Nelson, Steven D Munger
BMC Genetics , 2005, DOI: 10.1186/1471-2156-6-36
Abstract: B6 mice were more sensitive than D2 mice to a subset of bitter stimuli, including quinine hydrochloride (QHCl), 6-n-propylthiouracil (PROP), and MgCl2. D2 mice were more sensitive than B6 mice to the bitter stimulus raffinose undecaacetate (RUA). These strains did not differ in sensitivity to cycloheximide (CYX), denatonium benzoate (DB), KCl or HCl.B6-D2 taste sensitivity differences indicate that differences in consumption of QHCl, PROP, MgCl2 and RUA are based on immediate orosensory cues, not post-ingestive effects. The absence of a strain difference for CYX suggests that polymorphisms in a T2R-type taste receptor shown to be differentially sensitive to CYX in vitro are unlikely to differentially contribute to the CYX behavioral response in vivo. The results of these studies point to the utility of these common mouse strains and their associated resources for investigation into the genetic mechanisms of taste.The majority of heritable traits in humans and other species are complex in nature, determined by interactions among multiple genes and environmental factors. Mouse genetic models have been critical in identifying genes that determine complex behavioral traits (e.g., [1-3]). The standard inbred strains C57BL/6J (B6) and DBA/2J (D2) have played a key role in mouse genetics, and they are among the strains included in the public and private genome sequencing projects. BXD/Ty (BXD) recombinant inbred (RI) mice, created from B6 and D2 progenitors, have been used to identify and map quantitative trait loci (QTLs) that influence diverse phenotypes such as addictive behavior (e.g., [4-6]), lifespan [7], central nervous system anatomy [8-10], and solution consumption [11-13]. Recently, the BXD set has been expanded to about 80 strains, which makes it the largest mouse RI mapping panel and a useful resource for QTL analysis [14].The characterization of behavioral taste sensitivity in B6 and D2 mice would facilitate the use of BXD mice in mapping QTLs for taste sensit
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