Pub Date : 2012-01-01DOI: 10.2174/1876524601205010001
Vaishali Jahagirdar, Justin Ramcharitar, Victoria E Cotero, Ewan C McNay
Recurrent hypoglycemia (RH) is the major complication of intensive insulin treatment for diabetes mellitus. Of particular concern is the perceived potential for long-term impact of RH on cognition. Because diabetic patients have been reported to have deficits in mental flexibility and judgment, both generally considered to be mediated predominantly by the prefrontal cortex, the purpose of the present study was to determine whether RH would affect prefrontal cortex function. Medial prefrontal cortex (mPFC)-mediated set-shifting ability was tested in male Sprague-Dawley rats using a maze-based, food-reward Set-Shift task analogous to the Wisconsin card-sorting task. The performance measure was the number of trials to criterion on both day 1 (initial rule-learning) and day 2 (set-shifting in response to a changed contingency). In vivo microdialysis was used to measure mPFC extracellular glucose, lactate, pyruvate, glutamate, and dopamine. Post-mortem measures within the mPFC included glucose transporter 3 (GluT3) and c-Fos. RH animals had enhanced performance on day 1, consistent with previous work that showed RH to improve subsequent hippocampal function when euglycemic. The key finding of the present work is that RH led to impaired set-shifting performance on day 2, suggesting impairment in e.g. mental flexibility. Consistent with this finding, RH animals show decreased mPFC glycolysis on day 2 compared to controls. Our data show that RH can lead to subsequent impaired judgment, accompanied by reduced prefrontal cortex function. The findings suggest a potential underlying mechanism for the impaired judgment seen in diabetic patients.
{"title":"Moderate Recurrent Hypoglycemia Markedly Impairs Set-Shifting Ability in a Rodent Model: Cognitive and Neurochemical Effects.","authors":"Vaishali Jahagirdar, Justin Ramcharitar, Victoria E Cotero, Ewan C McNay","doi":"10.2174/1876524601205010001","DOIUrl":"https://doi.org/10.2174/1876524601205010001","url":null,"abstract":"<p><p>Recurrent hypoglycemia (RH) is the major complication of intensive insulin treatment for diabetes mellitus. Of particular concern is the perceived potential for long-term impact of RH on cognition. Because diabetic patients have been reported to have deficits in mental flexibility and judgment, both generally considered to be mediated predominantly by the prefrontal cortex, the purpose of the present study was to determine whether RH would affect prefrontal cortex function. Medial prefrontal cortex (mPFC)-mediated set-shifting ability was tested in male Sprague-Dawley rats using a maze-based, food-reward Set-Shift task analogous to the Wisconsin card-sorting task. The performance measure was the number of trials to criterion on both day 1 (initial rule-learning) and day 2 (set-shifting in response to a changed contingency). <i>In vivo</i> microdialysis was used to measure mPFC extracellular glucose, lactate, pyruvate, glutamate, and dopamine. Post-mortem measures within the mPFC included glucose transporter 3 (GluT3) and c-Fos. RH animals had enhanced performance on day 1, consistent with previous work that showed RH to improve subsequent hippocampal function when euglycemic. The key finding of the present work is that RH led to impaired set-shifting performance on day 2, suggesting impairment in e.g. mental flexibility. Consistent with this finding, RH animals show decreased mPFC glycolysis on day 2 compared to controls. Our data show that RH can lead to subsequent impaired judgment, accompanied by reduced prefrontal cortex function. The findings suggest a potential underlying mechanism for the impaired judgment seen in diabetic patients.</p>","PeriodicalId":22762,"journal":{"name":"The Open Diabetes Journal","volume":"5 ","pages":"1-7"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3882127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32011973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2011-11-29DOI: 10.2174/1876524601104010123
L. Barker, E. Tierney, A. Lanza, K. Kirtland
Introduction: Differences in incidence of diabetes and prevalence of risk factors for diabetes exist among states. It is unknown how much of this variability in incidence of diagnosed diabetes is due to variability in risk factor prevalence. We investigate the contribution of selected risk factors to state level incidence of diagnosed diabetes. Materials and Methods: Using 2005-2007 data from the Behavioral Risk Factor Surveillance System, we conducted two logistic regressions, both with incident case status as dependent variable. One model considered only state of residence as an independent variable. The other added: age; sex; race/ethnicity; education; inactive lifestyle; and obesity. We compared adjusted and unadjusted odds of incident diabetes among states, and calculated excess risk. Results: Adjusted and unadjusted odds of incident diabetes were similar. Sensitivity analyses showed that this differed little if we used data from earlier years or if we included income or insurance as a risk factor. In most states, the excess risk associated with risk factors was less than 30%. Discussion: Factors other than age, sex, race/ethnicity, education, inactivity, and obesity (i.e., established risk factors for diabetes) might substantially influence the differences in state incidence rates. These factors' identities are unknown. If these factors are identified and modifiable, states might use them to reduce between-state disparities in diabetes incidence.
{"title":"Selected Risk Factors' Contribution to State-Level Incidence of DiagnosedDiabetes, 2005-2007","authors":"L. Barker, E. Tierney, A. Lanza, K. Kirtland","doi":"10.2174/1876524601104010123","DOIUrl":"https://doi.org/10.2174/1876524601104010123","url":null,"abstract":"Introduction: Differences in incidence of diabetes and prevalence of risk factors for diabetes exist among states. It is unknown how much of this variability in incidence of diagnosed diabetes is due to variability in risk factor prevalence. We investigate the contribution of selected risk factors to state level incidence of diagnosed diabetes. Materials and Methods: Using 2005-2007 data from the Behavioral Risk Factor Surveillance System, we conducted two logistic regressions, both with incident case status as dependent variable. One model considered only state of residence as an independent variable. The other added: age; sex; race/ethnicity; education; inactive lifestyle; and obesity. We compared adjusted and unadjusted odds of incident diabetes among states, and calculated excess risk. Results: Adjusted and unadjusted odds of incident diabetes were similar. Sensitivity analyses showed that this differed little if we used data from earlier years or if we included income or insurance as a risk factor. In most states, the excess risk associated with risk factors was less than 30%. Discussion: Factors other than age, sex, race/ethnicity, education, inactivity, and obesity (i.e., established risk factors for diabetes) might substantially influence the differences in state incidence rates. These factors' identities are unknown. If these factors are identified and modifiable, states might use them to reduce between-state disparities in diabetes incidence.","PeriodicalId":22762,"journal":{"name":"The Open Diabetes Journal","volume":"31 1","pages":"123-130"},"PeriodicalIF":0.0,"publicationDate":"2011-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82367443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2011-03-29DOI: 10.2174/1876524601104010006
A. Akhter, K. Fatema, A. Afroz, B. Bhowmik, L. Ali, A. Hussain
Background: Substantial racial heterogeneity in diabetes leads to the necessity of conducting epidemiological studies in different communities. Such studies are still inadequate in Bangladeshi population, particularly in truly respective rural areas. The objectives of the study were to estimate the prevalence of diabetes and to identify its associated risk indicators in a rural population of Bangladesh. Methods: This population based cross-sectional study was conducted in remote rural areas of Northern Bangladesh, which included a total of 836 participants aged at or above 25 years through screening in camp settings. Diabetes was diagnosed by WHO criteria after a 2-sample OGTT. BMI, waist-hip ratio, blood pressure, lipid profile and serum creatinine were also estimated. Results: The prevalence of diabetes was found to be 7.2% (95% CI 5.4-9.0) and that of impaired glucose regulation (including both impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG)) was 6.5% (95% CI 4.8-8.2). The prevalence of diabetes and impaired glucose regulation differed between males and females, but, both increased with age in males as well as females. A good correlation was observed between fasting blood glucose and 2hr after glucose (Kappa value 0.86) among the study participants. After adjusting for potential confounders BMI and WHR were found as significant independent risk indicators for the occurrence of diabetes in this population.
背景:糖尿病存在明显的种族异质性，因此有必要在不同社区开展流行病学研究。在孟加拉国人口中，特别是在真正各自的农村地区，这种研究仍然不足。该研究的目的是估计孟加拉国农村人口中糖尿病的患病率，并确定其相关风险指标。方法:这项基于人口的横断面研究是在孟加拉国北部偏远的农村地区进行的，其中包括836名年龄在25岁或以上的参与者，他们在营地环境中进行了筛查。2个样本OGTT后，根据WHO标准诊断为糖尿病。BMI、腰臀比、血压、血脂和血清肌酐也进行了评估。结果:糖尿病患病率为7.2% (95% CI 5.4-9.0)，葡萄糖调节受损(包括糖耐量受损(IGT)和/或空腹血糖受损(IFG))的患病率为6.5% (95% CI 4.8-8.2)。糖尿病患病率和血糖调节障碍在男性和女性之间存在差异，但两者都随着年龄的增长而增加。在研究参与者中，空腹血糖与葡萄糖后2小时之间存在良好的相关性(Kappa值0.86)。在对潜在混杂因素进行调整后，BMI和WHR被发现是该人群发生糖尿病的重要独立风险指标。
{"title":"Prevalence of Diabetes Mellitus and its Associated Risk Indicators in a Rural Bangladeshi Population","authors":"A. Akhter, K. Fatema, A. Afroz, B. Bhowmik, L. Ali, A. Hussain","doi":"10.2174/1876524601104010006","DOIUrl":"https://doi.org/10.2174/1876524601104010006","url":null,"abstract":"Background: Substantial racial heterogeneity in diabetes leads to the necessity of conducting epidemiological studies in different communities. Such studies are still inadequate in Bangladeshi population, particularly in truly respective rural areas. The objectives of the study were to estimate the prevalence of diabetes and to identify its associated risk indicators in a rural population of Bangladesh. Methods: This population based cross-sectional study was conducted in remote rural areas of Northern Bangladesh, which included a total of 836 participants aged at or above 25 years through screening in camp settings. Diabetes was diagnosed by WHO criteria after a 2-sample OGTT. BMI, waist-hip ratio, blood pressure, lipid profile and serum creatinine were also estimated. Results: The prevalence of diabetes was found to be 7.2% (95% CI 5.4-9.0) and that of impaired glucose regulation (including both impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG)) was 6.5% (95% CI 4.8-8.2). The prevalence of diabetes and impaired glucose regulation differed between males and females, but, both increased with age in males as well as females. A good correlation was observed between fasting blood glucose and 2hr after glucose (Kappa value 0.86) among the study participants. After adjusting for potential confounders BMI and WHR were found as significant independent risk indicators for the occurrence of diabetes in this population.","PeriodicalId":22762,"journal":{"name":"The Open Diabetes Journal","volume":"47 1","pages":"6-13"},"PeriodicalIF":0.0,"publicationDate":"2011-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75746844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2011-03-28DOI: 10.2174/1876524601104010050
T. Sasase, T. Ohta
To aid in the study of diabetes and its complications, many diabetic animal models have been reported. Although most diabetic patients suffer type 2 diabetes, studies using type 2 diabetic animal models have been carried out less frequently. Spontaneously Diabetic Torii (SDT) rat, a non-obese type 2 diabetes model, shows neuropathies and severe ocular complications. Decreased nerve conduction velocity and thermal hypoalgesia were improved by insulin treatment, indicating that the peripheral neuropathies in SDT rats are caused by sustained hyperglycemia. Autonomic nerve dysfunctions such as decreased coefficients of variance of R-R intervals (CVR-R) in electrocardiogram, functional gastrointestinal disorders, and voiding dysfunction are also observed in SDT rats. Therefore, SDT rat is a useful diabetic animal model for studies of diabetic neuropathies in type 2 diabetes and development of new drugs and therapies for diabetic neuropathies.
{"title":"Diabetic Neuropathy in Spontaneously Diabetic Torii Rat","authors":"T. Sasase, T. Ohta","doi":"10.2174/1876524601104010050","DOIUrl":"https://doi.org/10.2174/1876524601104010050","url":null,"abstract":"To aid in the study of diabetes and its complications, many diabetic animal models have been reported. Although most diabetic patients suffer type 2 diabetes, studies using type 2 diabetic animal models have been carried out less frequently. Spontaneously Diabetic Torii (SDT) rat, a non-obese type 2 diabetes model, shows neuropathies and severe ocular complications. Decreased nerve conduction velocity and thermal hypoalgesia were improved by insulin treatment, indicating that the peripheral neuropathies in SDT rats are caused by sustained hyperglycemia. Autonomic nerve dysfunctions such as decreased coefficients of variance of R-R intervals (CVR-R) in electrocardiogram, functional gastrointestinal disorders, and voiding dysfunction are also observed in SDT rats. Therefore, SDT rat is a useful diabetic animal model for studies of diabetic neuropathies in type 2 diabetes and development of new drugs and therapies for diabetic neuropathies.","PeriodicalId":22762,"journal":{"name":"The Open Diabetes Journal","volume":"16 1","pages":"50-54"},"PeriodicalIF":0.0,"publicationDate":"2011-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73843281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2011-03-28DOI: 10.2174/1876524601104010101
A. Kakehashi, Mikiko Takezawa, Fumihiko Toyoda, Nozomi Kinoshita, C. Kambara, H. Yamagami, N. Kato, S. Ishikawa, M. Kawakami, Y. Kanazawa
We evaluated the effect of an aldose reductase inhibitor, fidarestat, on diabetic retinopathy (DR) and cataract in spontaneously diabetic Torii (SDT) rats. Four rat groups were included: untreated, low- and high-dose (8 and 32 mg/kg/day) fidarestat-treated SDT rats, and nondiabetic control Sprague-Dawley rats. DR and cataract were evaluated and retinal and lens sorbitol, reduced glutathione (GSH), ocular fluid vascular endothelial growth factor (VEGF), and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) was measured. The incidence rates of DR and cataract were significantly lower in the low- and high-dose fidarestat groups vs the untreated group (p<0.001/p<0.001). Retinal and lens sorbitol levels were lower in the control (1.1±0.1/3.1±0.2 nmol/mg protein) (p<0.05/p<0.01) and low- (2.7±1.1/30.0±3.3 nmol/mg protein) (p<0.01/p<0.01) and high-dose groups (0.7±0.2/5.9±0.6 nmol/mg protein) (p<0.001/p<0.001) vs the untreated group (23.2±4.7/123.9±29.6 nmol/mg protein). Retinal and lens GSH levels were higher in the nondiabetic control (52.2±5.8/29.0±2.7 � mol/mg protein) (p<0.01/p<0.001) and the low- (46.8±8.2/24.7±2.8 � mol/mg protein) (not significant (NS)/p<0.001) and high-dose groups (63.3±14.6/26.9±3.6 � mol/mg protein) (p<0.05/p<0.001) vs the untreated group (30.3±2.0/1.6±0.4 � mol/mg protein). VEGF levels were lower in the nondiabetic control (40.4±10.0 pg/ml) (p<0.01) and low- (65.3±4.5 pg/ml) (p<0.05) and high-dose groups (47.7±10 pg/ml) (p<0.001) vs the untreated group (324.7±76.4 pg/ml). 8-OHdG levels were lower in the nondiabetic control (0.73±0.11 ng/mg creatinine) (p<0.01) and low- (4.57±0.42 ng/mg creatinine) (NS) and high-dose groups (3.58±0.70 ng/mg creatinine) (NS) vs the untreated group (6.04±1.28 ng/ml). Fidarestat inhibited activation of the polyol pathway, reduced oxidative stress and VEGF, and prevented DR and cataract in SDT rats.
{"title":"Aldose Reductase Inhibitor Fidarestat Prevents Diabetic Ocular Complications in Spontaneously Diabetic Torii Rats","authors":"A. Kakehashi, Mikiko Takezawa, Fumihiko Toyoda, Nozomi Kinoshita, C. Kambara, H. Yamagami, N. Kato, S. Ishikawa, M. Kawakami, Y. Kanazawa","doi":"10.2174/1876524601104010101","DOIUrl":"https://doi.org/10.2174/1876524601104010101","url":null,"abstract":"We evaluated the effect of an aldose reductase inhibitor, fidarestat, on diabetic retinopathy (DR) and cataract in spontaneously diabetic Torii (SDT) rats. Four rat groups were included: untreated, low- and high-dose (8 and 32 mg/kg/day) fidarestat-treated SDT rats, and nondiabetic control Sprague-Dawley rats. DR and cataract were evaluated and retinal and lens sorbitol, reduced glutathione (GSH), ocular fluid vascular endothelial growth factor (VEGF), and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) was measured. The incidence rates of DR and cataract were significantly lower in the low- and high-dose fidarestat groups vs the untreated group (p<0.001/p<0.001). Retinal and lens sorbitol levels were lower in the control (1.1±0.1/3.1±0.2 nmol/mg protein) (p<0.05/p<0.01) and low- (2.7±1.1/30.0±3.3 nmol/mg protein) (p<0.01/p<0.01) and high-dose groups (0.7±0.2/5.9±0.6 nmol/mg protein) (p<0.001/p<0.001) vs the untreated group (23.2±4.7/123.9±29.6 nmol/mg protein). Retinal and lens GSH levels were higher in the nondiabetic control (52.2±5.8/29.0±2.7 � mol/mg protein) (p<0.01/p<0.001) and the low- (46.8±8.2/24.7±2.8 � mol/mg protein) (not significant (NS)/p<0.001) and high-dose groups (63.3±14.6/26.9±3.6 � mol/mg protein) (p<0.05/p<0.001) vs the untreated group (30.3±2.0/1.6±0.4 � mol/mg protein). VEGF levels were lower in the nondiabetic control (40.4±10.0 pg/ml) (p<0.01) and low- (65.3±4.5 pg/ml) (p<0.05) and high-dose groups (47.7±10 pg/ml) (p<0.001) vs the untreated group (324.7±76.4 pg/ml). 8-OHdG levels were lower in the nondiabetic control (0.73±0.11 ng/mg creatinine) (p<0.01) and low- (4.57±0.42 ng/mg creatinine) (NS) and high-dose groups (3.58±0.70 ng/mg creatinine) (NS) vs the untreated group (6.04±1.28 ng/ml). Fidarestat inhibited activation of the polyol pathway, reduced oxidative stress and VEGF, and prevented DR and cataract in SDT rats.","PeriodicalId":22762,"journal":{"name":"The Open Diabetes Journal","volume":"49 1","pages":"101-107"},"PeriodicalIF":0.0,"publicationDate":"2011-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88610349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2011-03-28DOI: 10.2174/1876524601104010119
H. Mizukami, M. Urabe, A. Kume, K. Ozawa
Gene therapy is considered as one of the innovative treatment modalities for diabetic retinopathy (DR). Since genuine animal models of DR are limited, only a few studies have reported the efficacy of gene therapy. For preclinical study of DR, spontaneously diabetic Torii (SDT) rat is a valuable model. Fortunately, we could evaluate the efficacy of adeno-associated virus (AAV)-mediated gene therapy in SDT rats and proved that sFlt-1 expression prevented DR progression. Because of a limited number of large-animal models of DR, it is uncertain whether gene therapy experiments using dogs or monkeys allow reliable conclusions. On the other hand, owing to the recent progress in AAV-mediated gene therapy for retinal diseases in monkeys and humans, gene therapy for DR using AAV vectors may become a reality in the near future.
{"title":"Gene Therapy for Diabetic Retinopathy in Animal Models and Humans","authors":"H. Mizukami, M. Urabe, A. Kume, K. Ozawa","doi":"10.2174/1876524601104010119","DOIUrl":"https://doi.org/10.2174/1876524601104010119","url":null,"abstract":"Gene therapy is considered as one of the innovative treatment modalities for diabetic retinopathy (DR). Since genuine animal models of DR are limited, only a few studies have reported the efficacy of gene therapy. For preclinical study of DR, spontaneously diabetic Torii (SDT) rat is a valuable model. Fortunately, we could evaluate the efficacy of adeno-associated virus (AAV)-mediated gene therapy in SDT rats and proved that sFlt-1 expression prevented DR progression. Because of a limited number of large-animal models of DR, it is uncertain whether gene therapy experiments using dogs or monkeys allow reliable conclusions. On the other hand, owing to the recent progress in AAV-mediated gene therapy for retinal diseases in monkeys and humans, gene therapy for DR using AAV vectors may become a reality in the near future.","PeriodicalId":22762,"journal":{"name":"The Open Diabetes Journal","volume":"31 1","pages":"119-122"},"PeriodicalIF":0.0,"publicationDate":"2011-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90719115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2011-03-28DOI: 10.2174/1876524601104010030
S. Fukuda, K. Miyajima, T. Sasase, T. Ohta
Diabetic animal models play critical roles in the elucidation of the mechanisms of diabetes mellitus and the complications, and in the development of novel drugs as treatments. Spontaneously Diabetic Torii Lepr fa (SDT fatty) rat, established by introducing the fa allele of the Zucker fatty rat into SDT rat genome, is a new model of obese type 2 diabetes. We have investigated the characteristics of SDT fatty rats. Both male and female SDT fatty rats show overt obesity, and hyperglycemia and hyperlipidemia are observed at a young age as compared with SDT rats. With early incidence of diabetes mellitus, diabetic complications in SDT fatty rats were seen at younger ages than those in the SDT rats. Furthermore, we evaluated the pharmacological effects of anti-diabetic drugs, such as metformin, pioglitazone, and dipeptidyl peptidase-4 inhibitor on SDT fatty rats. SDT fatty rat is a useful model for analysis of metabolic disease and the evaluation of drugs related to metabolic disease.
糖尿病动物模型在阐明糖尿病及其并发症的发病机制、开发新型治疗药物等方面具有重要作用。将Zucker脂肪大鼠的fa等位基因导入SDT大鼠基因组，建立了自发性糖尿病Torii Lepr fa (SDT fatty)大鼠，是肥胖型2型糖尿病的新模型。我们研究了SDT脂肪大鼠的特征。与SDT大鼠相比，雄性和雌性SDT脂肪大鼠均表现出明显的肥胖，并且在年轻时观察到高血糖和高脂血症。肥胖大鼠糖尿病发病早，糖尿病并发症出现的年龄比肥胖大鼠小。此外，我们评估了抗糖尿病药物，如二甲双胍、吡格列酮和二肽基肽酶-4抑制剂对SDT脂肪大鼠的药理作用。SDT脂肪大鼠是分析代谢性疾病和评价代谢性疾病相关药物的有用模型。
{"title":"Spontaneously Diabetic Torii Leprfa (SDT Fatty) Rat: A Novel Model of Obese Type 2 Diabetes","authors":"S. Fukuda, K. Miyajima, T. Sasase, T. Ohta","doi":"10.2174/1876524601104010030","DOIUrl":"https://doi.org/10.2174/1876524601104010030","url":null,"abstract":"Diabetic animal models play critical roles in the elucidation of the mechanisms of diabetes mellitus and the complications, and in the development of novel drugs as treatments. Spontaneously Diabetic Torii Lepr fa (SDT fatty) rat, established by introducing the fa allele of the Zucker fatty rat into SDT rat genome, is a new model of obese type 2 diabetes. We have investigated the characteristics of SDT fatty rats. Both male and female SDT fatty rats show overt obesity, and hyperglycemia and hyperlipidemia are observed at a young age as compared with SDT rats. With early incidence of diabetes mellitus, diabetic complications in SDT fatty rats were seen at younger ages than those in the SDT rats. Furthermore, we evaluated the pharmacological effects of anti-diabetic drugs, such as metformin, pioglitazone, and dipeptidyl peptidase-4 inhibitor on SDT fatty rats. SDT fatty rat is a useful model for analysis of metabolic disease and the evaluation of drugs related to metabolic disease.","PeriodicalId":22762,"journal":{"name":"The Open Diabetes Journal","volume":"36 1","pages":"30-36"},"PeriodicalIF":0.0,"publicationDate":"2011-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76987174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2011-03-28DOI: 10.2174/1876524601104010075
Michael DeNiroa, F. Al-Mohanna
The elucidation of the molecular pathogenesis of ocular disease provides candidate targets for treatment. Animal models allow for identification and quantitation of ocular diseases. By gaining insight regarding the molecular signals involved in various types of ocular angiogenesis, general concepts can emerge that may apply to other settings, including tumor angiogenesis. The hypoxia inducible factor-1 (HIF-1) pathway is relatively well understood and serves as a good example of how knowledge of the biological responses to hypoxia can translate into new therapies. Furthermore, HIF pathway can be used as a therapeutic target and that the manipulation of the HIF pathway at several points has potential use for the treatment of oxygen-dependent diseases in retina. However, there are numerous other molecular and cellular responses to hypoxia that are independent of HIF-1, perhaps each with unique oxygen sensors. Despite participation of multiple stimulatory factors for ocular neovascularization (NV), vascular endothelial growth factor (VEGF) emerges as a pivotal player, thus manipulation of VEGF signaling represents an important therapeutic strategy. While most studies have focused on prevention of ocular NV, regression of new vessels is desirable and is achievable with various small molecules. Screens are underway to identify and test the efficacy of these small-molecules to target various mechanisms involved in ocular NV. These small molecules might represent an important component of novel combination therapies to target various molecular signaling mechanisms in neovascular tissues.
{"title":"Reversal of Retinal Vascular Changes Associated with Ocular Neovascularization by Small Molecules: Progress toward Identifying Molecular Targets for Therapeutic Intervention","authors":"Michael DeNiroa, F. Al-Mohanna","doi":"10.2174/1876524601104010075","DOIUrl":"https://doi.org/10.2174/1876524601104010075","url":null,"abstract":"The elucidation of the molecular pathogenesis of ocular disease provides candidate targets for treatment. Animal models allow for identification and quantitation of ocular diseases. By gaining insight regarding the molecular signals involved in various types of ocular angiogenesis, general concepts can emerge that may apply to other settings, including tumor angiogenesis. The hypoxia inducible factor-1 (HIF-1) pathway is relatively well understood and serves as a good example of how knowledge of the biological responses to hypoxia can translate into new therapies. Furthermore, HIF pathway can be used as a therapeutic target and that the manipulation of the HIF pathway at several points has potential use for the treatment of oxygen-dependent diseases in retina. However, there are numerous other molecular and cellular responses to hypoxia that are independent of HIF-1, perhaps each with unique oxygen sensors. Despite participation of multiple stimulatory factors for ocular neovascularization (NV), vascular endothelial growth factor (VEGF) emerges as a pivotal player, thus manipulation of VEGF signaling represents an important therapeutic strategy. While most studies have focused on prevention of ocular NV, regression of new vessels is desirable and is achievable with various small molecules. Screens are underway to identify and test the efficacy of these small-molecules to target various mechanisms involved in ocular NV. These small molecules might represent an important component of novel combination therapies to target various molecular signaling mechanisms in neovascular tissues.","PeriodicalId":22762,"journal":{"name":"The Open Diabetes Journal","volume":"46 1","pages":"75-95"},"PeriodicalIF":0.0,"publicationDate":"2011-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75269630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2011-03-28DOI: 10.2174/1876524601104010060
Michael DeNiroa, F. Al-Mohanna
Hypoxia-inducible factor-1 (HIF-1) plays crucial roles in retinal neovascularization (NV) by upregulating its target genes, which are involved in anaerobic energy metabolism, angiogenesis, cell survival, cell invasion, and drug resistance. Therefore, it is apparent that the inhibition of HIF-1 activity may be a strategy for treating retinal angiopathies. Many efforts to develop new HIF-1-targeting agents have been made by both academic and pharmaceutical industry laboratories. The future success of these efforts will be a new class of HIF-1-targeting agents, which could be utilized in the treatment of several ocular pathologies. This review focuses on the potential of HIF-1 as a target molecule for the treatment of retinal NV, and on possible strategies to inhibit HIF-1 activity. In addition, we introduce YC-1 as a new anti- HIF-1, anti-neovascular agent in the retinal model. Although YC-1 was originally developed as a potential therapeutic agent for thrombosis and hypertension, recent studies demonstrated that YC-1 suppressed HIF-1 activity and vascular endothelial growth factor expression in retinal microvascular endothelial cells. Moreover, it inhibited retinal NV in the oxygen-induced retinopathy (OIR) mouse model without serious toxicity during the treatment period. Thus, we propose that YC-1 is a good lead compound for the development of new anti-HIF-1, anti-neovascular agents that could be used in the retinal pathologies.
{"title":"Dual Targeting of Retinal Vasculature in the Mouse Model of Oxygen Induced Retinopathy","authors":"Michael DeNiroa, F. Al-Mohanna","doi":"10.2174/1876524601104010060","DOIUrl":"https://doi.org/10.2174/1876524601104010060","url":null,"abstract":"Hypoxia-inducible factor-1 (HIF-1) plays crucial roles in retinal neovascularization (NV) by upregulating its target genes, which are involved in anaerobic energy metabolism, angiogenesis, cell survival, cell invasion, and drug resistance. Therefore, it is apparent that the inhibition of HIF-1 activity may be a strategy for treating retinal angiopathies. Many efforts to develop new HIF-1-targeting agents have been made by both academic and pharmaceutical industry laboratories. The future success of these efforts will be a new class of HIF-1-targeting agents, which could be utilized in the treatment of several ocular pathologies. This review focuses on the potential of HIF-1 as a target molecule for the treatment of retinal NV, and on possible strategies to inhibit HIF-1 activity. In addition, we introduce YC-1 as a new anti- HIF-1, anti-neovascular agent in the retinal model. Although YC-1 was originally developed as a potential therapeutic agent for thrombosis and hypertension, recent studies demonstrated that YC-1 suppressed HIF-1 activity and vascular endothelial growth factor expression in retinal microvascular endothelial cells. Moreover, it inhibited retinal NV in the oxygen-induced retinopathy (OIR) mouse model without serious toxicity during the treatment period. Thus, we propose that YC-1 is a good lead compound for the development of new anti-HIF-1, anti-neovascular agents that could be used in the retinal pathologies.","PeriodicalId":22762,"journal":{"name":"The Open Diabetes Journal","volume":"31 1","pages":"60-74"},"PeriodicalIF":0.0,"publicationDate":"2011-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91100098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2011-03-28DOI: 10.2174/1876524601104010021
N. Yokoi, Masanori Fuse, S. Seino
The Spontaneously Diabetic Torii (SDT) rat has recently been established as a novel model of nonobese type 2 diabetes. SDT rats exhibit inflammation and fibrosis in and around the islets during development of the disease. To clarify the genetic basis of the disease, we previously performed quantitative trait locus (QTL) analysis of glucose tolerance at 20 weeks of age using backcrossed progeny produced from the (BNSDT)F1� SDT cross. The analysis identified three major QTLs (Gisdt1, Gisdt2, and Gisdt3) on rat chromosomes 1, 2, and X, respectively. To examine genetic factors for diabetes, glucose tolerance, islet inflammation, and fibrosis in the SDT rat, we also performed genetic analysis of these traits at 60 weeks of age using intercrossed progeny produced from the (F344� SDT)F2 cross. Genetic analysis of diabetes identified a major locus, Dmsdt1, on chromosome 3. QTL analysis of blood glucose levels revealed, in addition to Dmsdt1, three other loci (Dmsdt2, Dmsdt3, and Dmsdt4) on chromosome 8, 13, and 14, respectively. Analysis of a congenic strain for Dmsdt1 (F344.SDT-Dmsdt1) indicates that the dominantly acting SDT allele induces islet inflammation and fibrosis. These data clearly demonstrate that development of diabetes in the SDT rat is controlled by the combination of several QTLs with considerable effects. Identification of the genes responsible would provide greater understanding of the pathogenesis and pathophysiology of diabetes.
{"title":"Genetics of the Spontaneously Diabetic Torii Rat","authors":"N. Yokoi, Masanori Fuse, S. Seino","doi":"10.2174/1876524601104010021","DOIUrl":"https://doi.org/10.2174/1876524601104010021","url":null,"abstract":"The Spontaneously Diabetic Torii (SDT) rat has recently been established as a novel model of nonobese type 2 diabetes. SDT rats exhibit inflammation and fibrosis in and around the islets during development of the disease. To clarify the genetic basis of the disease, we previously performed quantitative trait locus (QTL) analysis of glucose tolerance at 20 weeks of age using backcrossed progeny produced from the (BNSDT)F1� SDT cross. The analysis identified three major QTLs (Gisdt1, Gisdt2, and Gisdt3) on rat chromosomes 1, 2, and X, respectively. To examine genetic factors for diabetes, glucose tolerance, islet inflammation, and fibrosis in the SDT rat, we also performed genetic analysis of these traits at 60 weeks of age using intercrossed progeny produced from the (F344� SDT)F2 cross. Genetic analysis of diabetes identified a major locus, Dmsdt1, on chromosome 3. QTL analysis of blood glucose levels revealed, in addition to Dmsdt1, three other loci (Dmsdt2, Dmsdt3, and Dmsdt4) on chromosome 8, 13, and 14, respectively. Analysis of a congenic strain for Dmsdt1 (F344.SDT-Dmsdt1) indicates that the dominantly acting SDT allele induces islet inflammation and fibrosis. These data clearly demonstrate that development of diabetes in the SDT rat is controlled by the combination of several QTLs with considerable effects. Identification of the genes responsible would provide greater understanding of the pathogenesis and pathophysiology of diabetes.","PeriodicalId":22762,"journal":{"name":"The Open Diabetes Journal","volume":"38 1","pages":"21-25"},"PeriodicalIF":0.0,"publicationDate":"2011-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81172431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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