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Davidson E.P.,University of Iowa | Coppey L.J.,University of Iowa | Lupachyk S.,University of Iowa | Dake B.L.,University of Iowa | And 3 more authors.
Journal of Diabetes Research | Year: 2014

Recently a new rat model for type 2 diabetes the Zucker diabetic Sprague-Dawley (ZDSD/Pco) was created. In this study we sought to characterize the development of diabetic neuropathy in ZDSD rats using age-matched Sprague-Dawley rats as a control. Rats were examined at 34 weeks of age 12 weeks after the onset of hyperglycemia in ZDSD rats. At this time ZDSD rats were severely insulin resistant with slowing of both motor and sensory nerve conduction velocities. ZDSD rats also had fatty livers, elevated serum free fatty acids, triglycerides, and cholesterol, and elevated sciatic nerve nitrotyrosine levels. The corneas of ZDSD rats exhibited a decrease in subbasal epithelial corneal nerves and sensitivity. ZDSD rats were hypoalgesic but intraepidermal nerve fibers in the skin of the hindpaw were normal compared to Sprague-Dawley rats. However, the number of Langerhans cells was decreased. Vascular reactivity of epineurial arterioles, blood vessels that provide circulation to the sciatic nerve, to acetylcholine and calcitonin gene-related peptide was impaired in ZDSD rats. These data indicate that ZDSD rats develop many of the neural complications associated with type 2 diabetes and are a good animal model for preclinical investigations of drug development for diabetic neuropathy. © 2014 Eric P. Davidson et al. Source


Lu X.,Indiana University | Guo X.,Indiana University | Karathanasis S.K.,Eli Lilly and Company | Karathanasis S.K.,Astrazeneca | And 5 more authors.
Cardiovascular Diabetology | Year: 2010

Objectives: Endothelial dysfunction precedes atherogenesis and clinical complications in type 2 diabetes. The vascular dysfunction in Zucker diabetic fatty (ZDF) rats was evaluated at different ages along with the effect of treatment with rosiglitazone (Rosi) on endothelial function and mechanical remodeling.Methods: The Rosi treatment was given to ZDF rats for 3 weeks. The endothelium-dependent vasodilation and α-adrenoceptor-dependent vasoconstriction of femoral arteries were studied using an ex-vivo isovolumic myograph. The biomechanical passive property of the arteries was studied in Ca2+-free condition. The expressions of endothelial nitric oxide synthase (eNOS), α-adrenoceptor, matrix metalloproteinase 9 (MMP9), and elastase were evaluated.Results: Endothelium-dependent vasorelaxation of the femoral artery was blunted at low doses in ZDF rats at 11 weeks of age and attenuated at all doses in ZDF rats at 19 weeks of age. The expression of eNOS was consistent with the endothelium-dependent vasorelaxation. The α-adrenoceptor was activated and the mechanical elastic modulus was increased in ZDF rats at 19 weeks of age. The expressions of α-adrenoceptor, MMP9, and elastase were up regulated in ZDF rats at 19 weeks of age. Rosi treatment for 3 weeks restored endothelium-dependent vasorelaxation and the expression of eNOS and the adrenoceptor activation at the doses below 10-6mole/L in ZDF rats at 19 weeks of age. Rosi treatment for 3 weeks did not, however, improve the mechanical properties of blood vessel, the expressions of α-adrenoceptor, MMP9, and elastase in ZDF rats.Conclusion: The endothelial dysfunction and mechanical remodeling are observed as early as 19 weeks of age in ZDF rat. Rosi treatment for 3 weeks improves endothelial function but not mechanical properties. © 2010 Lu et al; licensee BioMed Central Ltd. Source


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 148.45K | Year: 2008

DESCRIPTION (provided by applicant): An estimated 18.2 million people (6.3 percent of the population) in the United States have diabetes; 90 to 95 percent of all diagnosed cases are type II diabetes (NIDDK, 2005). Obesity and metabolic syndrome are the lea ding causes of type II diabetes. The search for new and more effective therapies to address the growing number of Americans with type II diabetes and related conditions is currently hindered by the lack of an obese research animal model that closely resemb les the conditions that lead to the human type II diabetic condition. Most rodent models currently available commercially, related to obesity, metabolic syndrome and type II diabetes, have genetic defects in leptin-receptors, leptin or in other hypothalami c peptides. These defects are not common causes for the etiology of obesity and diabetes in the human population. A new mouse model without these defects would more closely resemble the human condition and thus be more appropriate for the study of diabetic -related conditions and metabolic syndrome. PreClinOmics (PCO) has begun to develop a new mouse model without leptin/leptin-receptor and other genetic defects, which would affect hypothalamic function, by crossing two inbred mouse models with the propensit y to develop diet induced obesity with insulin resistance. The long-term goal of this project is to create a mouse model that will be accepted by the biotech or pharmaceutical industries, and the research community to advance the study and development of o besity and type II diabetic therapies in humans. Phase I of the project will focus on the continued development, defining, and characterization of this new obese mouse model. The project has four specific aims. First, continue the development of a mouse mo del (Fatzo) for obesity, metabolic syndrome, and type II diabetes without leptin/leptin-receptor defects using both phenotypic and genetic monitoring to achieve phenotypic and genetic homogeneity. Second, investigate the effects of diet manipulation on the onset, consistency and synchronicity of the phenotypic expression (obesity and type II diabetes). Third, demonstrate the efficacy of typical anti-obesity/anti-diabetic compounds on the reversal of obesity and prevention of diabetes to show the utility of this mouse model. Fourth, examine the effect of leptin on food consumption in Fatzo and control strains. PUBLIC HEALTH RELEVANCE:: Current commercially available animal models that are used for obesity, metabolic syndrome and diabetes research and drug dev elopment have leptin and leptin-related genetic defects that cause obesity. These defects are not found in the typical obese and diabetic individuals where multiple genes seem to be responsible for the condition. The purpose of this project is to develop a nd produce a new obese and diabetes-prone mouse model which has multiple contributing genetic factors but without a leptin or leptin receptor defect. This will be a very important model for the development of drugs that will control obesity and adult onset diabetes.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.01M | Year: 2008

DESCRIPTION (provided by applicant): An estimated 18.2 million people (6.3 percent of the population) in the United States have diabetes; 90 to 95 percent of all diagnosed cases are type II diabetes (NIDDK, 2005). The search for new and more effective ther apies to address the growing number of Americans with type II diabetes and related conditions is currently hindered by the lack of a research animal model that closely resembles the human diabetic condition. All rat models currently available commercially, related to metabolic syndrome and overt type II diabetes, have a genetic defect in leptin-receptor. On the contrary, leptin and leptin-receptor defects are not common causes for the etiology of obesity and diabetes in the human population. A rat model wit hout this defect would more closely resemble the human condition and thus be more appropriate for the study of diabetic-related conditions and metabolic syndrome. PreClinOmics (PCO) has begun to develop a new rat model without leptin/leptin-receptor defect s by crossing a selected rat model with the propensity to develop diabetes with a model that has the propensity to develop obesity. The long-term goal of this project is to create a rat model that will be accepted by biotech and pharmaceutical industries, and the research community to advance the study and development of type II diabetic therapies in humans. PCO achieved and exceeded its specific aims in Phase I of this project. Phase II will focus on the continued development, defining, characterization an d utility of the new diabetic rat model. This project has six specific aims: 1) Continue selective breeding and utilize genetic monitoring to achieve genetic and phenotypic homogeneity. 2) Use dietary manipulation to modify obesity, other character istics of metabolic syndrome and the age of onset and synchronization of the onset of diabetes. 3) Test therapeutic compounds for the prevention and treatment of obesity and diabetes. 4) Evaluate the time of appearance and levels of known markers and end points of obesity, metabolic syndrome and diabetes. 5) Evaluate leptin tolerance. 6) Collaborate with University and pharmaceutical partners to generate interest, independent data and publications. A strong commercial market exists for this new rat model; drug developers including Eli Lilly and Company, Glaxo Smith Kline, and others PCO has met with have already expressed a strong interest in establishing collaborative arrangements and eventually purchase agreements. Project Narrative: Current commer cially available animal models that are used for obesity and diabetes research and drug development have genetic defects that cause obesity. These defects are not found in the typical obese and diabetic individuals where polygenetic genes seem to be respon sible for the condition. The purpose of this project is to develop and produce a new animal model that has polygenetic obesity (does not have a leptin or leptin receptor defect) which develops into diabetes. This should be a very important model to develop drugs that will control obesity and adult onset diabetes.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 147.94K | Year: 2006

DESCRIPTION (provided by applicant): An estimated 18.2 million people (6.3 percent of the population) in the United States have diabetes; 90 to 95 percent of all diagnosed cases are type II diabetes (NIDDK, 2005). The search for new and more effective therapies to address the growing number of Americans with type II diabetes and related conditions is currently hindered by the lack of a research animal model that closely resembles the human diabetic condition. All rat models currently available commercially, related to metabolic syndrome and overt type II diabetes, have a genetic defect in leptin-receptor. On the contrary, leptin and leptin-receptor defects are not common causes for the etiology of obesity and diabetes in the human population. A rat model without this defect would more closely resemble the human condition and thus be more appropriate for the study of diabetic- related conditions and metabolic syndrome. PreClinOmics (PCO) has begun to develop a new rat model without leptin/leptin-receptor defects by crossing a selected rat model with the propensity to develop diabetes with a model that has the propensity to develop obesity. The long-term goal of this project is to create a rat model that will be accepted by biotech and pharmaceutical industries, and the research community to advance the study and development of type II diabetic therapies in humans. Phase I of the project will focus on the continued development, defining, and characterization of the new diabetic rat model. This project has three specific aims. First, continue to develop obese-diabetic strains, as well as an obese non-diabetic strain. Second, test the effects of diet manipulation on the onset and consistency of the phenotypic expression (type II diabetes) in the obese-diabetic rat model. Third, study the effects of a typical anti-diabetic compound on the prevention of diabetes in this model to demonstrate the value of the model in its ability to respond to anti-diabetic compounds. Project Narrative: Current commercially available animal models that are used for obesity and diabetes research and drug development have genetic defects that cause obesity. These defects are not found in the typical obese and diabetic individuals where polygenetic genes seem to be responsible for the condition. The purpose of this project is to develop and produce a new animal model that has polygenetic obesity which develops into diabetes. This should be very important model to develop drugs that will control obesity and adult onset diabetes.

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