Zucker Diabetic Sprague Dawley Research Articles

Modeling the Disease Progression from Healthy to Overt Diabetes in ZDSD Rats.

Studying the critical transitional phase between healthy to overtly diabetic in type 2 diabetes mellitus (T2DM) is of interest, but acquiring such clinical data is impractical due to ethical concerns and would require a long study duration. A population model using Zucker diabetic Sprague-Dawley (ZDSD) rats was developed to describe this transition through altering insulin sensitivity (IS, %) as a result of accumulating excess body weight and β-cell function (BCF, %) to affect glucose-insulin homeostasis. Body weight, fasting plasma glucose (FPG), and fasting serum insulin (FSI) were collected biweekly over 24 weeks from ZDSD rats (n = 23) starting at age 7 weeks. A semi-mechanistic model previously developed with clinical data was adapted to rat data with BCF and IS estimated relative to humans. Non-linear mixed-effect model estimation was performed using NONMEM. Baseline IS and BCF were 41% compared to healthy humans. BCF was described with a non-linear rise which peaked at 14 weeks before gradually declining to a negligible level. A component for excess growth reflecting obesity was used to affect IS, and a glucose-dependent renal effect exerted a two- to sixfold increase on the elimination of glucose. A glucose-dependent weight loss effect towards the end of experiment was implemented. A semi-mechanistic model to describe the dynamics of glucose and insulin was successfully developed for a rat population, transitioning from healthy to advanced diabetes. It is also shown that weight loss can be modeled to mimic the glucotoxicity phenomenon seen in advanced hyperglycemia.

Raloxifene prevents skeletal fragility in adult female Zucker Diabetic Sprague-Dawley rats.

Fracture risk in type 2 diabetes is increased despite normal or high bone mineral density, implicating poor bone quality as a risk factor. Raloxifene improves bone material and mechanical properties independent of bone mineral density. This study aimed to determine if raloxifene prevents the negative effects of diabetes on skeletal fragility in diabetes-prone rats. Adult Zucker Diabetic Sprague-Dawley (ZDSD) female rats (20-week-old, n = 24) were fed a diabetogenic high-fat diet and were randomized to receive daily subcutaneous injections of raloxifene or vehicle for 12 weeks. Blood glucose was measured weekly and glycated hemoglobin was measured at baseline and 12 weeks. At sacrifice, femora and lumbar vertebrae were harvested for imaging and mechanical testing. Raloxifene-treated rats had a lower incidence of type 2 diabetes compared with vehicle-treated rats. In addition, raloxifene-treated rats had blood glucose levels significantly lower than both diabetic vehicle-treated rats as well as vehicle-treated rats that did not become diabetic. Femoral toughness was greater in raloxifene-treated rats compared with both diabetic and non-diabetic vehicle-treated ZDSD rats, due to greater energy absorption in the post-yield region of the stress-strain curve. Similar differences between groups were observed for the structural (extrinsic) mechanical properties of energy-to-failure, post-yield energy-to-failure, and post-yield displacement. These results show that raloxifene is beneficial in preventing the onset of diabetes and improving bone material properties in the diabetes-prone ZDSD rat. This presents unique therapeutic potential for raloxifene in preserving bone quality in diabetes as well as in diabetes prevention, if these results can be supported by future experimental and clinical studies.

Characterization of diabetic neuropathy in the Zucker diabetic Sprague-Dawley rat: a new animal model for type 2 diabetes.

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.

Multiscale analysis of morphology and mechanics in tail tendon from the ZDSD rat model of type 2 diabetes

Type 2 diabetes (T2D) impacts multiple organ systems including the circulatory, renal, nervous and musculoskeletal systems. In collagen-based tissues, one mechanism that may be responsible for detrimental mechanical impacts of T2D is the formation of advanced glycation end products (AGEs) leading to increased collagen stiffness and decreased toughness, resulting in brittle tissue behavior. The purpose of this study was to investigate tendon mechanical properties from normal and diabetic rats at two distinct length scales, testing the hypothesis that increased stiffness and strength and decreased toughness at the fiber level would be associated with alterations in nanoscale morphology and mechanics. Individual fascicles from female Zucker diabetic Sprague-Dawley (ZDSD) rats had no differences in fascicle-level mechanical properties but had increased material-level strength and stiffness versus control rats (CD). At the nanoscale, collagen fibril D-spacing was shifted towards higher spacing values in diabetic ZDSD fibrils. The distribution of nanoscale modulus values was also shifted to higher values. Material-level strength and stiffness from whole fiber tests were increased in ZDSD tails. Correlations between nanoscale and microscale properties indicate a direct positive relationship between the two length scales, most notably in the relationship between nanoscale and microscale modulus. These findings indicate that diabetes-induced changes in material strength and modulus were driven by alterations at the nanoscale.

Nanoscale changes in collagen are reflected in physical and mechanical properties of bone at the microscale in diabetic rats

Diabetes detrimentally affects the musculoskeletal system by stiffening the collagen matrix due to increased advanced glycation end products (AGEs). In this study, tibiae and tendon from Zucker diabetic Sprague–Dawley (ZDSD) rats were compared to Sprague–Dawley derived controls (CD) using Atomic Force Microscopy. ZDSD and CD tibiae were compared using Raman Spectroscopy and Reference Point Indentation (RPI). ZDSD bone had a significantly different distribution of collagen D-spacing than CD (p=0.015; ZDSD n=294 fibrils; CD n=274 fibrils) which was more variable and shifted to higher values. This shift between ZDSD and CD D-spacing distribution was more pronounced in tendon (p<0.001; ZDSD n=350; CD n=371). Raman revealed significant increases in measures of bone matrix mineralization in ZDSD (PO43− ν1/Amide I p=0.008; PO43− ν1/CH2 wag p=0.047; n=5 per group) despite lower bone mineral density (aBMD) and ash fraction indicating diabetes may preferentially reduce the Raman signature of collagen. Decreased indentation distance increase (p=0.010) and creep indentation distance (p=0.040) measured by RPI (n=9 per group) in ZDSD rats suggest a matrix more resistant to indentation under the high stresses associated with RPI at this length scale. There were significant correlations between Raman and RPI measurements in the ZDSD population (n=18 locations) but not the CD population (n=16 locations) indicating that while RPI is relatively unaffected by biological noise, it is sensitive to disease-induced compositional changes. In conclusion, diabetes in the ZDSD rat causes changes to the nanoscale morphology of collagen that result in compositional and mechanical effects in bone at the microscale.

Age-Related Differences in Response to High-Fat Feeding on Adipose Tissue and Metabolic Profile in ZDSD Rats

The recruitment of new fat cells through adipogenesis may prevent the development of obesity-related comorbidities. However, adipogenic capacity is markedly reduced in mature adults. This study examined how initiation of high-fat feeding at different phases of adulthood modified adipose tissue (AT) morphology and obesity phenotype in obese and diabetic Zucker Diabetic Sprague Dawley (ZDSD) rats. For this, rodents were provided high-fat diet (HFD) beginning at 63, 84, or 112 d after parturition until termination (n = 6). At termination, ZDSD rats fed HFD beginning at 63 d after parturition (early adulthood) exhibited greater body fat and lower lean mass without significant changes to energy intake or body weight. Moreover, early high fat feeding increased adipocyte size and number, whereas these effects were absent at 84 or 112 d after parturition. At 126 d after parturition, there were no detectable transcript differences in PPARγ or C/EBPα. However, rodents provided HFD in early adolescence exhibited lower expression of canonical Wnt signaling intermediates. Corresponding with these changes was a marked reduction in AT-specific inflammation, as well as overall improvement in systemic glucose, lipid, and inflammatory homeostasis. Taken together, these data indicate that dietary regulation of adipocyte recruitment in adolescence may represent a major determinant of obesity phenotype.