American Diabetes Association 66th Annual Scientific Sessions, 2186-PO (2006)
Abstract
The T2DN rat is a new model of type 2 diabetes
that develops progressive diabetic nephropathy similar to that seen in humans.
The T2DN was derived from crossing the diabetic GK with the FHH, a hypertension-associated
end stage renal disease model. Studies to characterize disease progression in
T2DN show that by three months of age fasting blood glucose levels are ~200 mg/dL and are
maintained at this level through 18 months of age. Average proteinuria
values increase from ~20 mg/day at 3 months of age to ~500 mg/day by 18 months
of age. By 12 months old, renal damage has advanced with glomerular
hypertrophy, thickening of glomerular and tubular basement membranes, expansion
of the mesangial matrix, and developmental of focal
segmental glomerulosclerosis leading to diffuse
global glomerulosclerosis and the formation of
glomerular nodules by 18 months of age. Because severe renal histological
damage is not seen until approximately 18 months of age, we explored the
possibility of accelerating renal damage to allow for the study of renoprotective effects of test compounds. Twelve month old
T2DN rats were uninephrectomized and disease
progression was monitored out to 18 months of age. While the uninephrectomy did not impact fasting glucose and proteinuria levels significantly, the progression of
diabetic nephropathy was accelerated and the time necessary for robust
development of renal lesions was reduced from 6 to 3 months. The T2DN rat will
be a model of choice for therapeutic intervention early in the pathogenesis of
diabetic nephropathy and in the understanding of the key genes that contribute
to disease progression. The acceleration of the T2DN model has allowed PhysioGenix to accelerate turn-over time of critical
results from drug candidate studies, thereby making our model cost efficient to
the pharmaceutical industry.
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