American Diabetes Association 66th Annual Scientific Sessions, 773-P (2006)
Abstract
A unique rat model of type 2 diabetes has been
developed with diabetic nephropathy that mimics the disease development seen in
humans. To produce this model, the diabetic GK was crossed with FHH, a
hypertension-associated end stage renal disease model, to produce the new T2DN
rat. Previous characterization of this normotensive
model shows that at 12 months of age renal damage includes focal segmental glomerulosclerosis, interstitial fibrosis, and formation of
protein casts. The damage increases with age and by 18 months has advanced to
severe global glomerulosclerosis with acellular nodules resembling Kimmelstiel-Wilson
nodules characteristic of human diabetic nephropathy. To evaluate whether the
development and progression of nephropathy is due to diabetes or influenced by
the hypertensive background from FHH, 12 month old T2DN were uninephrectomized to accelerate renal damage and treated
with either exogenous insulin (4 U/day) or glyburide
(2, 5, or 7 mg/kg/day). Fasting blood glucose was reduced from 174.0 ± 13.8 mg/dL to 75.0 ± 7.0 mg/dL in insulin
treated animals, while glyburide had no effect on
fasting glucose levels. After 4 months, animals treated with insulin had a
significant reduction in renal damage with decreased interstitial fibrosis, glomerulosclerosis and protein casts and demonstrate the
nephropathy in the T2DN is a result of diabetes and not due to the hypertensive
background of the FHH. The T2DN has become the new model of choice for the
identification of new targets in the treatment of diabetic nephropathy and will
provide proof-of-therapeutic-concept studies.
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