Objective: Diabetic nephropathy is the leading cause of end-stage renal disease and the largest contributor to the total cost of diabetes care. Rodent models are excellent tools to gain more insight into the pathogenesis of diabetic nephropathy. In the present study we characterize the age-related sequence of diabetes-associated kidney lesions in GIPR^dn transgenic mice, a novel mouse model of early onset diabetes mellitus. Research Design and Methods: Clinical-chemical analyses, as well as qualitative and quantitative morphological analyses of the kidneys of GIPR^dn transgenic animals and non-transgenic littermate controls were performed at 3, 8, 20 and 28 weeks of age. Results: Early renal changes of transgenic mice consisted of podocyte hypertrophy, reduced numerical volume density of podocytes in glomeruli, and homogenous thickening of the glomerular basement membrane, followed by renal and glomerular hypertrophy as well as mesangial expansion and matrix accumulation. At 28 weeks of age, glomerular damage was most prominent, including advanced glomerulosclerosis, tubulointerstitial lesions and proteinuria. Real-time PCR demonstrated increased glomerular expression of collagen type IV alpha 1, fibronectin, and Tgfb1. Immunohistochemistry revealed increased mesangial deposition of collagen type IV, fibronectin and laminin. Conclusion: The present study shows that GIPR^dn transgenic mice exhibit renal changes that closely resemble diabetes-associated kidney alterations in humans. Data particularly from male transgenic mice indicate that podocyte hypertrophy is directly linked to hyperglycemia, without the influence of mechanical stress. GIPR^dn transgenic mice are considered an excellent new tool to study the mechanisms involved in onset and progression of diabetic nephropathy.