The major renal pathologic changes of diabetes include thickening of all renal extracellular basement membranes and mesangial matrix and, to a lesser extent, mesangial cell expansion. Two renal lesions appear critical in diabetic nephropathy. Mesangial expansion out of proportion to the size of the glomerulus is closely and inversely related to measures of peripheral capillary wall filtration surface and to clinical features of proteinuria, hypertension, and decreasing glomerular filtration rate (GFR). Arteriolar hyalinosis is related to global glomerulosclerosis, and both are correlated with the clinical features of nephropathy. These lesions are markedly advanced by the time renal dysfunction is clinically detectable. Relationships of structure and function early in the course of the diabetes have not been examined satisfactorily.