Renal injury in diabetes mellitus is an important clinical as well as biological problem. Approximately 30% of patients with type I or insulin-dependent diabetes mellitus [1] and 5 to 10% of patients with type II or non-insulin-dependent diabetes mellitus [2] will develop chronic renal insufficiency requiring treatment in an end-stage renal disease program. The mechanism of this injury, the underlying cause, and the nature of progressive renal insufficiency are unclear. In general, it has been proposed that diabetes is predominantly a glomerular disease as there is a progressive increase in urinary albumin excretion from 15 to 30 µg/min up to nephrotic range proteinuria over 5 to 12 years, followed by hypertension and decline in glomerular filtration rate (GFR) after a mean duration of 17 years of diabetes in the segment of patients at risk. The pathologic lesion of diffuse glomerular sclerosis or nodular intercapillary glomerular sclerosis is typically seen in biopsies from patients with advanced diabetic nephropathy [3, 4]. Moreover, Mauer and colleagues [5] and Osterby and Gunderson [6] have shown that there is a close correlation between the expansion of the glomerular mesangium and the declining filtration surface area, as well as the declining GFR in affected patients. These results support the view of diabetic nephropathy as a primary glomerular and perhaps primary mesangial disorder.

However, a number of contradictory observations suggest a potentially important role for alterations in non-glomerular structures which reside within the renal interstitium in the development of renal insufficiency in patients with diabetes mellitus. The following discussion will review the evidence for a role of altered structure and function of the renal tubulointerstitium in diabetes, and propose the hypotheses that altered tubular transport and metabolic activity contributes to proteinuria and altered renal hemodynamics in diabetes, and that interstitial fibrosis plays an important role in the ultimate expression of renal insufficiency in diabetic nephropathy. We will discuss several potential mechanisms for these functional and structural changes and suggest a central pathogenetic role for hyperglycemia per se in the induction of these abnormalities.