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To establish the method by which the optimal dietary protein content for type 2 diabetic patients with nephropathy could be determined, dietary protein content was reduced in gradated steps and renal function was evaluated at the completion of each diet. Eight type 2 diabetic patients with microalbuminuria were examined in this study. Renal function, urinary albumin excretion rate (AER) and urinary excretion rates of prostaglandins were evaluated at the completion of each of three consecutive one-week dietary periods where the protein content was 1.2, 0.8 and 0.6 g x kg Body Weight (BW)(-1) x day(-1) on the first, second and third week, respectively. Filtration fraction (FF), AER and urinary excretion rates of prostaglandin E2 and 6-keto-prostaglandin F1alpha significantly decreased in response to reduced dietary protein content from 1.2 to 0.8 g x kg BW(-1) x day(-1). No additional decreases in FF, AER and urinary excretion rates of these two prostaglandins were obtained after the 0.6 g x kg BW(-1) x day(-1) low protein diet period. The method evaluating renal hemodynamics at the completion of several consecutive one-week dietary periods was confirmed to be useful to determine the optimal protein contents in type 2 diabetic patients with nephropathy. The result showed that the optimal protein content in type 2 diabetic patients with microalbuminuria was 0.8 g x kg BW(-1) x day(-1) and protein restriction of less than 0.8 g x kg BW(-1) x day(-1) was not necessary for patients with this stage of diabetic nephropathy. A part of reasons in which FF decreased after reduced protein content in diet may be due to decreased prostaglandins production in the kidneys.

To determine whether each of glycemic control (GC), low protein diet (LPD) or administration of angiotensin converting enzyme inhibitor (ACEI) has beneficial effects on diabetic nephropathy through the different mechanisms, changes in charge and size selectivity of glomerulus and renal hemodynamics were analyzed in microalbuminuric type 2 diabetic patients after additive combination therapy (first period: GC only, second period: GC-LPD, third period: GC+LPD+ACEI). To detect improvement of the impairments of glomerular charge selectivity and size selectivity, changes in the ratio of the renal clearance of two plasma proteins with similar molecular radii and different isoelectric points (pIs) (ceruloplasmin and IgG: CRL/IgG) and changes in the ratio of the renal clearance of two plasma proteins with similar pIs and different molecular radii (alpha2-macroglobulin and albumin: alpha2/Alb) were examined before and after each therapy. Creatinine clearance decreased significantly in the first and third periods although slight but not significant decrease was detected in the second period. Filtration fraction was significantly decreased only in the third period. Although renal clearances of Alb, IgG and CRL were decreased in periods of all three therapies, that of alpha2-macroglobulin with a large molecular radius was decreased significantly only after the third therapy. Neither CRL/IgG nor alpha2/Alb changed during these three therapies. These findings suggest that each of three short-term therapies consisting of GC, GC+LPD and GC+LPD+ACEI, reduced proteinuria in microalbuminuric type 2 diabetic patients not through the improvement of renal size and charge selectivities, but through improvement of renal hemodynamics.