To characterize the renal handling of protein in diabetics, the 24-h total protein excretion (Shevky-Stafford method), as well as urinary excretion, plasma concentration, and clearance of each of 17 proteins (radial immunodiffusion technique) were determined in 25 nondiabetic and 31 diabetic Pima Indians and in 25 nondiabetic Caucasians.
Determination of 24-h total protein excretion demonstrated similar levels in nondiabetic Pimas [8.6 mg/24 h (median), 5.0-18.0 mg/24 h (95% confidence interval)] and nondiabetic Caucasians [10.1 mg/24 h, 7.0-24.0 mg/24 h] but significantly elevated levels in Pima diabetics [41.0 mg/24 h, 24.0-163.0 mg/24 h]. Total protein excretion was significantly greater among those with diabetes of 10 or more yr duration with retinopathy [163.0 mg/24 h, 24.0-436.0 mg/24 h] and those with recent onset of diabetes [39.5 mg/24 h, 24.7-81.0 mg/24 h], whereas long-duration diabetics without retinopathy [11.5 mg/24 h, 6.7-29.0 mg/24 h] and nondiabetic Pimas had similar values. Mean blood pressure and fasting plasma glucose levels were positively correlated with total protein excretion in the diabetic Pimas.
Measurable quantities of only 9 of the 17 individual proteins were detected in the urine in more than 50% of all nondiabetic and diabetic subjects. They were β2- microglobulin, β2-glycoprotein I, α1-acid glycoprotein, α2 HS-glycoprotein, α1-antitrypsin, albumin, hemopexin, transferrin, and IgG. The excretions and clearances ofthese proteins were comparable in nondiabetic Pimas and Caucasians. Compared with nondiabetic Pimas, diabetics had significantly higher clearance and excretion of each of these proteins, except β2-microglobulin (mol. wt. = 11,600) and α-glycoprotein I (mol.wt. = 40,000). Long-duration diabetics with retinopathy and recent-onset diabetics both had significantly elevated clearance and excretion of the same proteins. In contrast, long-duration diabetics without retinopathy had significant increases of clearance and excretion only of hemopexin, transferrin, and IgG. The IgG/transferrin clearance ratios were not significantly different among the nondiabetic and diabetic groups.
The other eight proteins were detected in the urine in measurable quantities in less than 50% of all subjects. These were prealbumin, gc-globulin, antithrombin III, plasminogen, haptoglobin, C3 activator, C4- component, and C3-component. While for statistical reasons, clearance data could not be analyzed for these proteins, a significantly higher percentage of diabetic Pimas had detectable excretion of these proteins except for C3 activator.
In conclusion, diabetics, even of recent onset, have increased urinary excretion and clearance of proteins with a molecular weight greater than 40,000 compared with nondiabetics. This increased glomerular permeability appears to be nonselective for the larger proteins and can be detected shortly after the onset of diabetes. It might be predictive of the development of more severe renal disease after longer duration of diabetes.