A three-step euglycemic insulin clamp was performed in six matched groups: nine healthy subjects, 10 insulin-dependent diabetic (IDD) subjects with normal kidney function, 10 nondiabetic uremic subjects, six nondialyzed uremic IDD subjects, seven uremic IDD subjects on chronic hemodialysis (HD), and six uremic IDD subjects on chronic ambulatory peritoneal dialysis (CAPD). Insulin was infused sequentially at rates of 0.5 (step 1), 2.0 (step 2), and 4.0 (step 3) mU · kg−1 · min−1. Each dose was given for 120 min; however, in theIDD subjects with fasting hyperglycemia, step 1 of the clamp was slightly extended. Average serumfree insulin levels at steady state ranged from 22 to 342 μU/ml and were comparable in all groups. Step 3 glucose infusion rate (GIR), the last 30 min of the infusion period, was extremely suppressed in nondialyzed uremic IDD subjects, amounting to 53% of that in healthy subjects (7.7 ± 0.7 versus 14.4 ± 0.9 mg · kg−1 · min−1 P < 0.001) indicating severe insulin resistance in peripheral tissues. As expected, step 3 glucose disposal was also reduced in IDD subjects with normal kidney function (12.4 ± 0.6 mg · kg−1 · min−1) and nondiabetic uremic subjects (9.2 ± 0.6 mg · kg−1 · min−1) as compared with healthy subjects (P = 0.06 and P < 0.001, respectively). The pronounced impairment of insulin responsiveness in nondialyzed uremic IDD subjects was almost equal to the sum of the defects in nondiabetic uremic and IDD subjects with normal kidney function. Step 2 of the sequential insulin infusion resulted in differences in GIR between the above-mentioned groups that were analogous to those encountered at the highest insulin infusion rate. During step 1 the average steady-state GIR, reflecting the sum of suppression of glucose production and stimulation of glucose utilization, was more than twofold higher in healthy subjects than in the nondialyzed patient groups. In contrast, the insulin action on Iipoiysis and ketogenesis as assessedby changes in serum NEFA and blood 3-hydroxybutyrate was normal in the patient groups. In the patients treated by HD and CAPD insulin responsiveness (step 3 GIR) was enhanced or tended to be so compared with nondialyzed uremic IDD individuals (9.5 ± 0.7 and 12.2 ± 0.7 mg kg−1 min−1 P = 0.07 and P < 0.001, respectively). Furthermore, GIR at all three steps was significantly higher in the CAPD group than in the HD group (P = 0.08, P < 0.001, and P < 0.03). No difference in degree of azotemia or glycemic and metabolic control wasobserved between the dialyzed groups.
In conclusion, nondialyzed uremic IDD individuals exhibit extreme insulin resistance in peripheral tissue that is probably the result of several intracellular defects. In uremic IDD subjectstreated with CAPD, the insulin-mediated glucose uptake is closer to normal than in IDD subjects on HD. Potentially lower peripheral insulinemia in diabetic CAPD patients having insulin administered intraperitoneally may contribute to this difference.