Renal and Metabolic Effects of Insulin Lispro in Type 2 Diabetic Subjects With Overt Nephropathy

Abstract

OBJECTIVE—To assess whether the insulin analog lispro may antagonize the renal effects of IGF-1, a mediator of glomerular hyperfiltration involved in the progression of diabetic and nondiabetic chronic nephropathies. RESEARCH DESIGN AND METHODS—In a randomized crossover study, we compared the renal and metabolic responses to regular or lispro insulin (0.1 units/kg body wt) administered after a euglycemic clamp and 5 and 30 min before a standard meal to 11 type 2 diabetic patients with macroalbuminuria. RESULTS—Two- and four-hour postprandial changes (vs. preprandial euglycemia) in glomerular filtration rate (GFR) followed a significantly different trend (5.8 ± 5.0 vs. −6.3 ± 4.7, P < 0.05; and 11.0 ± 6.8 vs. 0.7 ± 5.1%, P < 0.05) after regular insulin and lispro injection, respectively. After lispro, postprandial GFR changes were negatively correlated (r = −0.48, P = 0.0001) with plasma insulin concentration. After regular insulin, renal plasma flow increased in parallel with a decrease in renal vascular resistances. Both changes were fully prevented by lispro. Postprandial blood glucose maximum concentration (278 ± 16 vs. 240 ± 16 mg/dl, P < 0.01) and area under the curve (79,381 ± 19,237 vs. 72,810 ± 16,211 mg/dl per min, P < 0,05) were significantly lower after insulin lispro than after regular insulin injection, respectively, despite comparable postprandial insulin profiles. Changes in total and gluconeogenic amino acids followed a similar trend. Changes in blood glucose and plasma amino acids did not correlate with concomitant changes in GFR. CONCLUSIONS—In overt nephropathy of type 2 diabetes, lispro prevents glomerular hyperfiltration and offsets the renal effects of meal or meal-associated hyperglycemia by mechanisms possibly related to IGF-1 antagonism.