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 Ϯ 5.0 vs. Ϫ6.3 Ϯ 4.7, P Ͻ 0.05; and 11.0 Ϯ 6.8 vs. 0.7 Ϯ 5.1%, P Ͻ 0.05) after regular insulin and lispro injection, respectively. After lispro, postprandial GFR changes were negatively correlated (r ϭ Ϫ0.48, P ϭ 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 Ϯ 16 vs. 240 Ϯ 16 mg/dl, P Ͻ 0.01) and area under the curve (79,381 Ϯ 19,237 vs. 72,810 Ϯ 16,211 mg/dl per min, P Ͻ 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. Diabetes Care 26:502-509, 2003

Treatment with insulin analogs, especially Glargine and Lispro, associates with better renal function and higher hemoglobin levels in Type 1 diabetic patients with impaired kidney function

“…Kulozik and Hasslacher [Kulozik and Hasslacher, 2015] recently showed that low 1,5-AG levels as indicator of transient hyperglycemia are not associated with an increased prevalence of nephropathy. Ruggenenti and colleagues [Ruggenenti et al 2003] found in a study on the renal hemodynamics that postprandial hyperperfusion of the glomeruli, which is detectable under HI therapy, does not occur under treatment with insulin lispro. It is not known to what extent this effect on glomerular hemodynamics can also be found with other IA, and whether this effect has a protective influence on the course of nephropathy.…”

Glomerular Hyperfiltration in Diabetes: Mechanisms, Clinical Significance, and Treatment

“…96,97 Interestingly, in T2DM with macroalbuminuria, the fast-acting insulin lispro blunted postprandial increase in GFR and RPF versus regular insulin, possibly due to inhibition of insulin-like growth factor-1-dependent renal vasodilation. 98 Glucagon Receptor Antagonists Hyperglucagonemia in the fasting and postprandial state contributes to elevated blood glucose and hyperfiltration in diabetes. 48,99 Interestingly, glucagon levels increase in the course of DKD.…”

Insulin therapy in renal disease

“…It has been recently reported that insulin lispro, a rapid‐acting insulin analogue with structural homology with IGF‐1, prevented glomerular hyperfiltration and offset the renal effects of meal‐associated hyperglycaemia in type 2 diabetic patients with overt nephropathy (serum creatinine <2.0 mg/dl and persistent macroalbuminuria ≥200 μg/min). The mechanism of this action might be related to IGF‐1 antagonism [55].…”