Renal and metabolic effects of insulin lispro in type 2 diabetic subjects with overt nephropathy.
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.


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.
Ruggenenti
Piero
P
Clinical Research Center for Rare Diseases Aldo & Cele Daccò, Ranica, Mario Negri Institute for Pharmacological Research, Bergamo, Italy. manuelap@marionegri.it
Flores
Claudio
C
Aros
Claudio
C
Ene-Iordache
Bogdan
B
Trevisan
Roberto
R
Ottomano
Cosimo
C
Remuzzi
Giuseppe
G
D000328:Adult; D000368:Aged; D000419:Albuminuria / Q000209:etiology; D001786:Blood Glucose / Q000032:analysis; D018592:Cross-Over Studies; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology / Q000652:urine; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use*; D061268:Insulin Lispro; D007668:Kidney / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D019518:Postprandial Period; D012079:Renal Circulation / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D061268:Insulin Lispro