Dose-dependent delay of the hypoglycemic effect of short-acting insulin analogs in obese subjects with type 2 diabetes: a pharmacokinetic and pharmacodynamic study.
OBJECTIVE
Injected volume and subcutaneous adipose tissue blood flow (ATBF) affect insulin absorption. Pharmacokinetics of short-acting insulin analogs were established by assessing injection of small doses in lean subjects, healthy or with type 1 diabetes. In obese patients, however, daily dosages are larger and ATBF is decreased. This study assessed the kinetics of a short-acting insulin analog in obese subjects with type 2 diabetes.


METHODS
Euglycemic clamps after subcutaneous lispro injections were performed. Six healthy control subjects received 10 units. Seven obese (BMI 38.3 ± 7.0 kg/m(2)) subjects with type 2 diabetes received 10, 30, and 50 units. Plasma lispro was measured by specific radioimmunoassay and ATBF by the (133)Xe-washout technique.


RESULTS
ATBF was 64% lower in subjects with type 2 diabetes than in control subjects. After 10 units injection, time to lispro plasma peak (T(max)) was similar (48.3 vs. 55.7 min; control subjects versus type 2 diabetic subjects), although maximal concentration (C(max))/dose was 41% lower in subjects with type 2 diabetes, with lower and delayed maximal glucose infusion rate (GIR(max): 9.0 vs. 0.6 mg/kg/min, P < 0.0001, 69 vs. 130 min, P < 0.0001, respectively). After 30- and 50-unit injections, T(max) (88.6 and 130.0 min, respectively) and time to GIR(max) (175 and 245 min) were further delayed and dose related (r(2) = 0.51, P = 0.0004 and r(2) = 0.76, P < 0.0001, respectively).


CONCLUSIONS
Absorption and hypoglycemic action of increasing dosages of lispro are critically delayed in obese subjects with type 2 diabetes.
Gagnon-Auger
Maude
M
Department of Medicine, Division of Endocrinology, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
du Souich
Patrick
P
Baillargeon
Jean-Patrice
JP
Martin
Elisabeth
E
Brassard
Pascal
P
Ménard
Julie
J
Ardilouze
Jean-Luc
JL
D000293:Adolescent; D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics*; D007279:Injections, Subcutaneous; D007328:Insulin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D061268:Insulin Lispro; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications*; D055815:Young Adult
D007004:Hypoglycemic Agents; D007328:Insulin; D061268:Insulin Lispro