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Dose-dependent delay of the hypoglycemic effect of short-acting insulin analogs in obese subjects with type 2 diabetes: a pharmacokinetic and pharmacodynamic study.

Gagnon-Auger M, du Souich P, Baillargeon JP, Martin E, Brassard P, Ménard J, Ardilouze JL - Diabetes Care (2010)

Bottom Line: Injected volume and subcutaneous adipose tissue blood flow (ATBF) affect insulin absorption.Plasma lispro was measured by specific radioimmunoassay and ATBF by the (133)Xe-washout technique.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Endocrinology, Université de Sherbrooke, Sherbrooke, Quebec, Canada.

ABSTRACT

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.

Research design and 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.

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Related in: MedlinePlus

Mean (± SD) plasma lispro concentration over 480-min euglycemic clamps after subcutaneous injection of 10 units in healthy subjects (●) and 10 units (○), 30 units (□), and 50 units (▵) in obese subjects with type 2 diabetes.
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Figure 1: Mean (± SD) plasma lispro concentration over 480-min euglycemic clamps after subcutaneous injection of 10 units in healthy subjects (●) and 10 units (○), 30 units (□), and 50 units (▵) in obese subjects with type 2 diabetes.

Mentions: After the 10-unit injection, the ratio Cmax/D was 41% lower (P < 0.001) in subjects with type 2 diabetes than in healthy subjects, but Cmax, Tmax, AUC0-∞, AUC0-∞/D, ka, and Cl were similar in both groups. Mean residence time, Vz, and t½ tended to be greater in subjects with type 2 diabetes than in control subjects (Fig. 1, Table 2). After the 30- and 50-unit injections, ka dropped by 60% (P = 0.035) and Tmax was delayed by 33 (P = 0.118) and 74 min (P < 0.001), respectively. Cmax/D, Cl, Vz, and t½ were not affected by the dose, although mean residence time tended to be greater. Tmax (r2 = 0.51, P = 0.0004), Cmax (r2 = 0.90, P < 0.0001), and AUC0-∞ (r2 = 0.94, P < 0.0001) were associated with dosage.


Dose-dependent delay of the hypoglycemic effect of short-acting insulin analogs in obese subjects with type 2 diabetes: a pharmacokinetic and pharmacodynamic study.

Gagnon-Auger M, du Souich P, Baillargeon JP, Martin E, Brassard P, Ménard J, Ardilouze JL - Diabetes Care (2010)

Mean (± SD) plasma lispro concentration over 480-min euglycemic clamps after subcutaneous injection of 10 units in healthy subjects (●) and 10 units (○), 30 units (□), and 50 units (▵) in obese subjects with type 2 diabetes.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992178&req=5

Figure 1: Mean (± SD) plasma lispro concentration over 480-min euglycemic clamps after subcutaneous injection of 10 units in healthy subjects (●) and 10 units (○), 30 units (□), and 50 units (▵) in obese subjects with type 2 diabetes.
Mentions: After the 10-unit injection, the ratio Cmax/D was 41% lower (P < 0.001) in subjects with type 2 diabetes than in healthy subjects, but Cmax, Tmax, AUC0-∞, AUC0-∞/D, ka, and Cl were similar in both groups. Mean residence time, Vz, and t½ tended to be greater in subjects with type 2 diabetes than in control subjects (Fig. 1, Table 2). After the 30- and 50-unit injections, ka dropped by 60% (P = 0.035) and Tmax was delayed by 33 (P = 0.118) and 74 min (P < 0.001), respectively. Cmax/D, Cl, Vz, and t½ were not affected by the dose, although mean residence time tended to be greater. Tmax (r2 = 0.51, P = 0.0004), Cmax (r2 = 0.90, P < 0.0001), and AUC0-∞ (r2 = 0.94, P < 0.0001) were associated with dosage.

Bottom Line: Injected volume and subcutaneous adipose tissue blood flow (ATBF) affect insulin absorption.Plasma lispro was measured by specific radioimmunoassay and ATBF by the (133)Xe-washout technique.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Endocrinology, Université de Sherbrooke, Sherbrooke, Quebec, Canada.

ABSTRACT

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.

Research design and 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.

Show MeSH
Related in: MedlinePlus