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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

Plot of mean glucose infusion rate as a function of insulin plasma concentrations in healthy subjects receiving subcutaneously 10 units of lispro (●) and in obese subjects with type 2 diabetes receiving 10 units (○), 30 units (□), and 50 units (▵) of lispro. Data points are connected in chronological order; as depicted by the arrows, the resulting relationship denotes a counterclockwise hysteresis.
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Figure 3: Plot of mean glucose infusion rate as a function of insulin plasma concentrations in healthy subjects receiving subcutaneously 10 units of lispro (●) and in obese subjects with type 2 diabetes receiving 10 units (○), 30 units (□), and 50 units (▵) of lispro. Data points are connected in chronological order; as depicted by the arrows, the resulting relationship denotes a counterclockwise hysteresis.

Mentions: When GIR was plotted as a function of lispro plasma concentrations, the sequential response-concentration relationship depicted a counterclockwise hysteresis for both healthy subjects and subjects with type 2 diabetes (Fig. 3). In healthy subjects receiving 10 units of insulin, an initial GIR response of 2.22 mg/kg/min was seen with insulin concentrations nearing 40 pmol/l. Thereafter, large increases of insulin concentrations were required to increase GIR, although once the response was triggered, it was maintained while plasma concentrations decreased to 20% of the Cmax. In obese subjects with type 2 diabetes, after a 10-unit injection, much greater concentrations of insulin were required to produce even a minimal effect (e.g., 273 pmol/l of insulin elicited a GIR of 0.1 mg/kg/min). The response later increased abruptly to attain GIRmax when plasma concentrations of insulin were already dropping; once GIRmax was attained, the response decreased linearly with insulin plasma concentrations. The same pattern was observed for 30- and 50-unit injections.


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)

Plot of mean glucose infusion rate as a function of insulin plasma concentrations in healthy subjects receiving subcutaneously 10 units of lispro (●) and in obese subjects with type 2 diabetes receiving 10 units (○), 30 units (□), and 50 units (▵) of lispro. Data points are connected in chronological order; as depicted by the arrows, the resulting relationship denotes a counterclockwise hysteresis.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 3: Plot of mean glucose infusion rate as a function of insulin plasma concentrations in healthy subjects receiving subcutaneously 10 units of lispro (●) and in obese subjects with type 2 diabetes receiving 10 units (○), 30 units (□), and 50 units (▵) of lispro. Data points are connected in chronological order; as depicted by the arrows, the resulting relationship denotes a counterclockwise hysteresis.
Mentions: When GIR was plotted as a function of lispro plasma concentrations, the sequential response-concentration relationship depicted a counterclockwise hysteresis for both healthy subjects and subjects with type 2 diabetes (Fig. 3). In healthy subjects receiving 10 units of insulin, an initial GIR response of 2.22 mg/kg/min was seen with insulin concentrations nearing 40 pmol/l. Thereafter, large increases of insulin concentrations were required to increase GIR, although once the response was triggered, it was maintained while plasma concentrations decreased to 20% of the Cmax. In obese subjects with type 2 diabetes, after a 10-unit injection, much greater concentrations of insulin were required to produce even a minimal effect (e.g., 273 pmol/l of insulin elicited a GIR of 0.1 mg/kg/min). The response later increased abruptly to attain GIRmax when plasma concentrations of insulin were already dropping; once GIRmax was attained, the response decreased linearly with insulin plasma concentrations. The same pattern was observed for 30- and 50-unit injections.

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