Effects of saxagliptin on β-cell stimulation and insulin secretion in patients with type 2 diabetes

TY - JOUR

T1 - Effects of saxagliptin on β-cell stimulation and insulin secretion in patients with type 2 diabetes

AU - Henry, R R

AU - Smith, Susanne

AU - Schwartz, Saul

AU - Mudaliar, S R

AU - Deacon, C F

AU - Holst, Jens Juul

AU - Duan, R Y

AU - Chen, R S

AU - List, J F

N1 - © 2011 Blackwell Publishing Ltd.

PY - 2011/9

Y1 - 2011/9

N2 - Aim: To study the effect of dipeptidyl peptidase-4 (DPP-4) inhibition with saxagliptin on β-cell function as reflected by the stimulated insulin secretion rate after an enteral glucose load in patients with type 2 diabetes. Methods: Patients in this randomized, parallel-group, double-blind, placebo-controlled study were drug-naÏve, aged 43-69 years, with baseline haemoglobin A1c (HbA1c) 5.9-8.1%. Twenty patients received saxagliptin 5 mg once daily; 16 received placebo. Patients were assessed at baseline and week 12 by intravenous hyperglycaemic clamp (0-180 min, fasting state), and intravenous-oral hyperglycaemic clamp (180-480 min, postprandial state) following oral ingestion of 75 g glucose. Primary and secondary endpoints were percent changes from baseline in insulin secretion during postprandial and fasting states, respectively. Insulin secretion was calculated by C-peptide deconvolution. Results: After 12 weeks, saxagliptin significantly increased insulin secretion percent change from baseline during the postprandial state by an 18.5% adjusted difference versus placebo (p = 0.04), an improvement associated with increased peak plasma concentrations of intact glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. In the fasting state, saxagliptin significantly increased insulin secretion by a 27.9% adjusted difference versus placebo (p = 0.02). Saxagliptin also improved glucagon area under the curve in the postprandial state (adjusted difference -21.8% vs. placebo, p = 0.03). Conclusions: DPP-4 inhibition with saxagliptin improves pancreatic β-cell function in postprandial and fasting states, and decreases postprandial glucagon concentration. Given the magnitude of enhancement of the insulin response in the fasting state, further study into the effect of DPP-4 inhibition on the β-cell is warranted.

AB - Aim: To study the effect of dipeptidyl peptidase-4 (DPP-4) inhibition with saxagliptin on β-cell function as reflected by the stimulated insulin secretion rate after an enteral glucose load in patients with type 2 diabetes. Methods: Patients in this randomized, parallel-group, double-blind, placebo-controlled study were drug-naÏve, aged 43-69 years, with baseline haemoglobin A1c (HbA1c) 5.9-8.1%. Twenty patients received saxagliptin 5 mg once daily; 16 received placebo. Patients were assessed at baseline and week 12 by intravenous hyperglycaemic clamp (0-180 min, fasting state), and intravenous-oral hyperglycaemic clamp (180-480 min, postprandial state) following oral ingestion of 75 g glucose. Primary and secondary endpoints were percent changes from baseline in insulin secretion during postprandial and fasting states, respectively. Insulin secretion was calculated by C-peptide deconvolution. Results: After 12 weeks, saxagliptin significantly increased insulin secretion percent change from baseline during the postprandial state by an 18.5% adjusted difference versus placebo (p = 0.04), an improvement associated with increased peak plasma concentrations of intact glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. In the fasting state, saxagliptin significantly increased insulin secretion by a 27.9% adjusted difference versus placebo (p = 0.02). Saxagliptin also improved glucagon area under the curve in the postprandial state (adjusted difference -21.8% vs. placebo, p = 0.03). Conclusions: DPP-4 inhibition with saxagliptin improves pancreatic β-cell function in postprandial and fasting states, and decreases postprandial glucagon concentration. Given the magnitude of enhancement of the insulin response in the fasting state, further study into the effect of DPP-4 inhibition on the β-cell is warranted.

KW - Adamantane

KW - Adult

KW - Aged

KW - Blood Glucose

KW - Diabetes Mellitus, Type 2

KW - Dipeptides

KW - Dipeptidyl-Peptidase IV Inhibitors

KW - Double-Blind Method

KW - Female

KW - Glucose Clamp Technique

KW - Hemoglobin A, Glycosylated

KW - Humans

KW - Insulin

KW - Insulin-Secreting Cells

KW - Male

KW - Middle Aged

KW - Treatment Outcome

U2 - 10.1111/j.1463-1326.2011.01417.x

DO - 10.1111/j.1463-1326.2011.01417.x

M3 - Journal article

C2 - 21554520

SN - 1462-8902

VL - 13

SP - 850

EP - 858

JO - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

IS - 9

ER -