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Differential effects of acute and extended infusions of glucagon-like peptide-1 on first- and second-phase insulin secretion in diabetic and nondiabetic humans.
Diabetes Care. 2003 Mar; 26(3):791-8.DC

Abstract

OBJECTIVE

The purpose of this study was to determine whether an extended infusion of the incretin hormone glucagon-like peptide 1 (GLP-1) has a greater effect to promote insulin secretion in type 2 diabetic subjects than acute administration of the peptide.

RESEARCH DESIGN AND METHODS

Nine diabetic subjects and nine nondiabetic volunteers of similar age and weight were studied in identical protocols. First-phase insulin release (FPIR; the incremental insulin response in the first 10 min after the intravenous glucose bolus) and second-phase insulin release (SPIR; the incremental insulin response from 10-60 min after intravenous glucose) were measured during three separate intravenous glucose tolerance tests (IVGTTs): 1). without GLP-1 (control); 2). with acute administration of GLP-1 as a square wave starting just before glucose administration; and 3). with an extended infusion of GLP-1 for 3 h before and during the IVGTT.

RESULTS

In the subjects with diabetes, FPIR was severely impaired-a defect that was only modestly improved by acute administration of GLP-1 (197 +/- 97 vs. 539 +/- 218 pmol/l. min, P < 0.05), while SPIR was substantially increased (1952 +/- 512 vs. 8072 +/- 1664 pmol/l. min, P < 0.05). In contrast, the 3-h preinfusion of GLP-1 normalized fasting hyperglycemia (7.9 +/- 0.5 vs. 5.2 +/- 0.6, P < 0.05), increased FPIR by 5- to 6-fold (197 +/- 97 vs. 1141 +/- 409 pmol/l. min, P < 0.05), and augmented SPIR significantly (1952 +/- 512 vs. 4026 +/- 851 pmol/l. min, P < 0.05), but to a lesser degree than the acute administration of GLP-1. In addition, only the 3-h GLP-1 preinfusion significantly improved intravenous glucose tolerance (K(g) control 0.61 +/- 0.04, acute infusion 0.71 +/- 0.04, P = NS; 3-h infusion 0.92 +/- 0.08%/min, P < 0.05). These findings were also noted in the nondiabetic subjects in whom acute administration of GLP-1 significantly increased SPIR relative to the control IVGTT (9439 +/- 2885 vs. 31553 +/- 11660 pmol/l. min, P < 0.001) with less effect on FPIR (3221 +/- 918 vs. 4917 +/- 1614 pmol/l. min, P = 0.075), while the 3-h preinfusion of GLP-1 significantly increased both FPIR (3221 +/- 918 vs. 7948 +/- 2647 pmol/l. min, P < 0.01) and SPIR (9439 +/- 2885 vs. 21997 +/- 9849 pmol/l. min, P < 0.03).

CONCLUSIONS

Extended administration of GLP-1 not only augments glucose-stimulated insulin secretion, but also shifts the dynamics of the insulin response to earlier release in both diabetic and nondiabetic humans. The restitution of some FPIR in subjects with type 2 diabetes is associated with significantly improved glucose tolerance. These findings demonstrate the benefits of a 3-h infusion of GLP-1 on beta-cell function beyond those of an acute insulin secretagogue, and support the development of strategies using continuous or prolonged GLP-1 receptor agonism for treating diabetic patients.

Authors+Show Affiliations

Quddusi S
Department of Medicine, University of Washington, Seattle, Washington, USA.
Vahl TP
No affiliation info available
Hanson K
No affiliation info available
Prigeon RL
No affiliation info available
D'Alessio DA
No affiliation info available

MeSH

AgedBlood GlucoseDiabetes Mellitus, Type 2FemaleGlucagonGlucagon-Like Peptide 1HumansInfusions, IntravenousInsulinInsulin SecretionIslets of LangerhansMaleMiddle AgedPeptide FragmentsProtein Precursors

Pub Type(s)

Clinical Trial
Controlled Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12610039

Citation

Quddusi, Shaista, et al. "Differential Effects of Acute and Extended Infusions of Glucagon-like Peptide-1 On First- and Second-phase Insulin Secretion in Diabetic and Nondiabetic Humans." Diabetes Care, vol. 26, no. 3, 2003, pp. 791-8.
Quddusi S, Vahl TP, Hanson K, et al. Differential effects of acute and extended infusions of glucagon-like peptide-1 on first- and second-phase insulin secretion in diabetic and nondiabetic humans. Diabetes Care. 2003;26(3):791-8.
Quddusi, S., Vahl, T. P., Hanson, K., Prigeon, R. L., & D'Alessio, D. A. (2003). Differential effects of acute and extended infusions of glucagon-like peptide-1 on first- and second-phase insulin secretion in diabetic and nondiabetic humans. Diabetes Care, 26(3), 791-8.
Quddusi S, et al. Differential Effects of Acute and Extended Infusions of Glucagon-like Peptide-1 On First- and Second-phase Insulin Secretion in Diabetic and Nondiabetic Humans. Diabetes Care. 2003;26(3):791-8. PubMed PMID: 12610039.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential effects of acute and extended infusions of glucagon-like peptide-1 on first- and second-phase insulin secretion in diabetic and nondiabetic humans. AU - Quddusi,Shaista, AU - Vahl,Torsten P, AU - Hanson,Kevin, AU - Prigeon,Ronald L, AU - D'Alessio,David A, PY - 2003/3/1/pubmed PY - 2003/9/13/medline PY - 2003/3/1/entrez SP - 791 EP - 8 JF - Diabetes care JO - Diabetes Care VL - 26 IS - 3 N2 - OBJECTIVE: The purpose of this study was to determine whether an extended infusion of the incretin hormone glucagon-like peptide 1 (GLP-1) has a greater effect to promote insulin secretion in type 2 diabetic subjects than acute administration of the peptide. RESEARCH DESIGN AND METHODS: Nine diabetic subjects and nine nondiabetic volunteers of similar age and weight were studied in identical protocols. First-phase insulin release (FPIR; the incremental insulin response in the first 10 min after the intravenous glucose bolus) and second-phase insulin release (SPIR; the incremental insulin response from 10-60 min after intravenous glucose) were measured during three separate intravenous glucose tolerance tests (IVGTTs): 1). without GLP-1 (control); 2). with acute administration of GLP-1 as a square wave starting just before glucose administration; and 3). with an extended infusion of GLP-1 for 3 h before and during the IVGTT. RESULTS: In the subjects with diabetes, FPIR was severely impaired-a defect that was only modestly improved by acute administration of GLP-1 (197 +/- 97 vs. 539 +/- 218 pmol/l. min, P < 0.05), while SPIR was substantially increased (1952 +/- 512 vs. 8072 +/- 1664 pmol/l. min, P < 0.05). In contrast, the 3-h preinfusion of GLP-1 normalized fasting hyperglycemia (7.9 +/- 0.5 vs. 5.2 +/- 0.6, P < 0.05), increased FPIR by 5- to 6-fold (197 +/- 97 vs. 1141 +/- 409 pmol/l. min, P < 0.05), and augmented SPIR significantly (1952 +/- 512 vs. 4026 +/- 851 pmol/l. min, P < 0.05), but to a lesser degree than the acute administration of GLP-1. In addition, only the 3-h GLP-1 preinfusion significantly improved intravenous glucose tolerance (K(g) control 0.61 +/- 0.04, acute infusion 0.71 +/- 0.04, P = NS; 3-h infusion 0.92 +/- 0.08%/min, P < 0.05). These findings were also noted in the nondiabetic subjects in whom acute administration of GLP-1 significantly increased SPIR relative to the control IVGTT (9439 +/- 2885 vs. 31553 +/- 11660 pmol/l. min, P < 0.001) with less effect on FPIR (3221 +/- 918 vs. 4917 +/- 1614 pmol/l. min, P = 0.075), while the 3-h preinfusion of GLP-1 significantly increased both FPIR (3221 +/- 918 vs. 7948 +/- 2647 pmol/l. min, P < 0.01) and SPIR (9439 +/- 2885 vs. 21997 +/- 9849 pmol/l. min, P < 0.03). CONCLUSIONS: Extended administration of GLP-1 not only augments glucose-stimulated insulin secretion, but also shifts the dynamics of the insulin response to earlier release in both diabetic and nondiabetic humans. The restitution of some FPIR in subjects with type 2 diabetes is associated with significantly improved glucose tolerance. These findings demonstrate the benefits of a 3-h infusion of GLP-1 on beta-cell function beyond those of an acute insulin secretagogue, and support the development of strategies using continuous or prolonged GLP-1 receptor agonism for treating diabetic patients. SN - 0149-5992 UR - https://www.unboundmedicine.com/medline/citation/12610039/Differential_effects_of_acute_and_extended_infusions_of_glucagon_like_peptide_1_on_first__and_second_phase_insulin_secretion_in_diabetic_and_nondiabetic_humans_ DB - PRIME DP - Unbound Medicine ER -