Inhibition of DPP-4 with vildagliptin improved insulin secretion in response to oral as well as "isoglycemic" intravenous glucose without numerically changing the incretin effect in patients with type 2 diabetes

Irfan Vardarli; Michael A Nauck; Lars D Köthe; Carolyn F Deacon; Jens Juul Holst; Anja Schweizer; James E Foley

doi:10.1210/jc.2010-2178

Inhibition of DPP-4 with vildagliptin improved insulin secretion in response to oral as well as "isoglycemic" intravenous glucose without numerically changing the incretin effect in patients with type 2 diabetes

Irfan Vardarli, Michael A Nauck, Lars D Köthe, Carolyn F Deacon, Jens Juul Holst, Anja Schweizer, James E Foley

Endocrinology and Metabolism

43 Citationer (Scopus)

Abstract

Background and Aims: Dipeptidyl peptidase-4 (DPP-4) inhibitors block the degradation of glucagon- like peptide-1 and glucose-dependent insulinotropic polypeptide. The aim of the present study was to quantitatively assess the incretin effect after treatment with the DPP-4 inhibitor vildagliptin (V) or placebo (P) in patients with type 2 diabetes. Materials and Methods: Twenty-one patients (three women, 18 men) with type 2 diabetes previously treated with metformin (mean age, 59 yr; body mass index, 28.6 kg/m2; glycosylated hemoglobin, 7.3%) were studied in a two-period crossover design. They received 100 mg V once daily or P for 13 d in randomized order. The incretin effect was measured on d 12 (75-g oral glucose) and d 13 ("isoglycemic" iv glucose) based on insulin and C-peptide determinations and insulin secretion rates (ISR). Results: V relative to P treatment significantly increased intact incretin concentrations after oral glucose and insulin secretory responses to both oral glucose and isoglycemic iv glucose (e.g.AUCISR oral, by 32.7%, P=0.0006; AUCISR iv, by 33.1%, P=0.01). The numerical incretin effect was not changed (IEISR, V vs. P, 35.7 ± 4.9 and 34.6 ± 4.0%, P = 0.80). Conclusions: DPP-4 inhibition augmented insulin secretory responses both after oral glucose and during isoglycemic iv glucose infusions, with no net change in the incretin effect. Thus, slight variations in basal incretin levels may be more important than previously thought. Or, DPP-4 inhibitor-induced change in the incretin-related environment of islets may persist overnight, augmenting insulin secretory responses to iv glucose as well. Alternatively, yet unidentified mediators of DPP-4 inhibition may have caused these effects.

Originalsprog	Engelsk
Tidsskrift	Journal of Clinical Endocrinology and Metabolism
Vol/bind	96
Udgave nummer	4
Sider (fra-til)	945-954
Antal sider	10
ISSN	0021-972X
DOI	https://doi.org/10.1210/jc.2010-2178
Status	Udgivet - apr. 2011

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Citationsformater

Vardarli, I., Nauck, M. A., Köthe, L. D., Deacon, C. F., Holst, J. J., Schweizer, A., & Foley, J. E. (2011). Inhibition of DPP-4 with vildagliptin improved insulin secretion in response to oral as well as "isoglycemic" intravenous glucose without numerically changing the incretin effect in patients with type 2 diabetes. Journal of Clinical Endocrinology and Metabolism, 96(4), 945-954. https://doi.org/10.1210/jc.2010-2178

Inhibition of DPP-4 with vildagliptin improved insulin secretion in response to oral as well as "isoglycemic" intravenous glucose without numerically changing the incretin effect in patients with type 2 diabetes. / Vardarli, Irfan; Nauck, Michael A; Köthe, Lars D et al.

I: Journal of Clinical Endocrinology and Metabolism, Bind 96, Nr. 4, 04.2011, s. 945-954.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Vardarli, I, Nauck, MA, Köthe, LD, Deacon, CF , Holst, JJ, Schweizer, A & Foley, JE 2011, 'Inhibition of DPP-4 with vildagliptin improved insulin secretion in response to oral as well as "isoglycemic" intravenous glucose without numerically changing the incretin effect in patients with type 2 diabetes', Journal of Clinical Endocrinology and Metabolism, bind 96, nr. 4, s. 945-954. https://doi.org/10.1210/jc.2010-2178

Vardarli I, Nauck MA, Köthe LD, Deacon CF , Holst JJ, Schweizer A et al. Inhibition of DPP-4 with vildagliptin improved insulin secretion in response to oral as well as "isoglycemic" intravenous glucose without numerically changing the incretin effect in patients with type 2 diabetes. Journal of Clinical Endocrinology and Metabolism. 2011 apr.;96(4):945-954. doi: 10.1210/jc.2010-2178

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title = "Inhibition of DPP-4 with vildagliptin improved insulin secretion in response to oral as well as {"}isoglycemic{"} intravenous glucose without numerically changing the incretin effect in patients with type 2 diabetes",

abstract = "Background and Aims: Dipeptidyl peptidase-4 (DPP-4) inhibitors block the degradation of glucagon- like peptide-1 and glucose-dependent insulinotropic polypeptide. The aim of the present study was to quantitatively assess the incretin effect after treatment with the DPP-4 inhibitor vildagliptin (V) or placebo (P) in patients with type 2 diabetes. Materials and Methods: Twenty-one patients (three women, 18 men) with type 2 diabetes previously treated with metformin (mean age, 59 yr; body mass index, 28.6 kg/m2; glycosylated hemoglobin, 7.3%) were studied in a two-period crossover design. They received 100 mg V once daily or P for 13 d in randomized order. The incretin effect was measured on d 12 (75-g oral glucose) and d 13 ({"}isoglycemic{"} iv glucose) based on insulin and C-peptide determinations and insulin secretion rates (ISR). Results: V relative to P treatment significantly increased intact incretin concentrations after oral glucose and insulin secretory responses to both oral glucose and isoglycemic iv glucose (e.g.AUCISR oral, by 32.7%, P=0.0006; AUCISR iv, by 33.1%, P=0.01). The numerical incretin effect was not changed (IEISR, V vs. P, 35.7 ± 4.9 and 34.6 ± 4.0%, P = 0.80). Conclusions: DPP-4 inhibition augmented insulin secretory responses both after oral glucose and during isoglycemic iv glucose infusions, with no net change in the incretin effect. Thus, slight variations in basal incretin levels may be more important than previously thought. Or, DPP-4 inhibitor-induced change in the incretin-related environment of islets may persist overnight, augmenting insulin secretory responses to iv glucose as well. Alternatively, yet unidentified mediators of DPP-4 inhibition may have caused these effects.",

keywords = "Adamantane, Administration, Oral, Adult, Aged, Blood Glucose, Cross-Over Studies, Diabetes Mellitus, Type 2, Dipeptidyl Peptidase 4, Dipeptidyl-Peptidase IV Inhibitors, Female, Glucose, Humans, Incretins, Injections, Intravenous, Insulin, Male, Middle Aged, Nitriles, Pyrrolidines, Up-Regulation",

author = "Irfan Vardarli and Nauck, {Michael A} and K{\"o}the, {Lars D} and Deacon, {Carolyn F} and Holst, {Jens Juul} and Anja Schweizer and Foley, {James E}",

year = "2011",

month = apr,

doi = "10.1210/jc.2010-2178",

language = "English",

volume = "96",

pages = "945--954",

journal = "Journal of Clinical Endocrinology and Metabolism",

issn = "0021-972X",

publisher = "Oxford University Press",

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}

TY - JOUR

T1 - Inhibition of DPP-4 with vildagliptin improved insulin secretion in response to oral as well as "isoglycemic" intravenous glucose without numerically changing the incretin effect in patients with type 2 diabetes

AU - Vardarli, Irfan

AU - Nauck, Michael A

AU - Köthe, Lars D

AU - Deacon, Carolyn F

AU - Holst, Jens Juul

AU - Schweizer, Anja

AU - Foley, James E

PY - 2011/4

Y1 - 2011/4

N2 - Background and Aims: Dipeptidyl peptidase-4 (DPP-4) inhibitors block the degradation of glucagon- like peptide-1 and glucose-dependent insulinotropic polypeptide. The aim of the present study was to quantitatively assess the incretin effect after treatment with the DPP-4 inhibitor vildagliptin (V) or placebo (P) in patients with type 2 diabetes. Materials and Methods: Twenty-one patients (three women, 18 men) with type 2 diabetes previously treated with metformin (mean age, 59 yr; body mass index, 28.6 kg/m2; glycosylated hemoglobin, 7.3%) were studied in a two-period crossover design. They received 100 mg V once daily or P for 13 d in randomized order. The incretin effect was measured on d 12 (75-g oral glucose) and d 13 ("isoglycemic" iv glucose) based on insulin and C-peptide determinations and insulin secretion rates (ISR). Results: V relative to P treatment significantly increased intact incretin concentrations after oral glucose and insulin secretory responses to both oral glucose and isoglycemic iv glucose (e.g.AUCISR oral, by 32.7%, P=0.0006; AUCISR iv, by 33.1%, P=0.01). The numerical incretin effect was not changed (IEISR, V vs. P, 35.7 ± 4.9 and 34.6 ± 4.0%, P = 0.80). Conclusions: DPP-4 inhibition augmented insulin secretory responses both after oral glucose and during isoglycemic iv glucose infusions, with no net change in the incretin effect. Thus, slight variations in basal incretin levels may be more important than previously thought. Or, DPP-4 inhibitor-induced change in the incretin-related environment of islets may persist overnight, augmenting insulin secretory responses to iv glucose as well. Alternatively, yet unidentified mediators of DPP-4 inhibition may have caused these effects.

AB - Background and Aims: Dipeptidyl peptidase-4 (DPP-4) inhibitors block the degradation of glucagon- like peptide-1 and glucose-dependent insulinotropic polypeptide. The aim of the present study was to quantitatively assess the incretin effect after treatment with the DPP-4 inhibitor vildagliptin (V) or placebo (P) in patients with type 2 diabetes. Materials and Methods: Twenty-one patients (three women, 18 men) with type 2 diabetes previously treated with metformin (mean age, 59 yr; body mass index, 28.6 kg/m2; glycosylated hemoglobin, 7.3%) were studied in a two-period crossover design. They received 100 mg V once daily or P for 13 d in randomized order. The incretin effect was measured on d 12 (75-g oral glucose) and d 13 ("isoglycemic" iv glucose) based on insulin and C-peptide determinations and insulin secretion rates (ISR). Results: V relative to P treatment significantly increased intact incretin concentrations after oral glucose and insulin secretory responses to both oral glucose and isoglycemic iv glucose (e.g.AUCISR oral, by 32.7%, P=0.0006; AUCISR iv, by 33.1%, P=0.01). The numerical incretin effect was not changed (IEISR, V vs. P, 35.7 ± 4.9 and 34.6 ± 4.0%, P = 0.80). Conclusions: DPP-4 inhibition augmented insulin secretory responses both after oral glucose and during isoglycemic iv glucose infusions, with no net change in the incretin effect. Thus, slight variations in basal incretin levels may be more important than previously thought. Or, DPP-4 inhibitor-induced change in the incretin-related environment of islets may persist overnight, augmenting insulin secretory responses to iv glucose as well. Alternatively, yet unidentified mediators of DPP-4 inhibition may have caused these effects.

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KW - Administration, Oral

KW - Adult

KW - Aged

KW - Blood Glucose

KW - Cross-Over Studies

KW - Diabetes Mellitus, Type 2

KW - Dipeptidyl Peptidase 4

KW - Dipeptidyl-Peptidase IV Inhibitors

KW - Female

KW - Glucose

KW - Humans

KW - Incretins

KW - Injections, Intravenous

KW - Insulin

KW - Male

KW - Middle Aged

KW - Nitriles

KW - Pyrrolidines

KW - Up-Regulation

U2 - 10.1210/jc.2010-2178

DO - 10.1210/jc.2010-2178

M3 - Journal article

C2 - 21239518

SN - 0021-972X

VL - 96

SP - 945

EP - 954

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 4

ER -