Physiological and pharmacological mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice
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Physiological and pharmacological mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice. / Waget, Aurélie; Cabou, Cendrine; Masseboeuf, Myriam; Cattan, Pierre; Armanet, Mattieu; Karaca, Mélis; Castel, Julien; Garret, Celine; Payros, Gaëlle; Maida, Adriano; Sulpice, Thierry; Holst, Jens Juul; Drucker, Daniel J; Magnan, Christophe; Burcelin, Rémy.
In: Endocrinology, Vol. 152, No. 8, 08.2011, p. 3018-3029.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Physiological and pharmacological mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice
AU - Waget, Aurélie
AU - Cabou, Cendrine
AU - Masseboeuf, Myriam
AU - Cattan, Pierre
AU - Armanet, Mattieu
AU - Karaca, Mélis
AU - Castel, Julien
AU - Garret, Celine
AU - Payros, Gaëlle
AU - Maida, Adriano
AU - Sulpice, Thierry
AU - Holst, Jens Juul
AU - Drucker, Daniel J
AU - Magnan, Christophe
AU - Burcelin, Rémy
PY - 2011/8
Y1 - 2011/8
N2 - Inhibition of dipeptidyl peptidase-4 (DPP-4) activity improves glucose homeostasis through a mode of action related to the stabilization of the active forms of DPP-4-sensitive hormones such as the incretins that enhance glucose-induced insulin secretion. However, the DPP-4 enzyme is highly expressed on the surface of intestinal epithelial cells; hence, the role of intestinal vs. systemic DPP-4 remains unclear. To analyze mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice, we administered low oral doses of the DPP-4 inhibitor sitagliptin that selectively reduced DPP-4 activity in the intestine. Glp1r(-/-) and Gipr(-/-) mice were studied and glucagon-like peptide (GLP)-1 receptor (GLP-1R) signaling was blocked by an i.v. infusion of the corresponding receptor antagonist exendin (9-39). The role of the dipeptides His-Ala and Tyr-Ala as DPP-4-generated GLP-1 and glucose-dependent insulinotropic peptide (GIP) degradation products was studied in vivo and in vitro on isolated islets. We demonstrate that very low doses of oral sitagliptin improve glucose tolerance and plasma insulin levels with selective reduction of intestinal but not systemic DPP-4 activity. The glucoregulatory action of sitagliptin was associated with increased vagus nerve activity and was diminished in wild-type mice treated with the GLP-1R antagonist exendin (9-39) and in Glp1r(-/-) and Gipr(-/-) mice. Furthermore, the dipeptides liberated from GLP-1 (His-Ala) and GIP (Tyr-Ala) deteriorated glucose tolerance, reduced insulin, and increased portal glucagon levels. The predominant mechanism through which DPP-4 inhibitors regulate glycemia involves local inhibition of intestinal DPP-4 activity, activation of incretin receptors, reduced liberation of bioactive dipeptides, and activation of the gut-to-pancreas neural axis.
AB - Inhibition of dipeptidyl peptidase-4 (DPP-4) activity improves glucose homeostasis through a mode of action related to the stabilization of the active forms of DPP-4-sensitive hormones such as the incretins that enhance glucose-induced insulin secretion. However, the DPP-4 enzyme is highly expressed on the surface of intestinal epithelial cells; hence, the role of intestinal vs. systemic DPP-4 remains unclear. To analyze mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice, we administered low oral doses of the DPP-4 inhibitor sitagliptin that selectively reduced DPP-4 activity in the intestine. Glp1r(-/-) and Gipr(-/-) mice were studied and glucagon-like peptide (GLP)-1 receptor (GLP-1R) signaling was blocked by an i.v. infusion of the corresponding receptor antagonist exendin (9-39). The role of the dipeptides His-Ala and Tyr-Ala as DPP-4-generated GLP-1 and glucose-dependent insulinotropic peptide (GIP) degradation products was studied in vivo and in vitro on isolated islets. We demonstrate that very low doses of oral sitagliptin improve glucose tolerance and plasma insulin levels with selective reduction of intestinal but not systemic DPP-4 activity. The glucoregulatory action of sitagliptin was associated with increased vagus nerve activity and was diminished in wild-type mice treated with the GLP-1R antagonist exendin (9-39) and in Glp1r(-/-) and Gipr(-/-) mice. Furthermore, the dipeptides liberated from GLP-1 (His-Ala) and GIP (Tyr-Ala) deteriorated glucose tolerance, reduced insulin, and increased portal glucagon levels. The predominant mechanism through which DPP-4 inhibitors regulate glycemia involves local inhibition of intestinal DPP-4 activity, activation of incretin receptors, reduced liberation of bioactive dipeptides, and activation of the gut-to-pancreas neural axis.
KW - Adult
KW - Animals
KW - Blood Glucose
KW - Dipeptides
KW - Dipeptidyl Peptidase 4
KW - Dipeptidyl-Peptidase IV Inhibitors
KW - Glucagon
KW - Glucose Tolerance Test
KW - Humans
KW - Insulin
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Middle Aged
KW - Pyrazines
KW - Receptors, Gastrointestinal Hormone
KW - Receptors, Glucagon
KW - Triazoles
KW - Vagus Nerve
U2 - 10.1210/en.2011-0286
DO - 10.1210/en.2011-0286
M3 - Journal article
C2 - 21673098
VL - 152
SP - 3018
EP - 3029
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0013-7227
IS - 8
ER -
ID: 38433163