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Physiological and Pharmacological Mechanisms through which the DPP-4 Inhibitor Sitagliptin Regulates Glycemia in Mice
- Source :
- Endocrinology, Endocrinology, Endocrine Society, 2011, 152 (8), pp.3018-29. 〈10.1210/en.2011-0286〉, Endocrinology, 2011, 152 (8), pp.3018-29. ⟨10.1210/en.2011-0286⟩, Endocrinology, Endocrine Society, 2011, 152 (8), pp.3018-29. ⟨10.1210/en.2011-0286⟩
- Publication Year :
- 2011
- Publisher :
- The Endocrine Society, 2011.
-
Abstract
- International audience; 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.
- Subjects :
- MESH : Insulin
medicine.medical_treatment
MESH : Vagus Nerve
MESH : Receptors, Glucagon
0302 clinical medicine
Endocrinology
MESH: Dipeptides
MESH: Vagus Nerve
Glucose homeostasis
MESH: Animals
[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
MESH : Dipeptidyl-Peptidase IV Inhibitors
0303 health sciences
Glucose tolerance test
MESH: Middle Aged
MESH: Dipeptidyl-Peptidase IV Inhibitors
medicine.diagnostic_test
MESH : Glucagon
MESH: Glucagon
digestive, oral, and skin physiology
[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
MESH : Adult
[ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
Glucagon-like peptide-1
3. Good health
MESH : Pyrazines
MESH: Pyrazines
Sitagliptin
hormones, hormone substitutes, and hormone antagonists
medicine.drug
endocrine system
medicine.medical_specialty
MESH: Glucose Tolerance Test
MESH : Male
MESH : Dipeptides
MESH : Receptors, Gastrointestinal Hormone
Incretin
030209 endocrinology & metabolism
MESH: Insulin
MESH : Mice, Inbred C57BL
Biology
Sitagliptin Phosphate
MESH : Glucose Tolerance Test
MESH: Receptors, Glucagon
03 medical and health sciences
MESH: Mice, Inbred C57BL
Internal medicine
MESH : Mice
MESH : Triazoles
medicine
MESH : Middle Aged
MESH: Mice
Dipeptidyl peptidase-4
030304 developmental biology
MESH: Humans
MESH: Receptors, Gastrointestinal Hormone
Insulin
MESH : Humans
MESH: Adult
MESH: Dipeptidyl Peptidase 4
MESH : Blood Glucose
MESH: Male
MESH: Triazoles
MESH : Dipeptidyl Peptidase 4
MESH: Blood Glucose
MESH : Animals
Subjects
Details
- ISSN :
- 19457170 and 00137227
- Volume :
- 152
- Database :
- OpenAIRE
- Journal :
- Endocrinology
- Accession number :
- edsair.doi.dedup.....b1f0300570214f5507362f1065f95366