scholarly journals Mechanisms Underlying Metformin-Induced Secretion of Glucagon-Like Peptide-1 from the Intestinal L Cell

Endocrinology ◽  
2011 ◽  
Vol 152 (12) ◽  
pp. 4610-4619 ◽  
Author(s):  
Andrew J. Mulherin ◽  
Amy H. Oh ◽  
Helena Kim ◽  
Anthony Grieco ◽  
Lina M. Lauffer ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Neural Stimulation ◽  
Amp Kinase ◽  
Dipeptidylpeptidase Iv ◽  
L Cell ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Kinase Phosphorylation ◽  
Plasma Activity

Glucagon-like peptide-17-36NH2 (GLP-1) is secreted by the intestinal L cell in response to both nutrient and neural stimulation, resulting in enhanced glucose-dependent insulin secretion. GLP-1 is therefore an attractive therapeutic for the treatment of type 2 diabetes. The antidiabetic drug, metformin, is known to increase circulating GLP-1 levels, although its mechanism of action is unknown. Direct effects of metformin (5–2000 μm) or another AMP kinase activator, aminoimidazole carboxamide ribonucleotide (100–1000 μm) on GLP-1 secretion were assessed in murine human NCI-H716, and rat FRIC L cells. Neither agent stimulated GLP-1 secretion in any model, despite increasing AMP kinase phosphorylation (P < 0.05–0.01). Treatment of rats with metformin (300 mg/kg, per os) or aminoimidazole carboxamide ribonucleotide (250 mg/kg, sc) increased plasma total GLP-1 over 2 h, reaching 37 ± 9 and 29 ± 9 pg/ml (P < 0.001), respectively, compared with basal (7 ± 1 pg/ml). Plasma activity of the GLP-1-degrading enzyme, dipeptidylpeptidase-IV, was not affected by metformin treatment. Pretreatment with the nonspecific muscarinic antagonist, atropine (1 mg/kg, iv), decreased metformin-induced GLP-1 secretion by 55 ± 11% (P < 0.05). Pretreatment with the muscarinic (M) 3 receptor antagonist, 1-1-dimethyl-4-diphenylacetoxypiperidinium iodide (500 μg/kg, iv), also decreased the GLP-1 area under curve, by 48 ± 8% (P < 0.05), whereas the antagonists pirenzepine (M1) and gallamine (M2) had no effect. Furthermore, chronic bilateral subdiaphragmatic vagotomy decreased basal secretion compared with sham-operated animals (7 ± 1 vs. 13 ± 1 pg/ml, P < 0.001) but did not alter the GLP-1 response to metformin. In contrast, pretreatment with the gastrin-releasing peptide antagonist, RC-3095 (100 μg/kg, sc), reduced the GLP-1 response to metformin, by 55 ± 6% (P < 0.01) at 30 min. These studies elucidate the mechanism underlying metformin-induced GLP-1 secretion and highlight the benefits of using metformin with dipeptidylpeptidase-IV inhibitors in patients with type 2 diabetes.

scholarly journals Novel Biological Action of the Dipeptidylpeptidase-IV Inhibitor, Sitagliptin, as a Glucagon-Like Peptide-1 Secretagogue

Endocrinology ◽  
2012 ◽  
Vol 153 (2) ◽  
pp. 564-573 ◽  
Author(s):  
Ganesh V. Sangle ◽  
Lina M. Lauffer ◽  
Anthony Grieco ◽  
Shivangi Trivedi ◽  
Roman Iakoubov ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Fold Increase ◽  
Dipeptidylpeptidase Iv ◽  
L Cells ◽  
L Cell ◽  
Dpp Iv ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted into the circulation by the intestinal L cell. The dipeptidylpeptidase-IV (DPP-IV) inhibitor, sitagliptin, prevents GLP-1 degradation and is used in the clinic to treat patients with type 2 diabetes mellitus, leading to improved glycated hemoglobin levels. When the effect of sitagliptin on GLP-1 levels was examined in neonatal streptozotocin rats, a model of type 2 diabetes mellitus, a 4.9 ± 0.9-fold increase in basal and 3.6 ± 0.4-fold increase in oral glucose-stimulated plasma levels of active GLP-1 was observed (P < 0.001), in association with a 1.5 ± 0.1-fold increase in the total number of intestinal L cells (P < 0.01). The direct effects of sitagliptin on GLP-1 secretion and L cell signaling were therefore examined in murine GLUTag (mGLUTag) and human hNCI-H716 intestinal L cells in vitro. Sitagliptin (0.1–2 μm) increased total GLP-1 secretion by mGLUTag and hNCI-H716 cells (P < 0.01–0.001). However, MK0626 (1–50 μm), a structurally unrelated inhibitor of DPP-IV, did not affect GLP-1 secretion in either model. Treatment of mGLUTag cells with the GLP-1 receptor agonist, exendin-4, did not modulate GLP-1 release, indicating the absence of feedback effects of GLP-1 on the L cell. Sitagliptin increased cAMP levels (P < 0.01) and ERK1/2 phosphorylation (P < 0.05) in both mGLUTag and hNCI-H716 cells but did not alter either intracellular calcium or phospho-Akt levels. Pretreatment of mGLUTag cells with protein kinase A (H89 and protein kinase inhibitor) or MAPK kinase-ERK1/2 (PD98059 and U0126) inhibitors prevented sitagliptin-induced GLP-1 secretion (P < 0.05–0.01). These studies demonstrate, for the first time, that sitagliptin exerts direct, DPP-IV-independent effects on intestinal L cells, activating cAMP and ERK1/2 signaling and stimulating total GLP-1 secretion.

Efficacy of dapagliflozin in combination therapy with the glucagon-like peptide-1 analog in obese patients with type 2 diabetes

2015 ◽  
Vol 2 (e1) ◽  
pp. 008-008
Author(s):  
Momoko Isono ◽  
Kazuya Fujihara ◽  
Shoko Furukawa ◽  
Ryo Kumagai ◽  
Hiroaki Yagyu
Keyword(s):  
Type 2 Diabetes ◽  
Combination Therapy ◽  
Obese Patients ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Patient-Reported Outcomes following Initiation of Glucagon-Like Peptide-1 Receptor AgonistS (GLP–1RA) in PatientS with Type 2 Diabetes—PROGRESS-DIABETES Study

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 1096-P
Author(s):  
RUTH E. BROWN ◽  
ALEXANDER ABITBOL ◽  
HARPREET S. BAJAJ ◽  
HASNAIN KHANDWALA ◽  
RONALD GOLDENBERG ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Patient Reported Outcomes ◽  
Receptor Agonists ◽  
Patient Reported ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-Like Peptide-1 Is a Significant Determinant of the Second-Meal Effect in Patients with Type 2 Diabetes

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 1963-P
Author(s):  
SIGRID BERGMANN ◽  
NATASHA C. BERGMANN ◽  
LÆRKE S. GASBJERG ◽  
JENS J. HOLST ◽  
TINA VILSBØLL ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Significant Determinant ◽  
Meal Effect ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

1019-P: Glucagon-Like Peptide-1 Receptor Agonists Predominantly Reduce Body Fat Mass in Patients with Type 2 Diabetes

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 1019-P
Author(s):  
YUKI FUJITA ◽  
SODAI KUBOTA ◽  
HITOSHI KUWATA ◽  
DAISUKE YABE ◽  
YOSHIYUKI HAMAMOTO ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Body Fat ◽  
Fat Mass ◽  
Body Fat Mass ◽  
Receptor Agonists ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 agonist therapy in patients with diabetes mellitus and obesity

2020 ◽  
Vol 98 (3) ◽  
pp. 210-217
Author(s):  
A. Yu. Babenko ◽  
Yu. A. Kononova ◽  
M. V. Martjanova ◽  
A. V. Simanenkova ◽  
M. A. Kokina ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Hba1c Level ◽  
High Efficiency ◽  
Receptor Agonists ◽  
Predictors Of Response ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Lipids Metabolism

Due to the high efficiency of glucagon-like peptide-1 (GLP-1) receptor agonists therapy in only a part of patients, the search for predictors of response to the treatment is a relevant problem. Purpose. The purpose is to compare the efficacy of liraglutide and exenatide therapy in obese patients with type 2 diabetes mellitus (T2DM) and to evaluate the predictors of response to glycated hemoglobin (HbA1c), weight and lipids reduction. Material and methods. The study included 47 patients with type 2 diabetes and obesity who received GLP-1 receptor agonists therapy. 26 patients were treated with liraglutide, 21 patients were treated with exenatide. We measured the parameters of carbohydrate and lipid metabolism, the levels of hormones involved in glucose and lipids metabolism and in appetite regulation. Blood pressure was measured. These parameters were evaluated at baseline and after 24 weeks of treatment. Results. Patients receiving exenatide therapy showed a tendency towards more frequent HbA1c level reduction by 1% or more (60% versus 30.4%, p = 0.07). The effects of liraglutide and exenatide on weight and waist circumference were comparable. When assessing the predictors of response to the therapy, a more pronounced decrease in HbA1c level (by 1% or more) was in the patients with a higher initial HbA1c level (8.7 (8.2; 9.7) versus 8.2 (6.9; 8.7)%, p = 0.04), as well as with a higher initial GLP-1 level (0.12 (0.05; 0.17) versus 0.040 (0.01; 0.09) ng/ml.) A more significant decrease in the triglycerides (TG) level was detected in patients with a higher level of glucose-dependent insulinotropic peptide (GIP) before therapy (409 (316.0; 431.4) pg/ml in patients who reduced TG level by 30% or more and 331.5 (324.9; 367.1) pg/ml in patients with a lower decrease in TG level). Among the studied parameters, no predictors of body mass reduction were revealed. Conclusion. Measurement of HbA1c, GLP-1, GIP level may be useful to predict the efficacy of GLP-1 receptor agonists therapy.

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