Exendin-4, but not dipeptidyl peptidase IV inhibition, increases small intestinal mass in GK rats

Simonsen, Lotte; Pilgaard, S.; Ørskov, Cathrine; Hartmann, Bolette; Holst, Jens J.; Deacon, Carolyn F.

doi:10.1152/ajpgi.00453.2006

Cited by 43 publications

(44 citation statements)

References 40 publications

(34 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also found that the hyperglycemic effect is adaptable in GK rats and chronic exposure of exendin-4 by osmotic pump decreased blood glucose compared with saline-treated controls (W. Gao and W. J. Jusko, unpublished data), consistent with the beneficial glycemic effects from chronic administration in rats (Xu et al, 1999;Simonsen et al, 2007).…”

Section: Pk/pd Modeling Of Exendin-4 In Goto-kakizaki Ratssupporting

confidence: 75%

Pharmacokinetic and Pharmacodynamic Modeling of Exendin-4 in Type 2 Diabetic Goto-Kakizaki Rats

Gao

Jusko²

2010

J Pharmacol Exp Ther

View full text Add to dashboard Cite

The pharmacokinetics (PK) and pharmacodynamics (PD) of exendin-4 were studied in type 2 diabetic Goto-Kakizaki rats after single doses at 0.5, 1, 5, or 10 g/kg by intravenous administration and 5 g/kg by subcutaneous administration. Plasma exendin-4, glucose, and insulin concentrations were determined. A target-mediated drug disposition model was used to characterize the PK of exendin-4. Glucose turnover was described by an indirect response model, with insulin stimulating glucose disposition. Insulin turnover was characterized by an indirect response model with a precursor compartment. After intravenous doses, exendin-4 rapidly disappeared from the circulation, whereas it exhibited rapid absorption (T max ϭ 15-20 min) and incomplete bioavailability (F ϭ 0.51) after the subcutaneous dose. Exendin-4 increased insulin release at 2 to 5 min with capacity S max ϭ 6.91 and sensitivity SC 50 ϭ 1.29 nM, followed by a rebound at 10 to 15 min and a slow return to the baseline. Glucose initially declined because of enhanced insulin secretion, and then gradually increased because of the activation of the neural system by exendin-4. The hyperglycemic action was modeled with increased hepatic glucose production with a linear factor S RC ϭ 0.112 1/nM. The mechanistic PK/PD model satisfactorily described the disposition and effects of exendin-4 on glucose and insulin homeostasis in type 2 diabetic rats.

show abstract

Section: Pk/pd Modeling Of Exendin-4 In Goto-kakizaki Ratssupporting

confidence: 75%

Pharmacokinetic and Pharmacodynamic Modeling of Exendin-4 in Type 2 Diabetic Goto-Kakizaki Rats

Gao

Jusko²

2010

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…3G). However, the actions of Ex-4 to increase small bowel mass (22) were not diminished in rapamycin-treated mice (Fig. 3F).…”

Section: Resultsmentioning

confidence: 91%

Glucagon-Like Peptide-1 Receptor Agonists Increase Pancreatic Mass by Induction of Protein Synthesis

et al. 2014

View full text Add to dashboard Cite

Glucagon-like peptide-1 (GLP-1) controls glucose homeostasis by regulating secretion of insulin and glucagon through a single GLP-1 receptor (GLP-1R). GLP-1R agonists also increase pancreatic weight in some preclinical studies through poorly understood mechanisms. Here we demonstrate that the increase in pancreatic weight following activation of GLP-1R signaling in mice reflects an increase in acinar cell mass, without changes in ductal compartments or β-cell mass. GLP-1R agonists did not increase pancreatic DNA content or the number of Ki67+ cells in the exocrine compartment; however, pancreatic protein content was increased in mice treated with exendin-4 or liraglutide. The increased pancreatic mass and protein content was independent of cholecystokinin receptors, associated with a rapid increase in S6 phosphorylation, and mediated through the GLP-1R. Rapamycin abrogated the GLP-1R–dependent increase in pancreatic mass but had no effect on the robust induction of Reg3α and Reg3β gene expression. Mass spectrometry analysis identified GLP-1R–dependent upregulation of Reg family members, as well as proteins important for translation and export, including Fam129a, eIF4a1, Wars, and Dmbt1. Hence, pharmacological GLP-1R activation induces protein synthesis, leading to increased pancreatic mass, independent of changes in DNA content or cell proliferation in mice.

show abstract

“…In fact, Ex-4, at a high concentration (10 À7 M), unlike GLP-1, moderately increased the cellular cAMP content in MC3T3-E1 cells; and although it induced the hydrolysis of GPIs, its effect was somewhat delayed by respect to that of GLP-1. In addition, previous reports have shown that Ex-4 does not act as an agonist of GLP-1 in some situations, where its effects are not mimicked by GLP-1 or dipeptidyl-peptidase 4 inhibitors, neither by Ex-9 (Pérez-Tilve et al, 2007;Simonsen et al, 2007).…”

Section: Discussionmentioning

confidence: 98%

Presence of a functional receptor for GLP‐1 in osteoblastic cells, independent of the cAMP‐linked GLP‐1 receptor

Nuche-Berenguer

Portal‐Núñez

Moreno

et al. 2010

Journal Cellular Physiology

127

View full text Add to dashboard Cite

Glucagon-like peptide 1 (GLP-1) controls glucose metabolism in extrapancreatic tissues through receptors other than the pancreatic cAMP-linked GLP-1 receptor; also, GLP-1 induces an insulin- and PTH-independent bone anabolic action in insulin-resistant and type-2 diabetic rats. Here we searched for the presence and characteristics of GLP-1 receptors in osteoblastic MC3T3-E1 cells. [(125)I]-GLP-1 specific binding to MC3T3-E1 cells was time- and temperature-dependent, reaching maximal value at 30 min at 25 degrees C; in these conditions, [(125)I]-GLP-1 binding was dissociable, and displaced by GLP-1, partially by GLP-2, but not by exendin-4 (Ex-4), exendin-9 (Ex-9), glucagon or insulin; Scatchard analysis of the unlabeled GLP-1 data showed high and low affinity binding sites; cross-linking of GLP-1 binding revealed an estimated 70 kDa band, almost undetectable in the presence of 10(-6) M GLP-1. GLP-1, Ex-9, insulin or glucagon failed to modify cellular cAMP content, while GLP-2 and Ex-4 increased it. However, GLP-1 induced an immediate hydrolysis of glycosylphosphatidylinositols (GPIs) generating short-lived inositolphosphoglycans (IPGs), and an increase in phosphatidylinositol-3 kinase (PI3K) and mitogen activated protein kinase (MAPK) activities; Ex-4 also affected GPIs, but its action was delayed with respect to that of GLP-1. This incretin was found to decrease Runx2 but increased osteocalcin gene expression, without affecting that of osteoprotegerin or the canonical Wnt pathway activity in MC3T3-E1 cells which do not express the pancreatic GLP-1 receptor. Our data demonstrate for the first time that GLP-1 can directly and functionally interact with osteoblastic cells, possibly through a GPI/IPG-coupled receptor.

show abstract

Exendin-4, but not dipeptidyl peptidase IV inhibition, increases small intestinal mass in GK rats

Cited by 43 publications

References 40 publications

Pharmacokinetic and Pharmacodynamic Modeling of Exendin-4 in Type 2 Diabetic Goto-Kakizaki Rats

Pharmacokinetic and Pharmacodynamic Modeling of Exendin-4 in Type 2 Diabetic Goto-Kakizaki Rats

Glucagon-Like Peptide-1 Receptor Agonists Increase Pancreatic Mass by Induction of Protein Synthesis

Presence of a functional receptor for GLP‐1 in osteoblastic cells, independent of the cAMP‐linked GLP‐1 receptor

Contact Info

Product

Resources

About