High-Level Expression of the GLP-I Receptor Results in Receptor Desensitization

Fehmann, Hans-Christoph; Pracht, Anne; Göke, Burkhard

doi:10.1097/00006676-199810000-00014

Cited by 8 publications

(4 citation statements)

References 18 publications

(20 reference statements)

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“…The minor variances in responsiveness obtained with the different receptors likely can be explained largely by potential differences in the density of receptor expression in the cell lines used. 59 In summary, the findings of the present study provide evidence for an essential role of GLP-2 in maintaining intestinal structure in the fed state, as well as during adaptation in response to nutrient deprivation and sub-sequent refeeding. Because no model of GLP-2 or GLP-2R deficiency is available, the characterization of GLP-2 as a GLP-2R antagonist provides a useful experimental reagent by which the physiologic roles of GLP-2 may be explored in other models of intestinal growth or insufficiency.…”

Section: Discussionsupporting

confidence: 60%

Mucosal Adaptation to Enteral Nutrients is Dependent on the Physiologic Actions of Glucagon-Like Peptide-2 in Mice

et al. 2005

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Section: Discussionsupporting

confidence: 60%

Mucosal Adaptation to Enteral Nutrients is Dependent on the Physiologic Actions of Glucagon-Like Peptide-2 in Mice

et al. 2005

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“…In the case of GLP-1, it has been shown in vitro that overexpression of GLP-1R can lead to desensitization (33). In view of the marked improvement in control of glucose homeostasis in this rat model following stabilization of GLP-1 action, one can hypothesize that an increased pancreatic GLP-1R population can be considered a positive factor.…”

Section: Discussionmentioning

confidence: 90%

Chronic Inhibition of Circulating Dipeptidyl Peptidase IV by FE 999011 Delays the Occurrence of Diabetes in Male Zucker Diabetic Fatty Rats

et al. 2002

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Acute suppression of dipeptidyl peptidase IV (DPP-IV) activity improves glucose tolerance in the Zucker fatty rat, a rodent model of impaired glucose tolerance, through stabilization of glucagon-like peptide (GLP)-1. This study describes the effects of a new and potent DPP-IV inhibitor, FE 999011, which is able to suppress plasma DPP-IV activity for 12 h after a single oral administration. In the Zucker fatty rat, FE 999011 dose-dependently attenuated glucose excursion during an oral glucose tolerance test and increased GLP-1(7-36) release in response to intraduodenal glucose. Chronic treatment with FE 999011 (10 mg/kg, twice a day for 7 days) improved glucose tolerance, as suggested by a decrease in the insulin-to-glucose ratio. In the Zucker diabetic fatty (ZDF) rat, a rodent model of type 2 diabetes, chronic treatment with FE 999011 (10 mg/kg per os, once or twice a day) postponed the development of diabetes, with the twice-a-day treatment delaying the onset of hyperglycemia by 21 days. In addition, treatment with FE 999011 stabilized food and water intake to prediabetic levels and reduced hypertriglyceridemia while preventing the rise in circulating free fatty acids. At the end of treatment, basal plasma GLP-1 levels were increased, and pancreatic gene expression for GLP-1 receptor was significantly upregulated. This study demonstrates that DPP-IV inhibitors such as FE 999011 could be of clinical value to delay the progression from impaired glucose tolerance to type 2 diabetes.

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“…This decrease in cAMP production could be a result of homologous or heterologous receptor desensitization with increased expression of transfected receptor. Use of another GLP-1R-negative cell line, the Chinese hamster ovary cells (CHO), demonstrated that cells expressing the greatest number of transfected GLP-1Rs exhibited desensitization (Fehmann et al 1998). This suggests that a threshold for functional receptor expression exists.…”

Section: Discussionmentioning

confidence: 99%

Exogenous expression of glucagon-like peptide 1 receptor and human insulin in AtT-20 corticotrophs confers cAMP-mediated gene transcription and insulin secretion

Sidhu¹,

Fowkes²,

Skelly³

et al. 2005

Journal of Endocrinology

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The insulinotrophic effects of glucagon-like peptide 1 (GLP-1) are mediated by its seven-transmembrane receptor (GLP-1R) in pancreatic -cells. We have transiently transfected the GLP-1R and a proopiomelanocortin (POMC) promoter-driven human preproinsulin gene vector (pIRES) into the AtT-20 pituitary corticotrophic cell line, to investigate the possibility of creating a regulated, insulin-expressing cell line. Receptor expression was confirmed by RT-PCR and functionality was demonstrated by measuring changes in cAMP levels in response to GLP-1. Rapid (5 min) stimulation of cAMP production was observed with 100 nM GLP-1, 24 h after transfection of 2 µg GLP-1R DNA. AtT-20 cells co-transfected with GLP-1R and human glycoprotein hormone -subunit or rat POMC promoters revealed GLP-1-stimulated cAMP activation of transcription. Co-transfection of the pIRES vector with the GLP-1R resulted in GLP-1-stimulated activation of POMC promoter-driven preproinsulin gene transcription but insulin secretion was not detected. However, using an adenoviral expression system to infect AtT-20 cells with GLP-1R and the preproinsulin gene (including 120 bp of its own promoter) resulted in a 6·4 0·6-fold increase in cAMP and a 4·9 0·8-fold increase in insulin secretion in response to 100 nM GLP-1. These results demonstrate, for the first time, functional GLP-1R-mediated preproinsulin gene transcription and secretion in a transplantable cell line.

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High-Level Expression of the GLP-I Receptor Results in Receptor Desensitization

Cited by 8 publications

References 18 publications

Mucosal Adaptation to Enteral Nutrients is Dependent on the Physiologic Actions of Glucagon-Like Peptide-2 in Mice

Mucosal Adaptation to Enteral Nutrients is Dependent on the Physiologic Actions of Glucagon-Like Peptide-2 in Mice

Chronic Inhibition of Circulating Dipeptidyl Peptidase IV by FE 999011 Delays the Occurrence of Diabetes in Male Zucker Diabetic Fatty Rats

Exogenous expression of glucagon-like peptide 1 receptor and human insulin in AtT-20 corticotrophs confers cAMP-mediated gene transcription and insulin secretion

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