CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion

2013 ◽  
Vol 304 (8) ◽  
pp. G700-G707 ◽  
Author(s):  
Yuji Nakamura ◽  
Takanori Kanai ◽  
Keita Saeki ◽  
Miho Takabe ◽  
Junichiro Irie ◽  
...  
Keyword(s):  
Cell Migration ◽  
Insulin Secretion ◽  
Chronic Pancreatitis ◽  
Immune Cells ◽  
Receptor Expression ◽  
Wild Type ◽  
Multiple Series ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
The Relationship

Glucagon-like peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b+Gr-1low macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b+/Gr-1− and CD11b+/Gr-1high cells, but not CD11b+/Gr-1low cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic cerulein-administered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b+-cell migration to the pancreas is critically involved in chronic pancreatitis-mediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.

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

2005 ◽  
Vol 187 (3) ◽  
pp. 419-427 ◽  
Author(s):  
K K Sidhu ◽  
R C Fowkes ◽  
R H Skelly ◽  
J M Burrin
Keyword(s):  
Insulin Secretion ◽  
Cell Line ◽  
Gene Transcription ◽  
Expression System ◽  
Fold Increase ◽  
Receptor Expression ◽  
Glycoprotein Hormone ◽  
Α Subunit ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The insulinotrophic effects of glucagon-like peptide 1 (GLP-1) are mediated by its seven-transmembrane receptor (GLP-1R) in pancreatic β-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 α-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.

Evaluation of glucagon-like peptide-1 receptor expression in non-diabetic and diabetic atherosclerotic mice using PET tracer 68Ga-NODAGA-exendin-4

2021 ◽  
Author(s):  
Mia Ståhle ◽  
Sanna Hellberg ◽  
Jenni Virta ◽  
Heidi Liljenbäck ◽  
Olli Metsälä ◽  
...  
Keyword(s):  
Vessel Wall ◽  
Vascular Inflammation ◽  
Tracer Uptake ◽  
Receptor Expression ◽  
Atherosclerotic Lesions ◽  
Pet Tracer ◽  
Positron Emission ◽  
Healthy Control ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Activation of glucagon-like peptide-1 receptor (GLP-1R) signaling attenuates development of atherosclerosis and vascular inflammation. However, the expression of GLP-1R in atherosclerotic arteries remains uncertain. We evaluated whether a positron emission tomography (PET) tracer 68Ga-NODAGA-exendin-4 enables detection and imaging of GLP-1R expression in the mouse atherosclerotic aorta. Hypercholesterolemic (LDLR-/-ApoB100/100), hypercholesterolemic and diabetic (IGF-II/LDLR-/-ApoB100/100) as well as healthy control (C57BL/6N) mice were utilized in the study. The uptake of 68Ga-NODAGA-exendin-4 in atherosclerotic lesions was studied by autoradiography of tissue sections followed by immunofluorescence evaluation of inflammatory and vascular cell markers and GLP-1R. A subset of mice was imaged with 68Ga-NODAGA-exendin-4 PET/computed tomography (CT). The aortas of both LDLR-/-ApoB100/100 and IGF-II/LDLR-/-ApoB100/100 mice contained prominent, macrophage-rich atherosclerotic lesions. Diabetic mice demonstrated hyperglycemia and glucose intolerance. We found that by autoradiography, 68Ga-NODAGA-exendin-4 uptake was focally increased in macrophage-rich lesion areas compared with corresponding healthy vessel wall (lesion-to-wall ratio 1.6 ± 0.10, p<0.0001) in both non-diabetic and diabetic hypercholesterolemic mice. Pre-injection of unlabeled exendin-4 peptide significantly reduced cellular uptake of 68Ga-NODAGA-exendin-4. Furthermore, PET/CT imaging showed 68Ga-NODAGA-exendin-4 accumulation in the atherosclerotic aorta. Immunofluorescence stainings demonstrated co-localization of GLP-1R with macrophage-rich areas in atherosclerotic lesions. Tracer uptake was low in the healthy vessel wall of C57BL/6N mice coupled with negative GLP-1R staining. In conclusion, 68Ga-NODAGA-exendin-4 detects GLP-1R expression in atherosclerotic lesions in both non-diabetic and diabetic hypercholesterolemic mice. These results provide evidence that GLP-1R expression is mainly localized in macrophage-rich area in atherosclerotic lesions and may have implications for studies of pharmacological modification of GLP-1R signaling in atherosclerosis.

scholarly journals Glucagon-like peptide-1 receptor expression after myocardial infarction: Imaging study using 68Ga-NODAGA-exendin-4 positron emission tomography

2018 ◽  
Vol 27 (6) ◽  
pp. 2386-2397 ◽  
Author(s):  
Mia Ståhle ◽  
Ville Kytö ◽  
Max Kiugel ◽  
Heidi Liljenbäck ◽  
Olli Metsälä ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Positron Emission Tomography ◽  
Smooth Muscle Actin ◽  
Receptor Expression ◽  
Emission Tomography ◽  
Sham Operation ◽  
Alpha Smooth Muscle Actin ◽  
Positron Emission ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Background Activation of glucagon-like peptide-1 receptor (GLP-1R) signaling protects against cardiac dysfunction and remodeling after myocardial infarction (MI). The aim of the study was to evaluate 68Ga-NODAGA-exendin-4 positron emission tomography (PET) for assessment of GLP-1R expression after MI in rats. Methods and Results Rats were studied at 3 days, 1 and 12 weeks after permanent coronary ligation or a sham-operation. Rats were injected with 68Ga-NODAGA-exendin-4 and scanned with PET and contrast-enhanced computed tomography (CT) followed by digital autoradiography and histology of left ventricle tissue sections. 68Ga-NODAGA-exendin-4 PET/CT showed focally increased tracer uptake in the infarcted regions peaking at 3 days and continuing at 1 week after MI. Pre-treatment with an unlabeled exendin-4 peptide significantly reduced 68Ga-NODAGA-exendin-4 uptake. By autoradiography, 68Ga-NODAGA-exendin-4 uptake was 8.6-fold higher in the infarcted region and slightly increased also in the remote, non-infarcted myocardium at 1 week and 12 weeks post-MI compared with sham. Uptake of 68Ga-NODAGA-exendin-4 correlated with the amount of CD68-positive macrophages in the infarcted area and alpha-smooth muscle actin staining in the remote myocardium. Conclusions 68Ga-NODAGA-exendin-4 PET detects up-regulation of cardiac GLP-1R expression during healing of MI in rats and may provide information on the activated repair mechanisms after ischemic myocardial injury.

The Effect of Zinc-Crystallized Glucagon-Like Peptide-1 on Insulin Secretion of Macroencapsulated Pancreatic Islets

2001 ◽  
Vol 7 (1) ◽  
pp. 35-44 ◽  
Author(s):  
Heather Gappa ◽  
Miroslav Baudyš ◽  
Jae Joon Koh ◽  
Sung Wan Kim ◽  
You Han Bae
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Subthreshold α2-Adrenergic Activation Counteracts Glucagon-Like Peptide-1 Potentiation of Glucose-Stimulated Insulin Secretion

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Minglin Pan ◽  
Guang Yang ◽  
Xiuli Cui ◽  
Shao-Nian Yang
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Adrenergic Agonist ◽  
Signaling Systems ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion ◽  
Insulin Secretory Response ◽  
Adrenergic Activation ◽  
Gi Proteins

The pancreatic β cell harbors α2-adrenergic and glucagon-like peptide-1 (GLP-1) receptors on its plasma membrane to sense the corresponding ligands adrenaline/noradrenaline and GLP-1 to govern glucose-stimulated insulin secretion. However, it is not known whether these two signaling systems interact to gain the adequate and timely control of insulin release in response to glucose. The present work shows that the α2-adrenergic agonist clonidine concentration-dependently depresses glucose-stimulated insulin secretion from INS-1 cells. On the contrary, GLP-1 concentration-dependently potentiates insulin secretory response to glucose. Importantly, the present work reveals that subthreshold α2-adrenergic activation with clonidine counteracts GLP-1 potentiation of glucose-induced insulin secretion. This counteractory process relies on pertussis toxin- (PTX-) sensitive Gi proteins since it no longer occurs following PTX-mediated inactivation of Gi proteins. The counteraction of GLP-1 potentiation of glucose-stimulated insulin secretion by subthreshold α2-adrenergic activation is likely to serve as a molecular mechanism for the delicate regulation of insulin release.

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