Glucagon-like-peptide-1 receptor expression in normal and diseased human thyroid and pancreas

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.

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

Journal of Nuclear Cardiology ◽

10.1007/s12350-018-01547-1 ◽

2018 ◽

Vol 27 (6) ◽

pp. 2386-2397 ◽

Cited By ~ 4

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.

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00318.2012 ◽

2013 ◽

Vol 304 (8) ◽

pp. G700-G707 ◽

Cited By ~ 7

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.

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Preservation of Glucagon-Like Peptide-1 Level Attenuates Angiotensin II-Induced Tissue Fibrosis by Altering AT1/AT2 Receptor Expression and Angiotensin-Converting Enzyme 2 Activity in Rat Heart

Cardiovascular Drugs and Therapy ◽

10.1007/s10557-015-6592-7 ◽

2015 ◽

Vol 29 (3) ◽

pp. 243-255 ◽

Cited By ~ 40

Author(s):

Li-Hui Zhang ◽

Xue-Fen Pang ◽

Feng Bai ◽

Ning-Ping Wang ◽

Ahmed Ijaz Shah ◽

...

Keyword(s):

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Rat Heart ◽

Receptor Expression ◽

At2 Receptor ◽

Converting Enzyme ◽

Tissue Fibrosis ◽

Angiotensin Converting Enzyme 2 ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Decreased Hypothalamic Glucagon-Like Peptide-1 Receptor Expression in Type 2 Diabetes Patients

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2015-3291 ◽

2016 ◽

Vol 101 (5) ◽

pp. 2122-2129 ◽

Cited By ~ 17

Author(s):

Jennifer S. ten Kulve ◽

Liselotte van Bloemendaal ◽

Rawien Balesar ◽

Richard G. IJzerman ◽

Dick F. Swaab ◽

...

Keyword(s):

Type 2 Diabetes ◽

Receptor Expression ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Diabetes Patients

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Glucagon-Like Peptide-1 Receptor Expression in Normal and Neoplastic Human Pancreatic Tissues

Pancreas ◽

10.1097/mpa.0000000000000521 ◽

2016 ◽

Vol 45 (4) ◽

pp. 613-619 ◽

Cited By ~ 1

Author(s):

Marco Dal Molin ◽

Haeryoung Kim ◽

Amanda Blackford ◽

Rajni Sharma ◽

Michael Goggins

Keyword(s):

Receptor Expression ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Involvement of gut microbiota in association between GLP-1/GLP-1 receptor expression and gastrointestinal motility

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00232.2016 ◽

2017 ◽

Vol 312 (4) ◽

pp. G367-G373 ◽

Cited By ~ 20

Author(s):

Mo Yang ◽

Hirokazu Fukui ◽

Hirotsugu Eda ◽

Xin Xu ◽

Yoshitaka Kitayama ◽

...

Keyword(s):

Gut Microbiota ◽

Gastrointestinal Motility ◽

Receptor Expression ◽

Pivotal Role ◽

Neural Cells ◽

Gi Tract ◽

Glucagon Like Peptide ◽

Host Physiology ◽

Glucagon Like Peptide 1 ◽

Gi Motility

The microbiota in the gut is known to play a pivotal role in host physiology by interacting with the immune and neuroendocrine systems in gastrointestinal (GI) tissues. Glucagon-like peptide 1 (GLP-1), a gut hormone, is involved in metabolism as well as GI motility. We examined how gut microbiota affects the link between GLP-1/GLP-1 receptor (GLP-1R) expression and motility of the GI tract. Germ-free (GF) mice (6 wk old) were orally administered a fecal bacterial suspension prepared from specific pathogen-free (SPF) mice, and then after fecal transplantation (FT) GI tissues were obtained from the GF mice at various time points. The expression of GLP-1 and its receptor was examined by immunohistochemistry, and gastrointestinal transit time (GITT) was measured by administration of carmine red solution. GLP-1 was expressed in endocrine cells in the colonic mucosa, and GLP-1R was expressed in myenteric neural cells throughout the GI wall. GLP-1R-positive cells throughout the GI wall were significantly fewer in GF mice with FT than in GF mice without gut microbiota reconstitution. GITT was significantly shorter in GF mice with FT than in control GF mice without FT and correlated with the number of GLP-1R-positive cells throughout the GI wall. GITT was significantly longer in GF control mice than in SPF mice. When those mice were treated with GLP-1 agonist extendin4, GITT was significantly longer in the GF mice. The gut microbiota may accelerate or at least modify GI motility while suppressing GLP-1R expression in myenteric neural cells throughout the GI tract. NEW & NOTEWORTHY The gut microbiota has been intensively studied, because it plays a pivotal role in various aspects of host physiology. On the other hand, glucagon-like peptide 1 (GLP-1) plays important roles in metabolism as well as gastrointestinal motility. In the present study, we have suggested that the gut microbiota accelerates gastrointestinal motility while suppressing the expression of GLP-1 receptor in myenteric neural cells throughout the gastrointestinal tract. We believe that this article is very timely and suggestive work.

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Renal Tubular Glucagon-Like Peptide-1 Receptor Expression Is Increased in Early Sepsis but Reduced in Chronic Kidney Disease and Sepsis-Induced Kidney Injury

International Journal of Molecular Sciences ◽

10.3390/ijms20236024 ◽

2019 ◽

Vol 20 (23) ◽

pp. 6024

Author(s):

Jae Hyun Choi ◽

Seung Jung Kim ◽

Soon Kil Kwon ◽

Hye-Young Kim ◽

Hyunjung Jeon

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Kidney Injury ◽

Receptor Expression ◽

Sepsis Group ◽

Renal Tubules ◽

Cecal Perforation ◽

Glucagon Like Peptide ◽

Early Sepsis ◽

Glucagon Like Peptide 1

Acute kidney injury (AKI) is common in patients with sepsis and causes renal ischemia. Glucagon-like peptide-1 (GLP-1) protects the vascular system and the kidney, and GLP-1 receptor (GLP-1R) is expressed in the kidney. Renal GLP-1R activity is decreased in chronic kidney disease (CKD), but is increased by the inflammatory response; however, the effect of AKI on GLP-1R expression is unknown. We investigated the role of GLP-1 by assessing GLP-1R expression in the renal cortex in animals with AKI-related sepsis, CKD, and CKD-with-sepsis. We generated a model of CKD by 5/6 nephrectomy, and sepsis induced by cecal perforation, in male Sprague–Dawley rats. We compared renal GLP-1R expression at 3, 6, 12, 24, and 72 h after cecal perforation, and in CKD and CKD-with-sepsis. We performed blood and urine tests, western blotting (WB), and immunohistochemistry (IHC) to assay GLP-1R expression in renal tubules. The CKD-with-sepsis group showed the lowest kidney function, urine volume, and serum glucose and albumin levels. GLP-1R expression in renal tubules was decreased at 3 h, increased at 24 h, and decreased at 72 h after sepsis induction. GLP-1R expression was decreased at 8 weeks after CKD and was lowest in the CKD-with-sepsis group. The WB results were verified against those obtained by IHC. GLP-1R expression in renal tubules is increased in early sepsis, which may explain the protective effect of endogenous GLP-1 against sepsis-related inflammation.

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