Diabetes & Metabolism Journal

Original Articles

Basic Research
Glucagon-Like Peptide Receptor Agonist Inhibits Angiotensin II-Induced Proliferation and Migration in Vascular Smooth Muscle Cells and Ameliorates Phosphate-Induced Vascular Smooth Muscle Cells Calcification: Jinmi Lee, Seok-Woo Hong, Min-Jeong Kim, Sun Joon Moon, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Won-Young Lee; Diabetes Metab J. 2024;48(1):83-96. Published online January 3, 2024; DOI: https://doi.org/10.4093/dmj.2022.0363

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Background
Glucagon-like peptide-1 receptor agonist (GLP-1RA), which is a therapeutic agent for the treatment of type 2 diabetes mellitus, has a beneficial effect on the cardiovascular system.
Methods
To examine the protective effects of GLP-1RAs on proliferation and migration of vascular smooth muscle cells (VSMCs), A-10 cells exposed to angiotensin II (Ang II) were treated with either exendin-4, liraglutide, or dulaglutide. To examine the effects of GLP-1RAs on vascular calcification, cells exposed to high concentration of inorganic phosphate (Pi) were treated with exendin-4, liraglutide, or dulaglutide.
Results
Ang II increased proliferation and migration of VSMCs, gene expression levels of Ang II receptors AT1 and AT2, proliferation marker of proliferation Ki-67 (Mki-67), proliferating cell nuclear antigen (Pcna), and cyclin D1 (Ccnd1), and the protein expression levels of phospho-extracellular signal-regulated kinase (p-Erk), phospho-c-JUN N-terminal kinase (p-JNK), and phospho-phosphatidylinositol 3-kinase (p-Pi3k). Exendin-4, liraglutide, and dulaglutide significantly decreased the proliferation and migration of VSMCs, the gene expression levels of Pcna, and the protein expression levels of p-Erk and p-JNK in the Ang II-treated VSMCs. Erk inhibitor PD98059 and JNK inhibitor SP600125 decreased the protein expression levels of Pcna and Ccnd1 and proliferation of VSMCs. Inhibition of GLP-1R by siRNA reversed the reduction of the protein expression levels of p-Erk and p-JNK by exendin-4, liraglutide, and dulaglutide in the Ang II-treated VSMCs. Moreover, GLP-1 (9-36) amide also decreased the proliferation and migration of the Ang II-treated VSMCs. In addition, these GLP-1RAs decreased calcium deposition by inhibiting activating transcription factor 4 (Atf4) in Pi-treated VSMCs.
Conclusion
These data show that GLP-1RAs ameliorate aberrant proliferation and migration in VSMCs through both GLP-1Rdependent and independent pathways and inhibit Pi-induced vascular calcification.

Citations

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Incretin Hormone Secretion in Women with Polycystic Ovary Syndrome: Roles of Obesity, Insulin Sensitivity and Treatment with Metformin and GLP-1s
Andrea Etrusco, Mislav Mikuš, Antonio D’Amato, Fabio Barra, Petar Planinić, Trpimir Goluža, Giovanni Buzzaccarini, Jelena Marušić, Mara Tešanović, Antonio Simone Laganà
Biomedicines.2024; 12(3): 653. CrossRef
Cardiometabolic Crossroads: Obesity, Sleep-Disordered Breathing, and Epicardial Adipose Tissue in Heart Failure with Preserved Ejection Fraction – A Mini-Review
Fulvio Cacciapuoti, Ciro Mauro, Valentina Capone, Angelo Sasso, Luca Gaetano Tarquinio, Federico Cacciapuoti
Heart and Mind.2024;[Epub] CrossRef
BRCC36 regulates β-catenin ubiquitination to alleviate vascular calcification in chronic kidney disease
Yalan Li, Xiaoyue Chen, Yiqing Xiong, Xueqiang Xu, Caidie Xie, Min Min, Dongmei Liang, Cheng Chen, Huijuan Mao
Journal of Translational Medicine.2024;[Epub] CrossRef

Mitogenic Effects and Signaling Pathway of Insulin-Like Growth Factor-I (IGF-I) in the Rat Beta Cell Line (INS-1).: In Kyung Jeong, Ja Young Kim, Hyung Joon Yoo, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim; Korean Diabetes J. 2004;28(6):478-489. Published online December 1, 2004

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Abstract PDF: BACKGROUND
Nutrients and growth factors are known to stimulate pancreatic beta cell mitogenesis. IGF-I acts as a survival factor by limiting apoptosis and stimulating proliferation in many cell types. However, the appropriate mitogenic signaling pathways have not been defined. The aim of this study is to elucidate the mitogenic effect and signaling pathways of IGF-I in the rat beta cell line (INS-I). METHODS: The studies were performed using the rat pancreatic beta cell line, INS-1. INS-1 cells were cultured in RPMI 1640 containing serum-free, 0.2% BSA and 11.1 mmol/L glucose media for 24 hours, and the cells were then treated with IGF-I and different concentrations of glucose or tyrosine phosphorylation inhibitors, or insulin. The cell proliferation was measured by the [3H]thymidine uptake and MTT assay. The cell cycle was analyzed by a flow cytometer by using propidium iodide staining. Western blot analyses were performed using antibodies against PY20 and phospho-MAPK. RESULTS: 1) MTT assay and the [3H]thymidine uptake showed that IGF-I stimulated the INS-1 cell proliferation in a dose dependent manner. Glucose was noted to independently increase the INS-1 cell proliferation. A combination of IGF-I and glucose has a synergistic effect on the proliferation of INS-I cells. Insulin did not influence on the mitogenic effect of IGF-I. 2) The S fraction of INS-1 cells treated with IGF-I was increased in a dose dependent manner. IGF-I stimulated the exit from G1 into the S phase of the cell cycle. 3) Investigation of the role of the PI3K and MAPK, by using of the inhibitors LY294002, wortmannin, and PD98059, demonstrated that the activation of MAPK, but not PI3K, required to stimulate the proliferation of INS-1 cells. 4) IGF-I stimulated the phosphorylation activation of pp60 and phospho-MAPK in the INS-1 cells. IGF-I induced the beta cell proliferation, and this was mediated via a signaling mechanism that was facilitated by MAPK. CONCLUSION: The proliferative effect of IGF-I on pancreatic beta cell seems to be mediated through MAPK signaling pathway.

Insulin Enhances Suppressive Effect of Lipopolysaccharide on Glucose-induced Proliferation of Vascular Smooth Muscle Cells.: Hyoung Chul Choi, Hyuk Jin Kwon, Kwang Youn Lee; Korean Diabetes J. 2004;28(4):265-272. Published online August 1, 2004

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Abstract PDF: BACKGROUND
Vascular smooth muscle cell (VSMC) proliferation is a major pathologic finding of atherosclerotic vessels in diabetes mellitus. Lipopolysaccharide (LPS) inhibits the VSMC proliferation by NO production via iNOS expression. This study attempted to investigate the effect of LPS on the glucose-induced proliferation of VSMC and its mechanism of action. The effects of insulin on glucose induced VSMC proliferation and on the expression of iNOS were also investigated. METHODS: VSMCs were primarily cultured from rat aorta. A proliferation assay for VSMC was performed by a cell count. The concentrations of nitrite in culture media were measured using the Griess reaction. Western blots were performed to analyze for iNOS protein. RESULTS: D-glucose induced VSMC proliferation in a concentration-dependent manner. LPS inhibited the D-glucose induced VSMC proliferation by increasing ing nitrite production. Insulin suppressed the D-glucose induced VSMC proliferation and potentiated the LPS-induced inhibition of VSMC proliferation by increasing the nitrite production. Insulin potentiated the LPS-induced expression of iNOS. CONCLUSION: These results suggest that in diabetes mellitus, glucose induces VSMC proliferation, and LPS and insulin inhibit the stimulatory action of glucose on VSMC proliferation, and insulin potentiates the inhibitory action of LPS on VSMC proliferation via a increase in the expression of iNOS.

Effect of Glucose Concentrations on the Cell Proliferation and Expression of L-type Calcium Channel mRNA in Cultured Rat Aortic Vascular Smooth Muscle Cells.: Young Jung Cho, Hyung Joon Yoo, Hong Woo Nam, Ji Young Suh, In Kyung Jeong, Sung Hee Ihm, Hyeon Kyu Kim, Cheol Young Park, Jae Myung Yoo, Doo Man Kim, Moon Gi Choi, Sung Woo Park; Korean Diabetes J. 2003;27(3):253-259. Published online June 1, 2003

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Abstract PDF: BACKGROUND
Vascular smooth muscle cell (VSMC) proliferation is one of the major pathogenic mechanisms for atherosclerosis. It is known that L-type calcium channels play a role in VSMC proliferation in diabetic rats. However, there have been no studies that show an association between the L-type calcium channels and the VSMC proliferation due to various glucose concentrations in the culture media. Therefore, the association between the voltage-dependent L-type calcium channels of the VSMCs, and the growth of vascular smooth muscle cells, was examined. METHODS: Rat aortic VSMCs were isolated from the aorta of Sprague-Dawley and OLETF rats, using an enzymic method. The VSMCs were cultured in various concentrations of glucose (5.5, 11.0, 16.6, 25, 30 and 40 mM). The VSMCs (1x10(4) cells in 24-well plates) were incubated in the presence of Bay K 8644 (10(-6)M), both with and without verapamil (10(-6)M), for 48 hours. The proliferation was then assessed by the MTT (methylthiazole tetrazolium) assay, and the expression of L-type calcium channel mRNA by RT-PCR. RESULTS: The vascular smooth muscle cell proliferation was significantly increased, in a dose-dependent manner, with glucose concentrations below 25 mM in both in a dose-dependent manner, with glucose concentrations below 25 mM in both kinds of rat. However, the increase in the VSMC proliferation of the OLETF rat was significantly higher than in the Sprague-Dawley rat. After the Bay K 8644 treatment, with the same glucose concentration, the VSMC proliferation and the expression of L-type calcium channel mRNA were significantly increased in both kinds of rat. After treatment with verapamil, the increased VSMC proliferation and expression of L-type calcium channel mRNA, due to the Bay K 8644, were suppressed to control levels in both kinds of rat. CONCLUSION: The results suggest that below certain concentrations of glucose, 25 mM, the L-type calcium channels may play a role in the VSMC proliferation of OLETF and Sprague-Dawley rats. The growth of the VSMCs in OLETF rats, due to various glucose concentrations (< 25 mM), was significantly higher than in the Sprague-Dawley rats.

Effects of Peroxisome Proliferator-activated Receptor-gamma(PPARgamma) on the Pancreatic beta Cell Proliferation.: Jung Hyun Noh, Tae Young Yang, In Kyung Jeong, Jae Hun Chung, Yong Ki Min, Myung Shik Lee, Kwang Won Kim, Moon Kyu Lee; Korean Diabetes J. 2003;27(3):241-252. Published online June 1, 2003

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Abstract PDF: BACKGROUND
The effects and mechanisms of PPARgamma ligands on the cell proliferation in pancreatic beta cells were examined. METHODS: PPARgamma 1 cDNA was overexpressed in INS-1 cells using an adenoviral vector. The cell proliferations were measured by the MTT assay method, following the treatments with troglitazone (TGZ), rosiglitazone (RGZ), 15d-prostaglandin J2 (15d-PGJ2) or retinoic acid (RA), at increasing doses, in INS-1 and PPARgamma overexpressed INS-1 cells. The apoptosis, telomere length and cell cycles were determined after the PPARgamma ligand treatment. RESULTS: The long-term incubation, with PPARgamma ligands over 24 hr, inhibited the INS-1 cell proliferation rate. Apoptosis was not observed with the PPARgamma ligand treatment. G1 cell cycle arrest was observed with the troglitazone treatment. The telomere length remained unchanged following the TGZ treatment. The basal cell proliferation rate was unaffected by the overexpression of PPARgamma . After 48 h of TGZ treatment, the proliferation of the INS-1 cells was inhibited, in a dose- dependent manner, both with and without the overexpression. Moreover, the degree of inhibition was exaggerated in the PPARgamma overexpressed cells compared to beta gal overexpressed cells. CONCLUSION: PPARgamma ligands have direct inhibitory effects on the proliferation of INS-1 cells. Although the basal cell proliferation rate was not affected by PPARgamma overexpression, the PPARgamma overexpression and PPARgamma ligands have a synergistic inhibitory effect on the cell proliferation rate in pancreatic beta cells. G1 cell cycle arrest may be involved in the reduction of cell proliferation due to PPARgamma ligands.

Effect of Transforming Growth Factor-Induced Gene Product, beta ig-h3 on Proliferation, Migration, and Adhesion of Aortic Smooth Muscle Cells Cultured in High Glucose.: Sung Woo Ha, Gui Hwa Jung, He Jin Yeo, Jong Sup Bae, Soon Hee Lee, Jung Guk Kim, Rang Woon Park, In San Kim, Bo Wan Kim; Korean Diabetes J. 2002;26(4):286-295. Published online August 1, 2002

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Abstract PDF: BACKGROUND
Diabetes mellitus is associated with a substantial increase in the prevalence of atherosclerotic disease. There are many factors which are involved in development of these processes. Transforming growth factor (TGF-beta) is known to be an important factor in the pathogenesis of diabetic vascular complications. TGF-beta-induced gene-h3 (beta ig-h3) is an adhesive molecule whose expression is induced by TGF-beta. Considering that TGF-beta plays an important role in diabetic complications and that beta ig-h3 is induced by TGF-beta, we hypothesized that beta ig-h3 may also play a role in the development of diabetic angiopathy. Then, we examined the effects of beta ig-h3 on biologic function of vascular smooth muscle cells (VSMCs) and potential roles of beta ig-h3 in the pathognesis of diabetic angiopathy. METHODS: VSMCs were isolated from rat thoracic aorta. We conditioned cells with different concentration of TGF-beta or glucose. We measured TGF-beta and beta ig-h3 protein in cell supernatant by ELISA. We also examined whether TGF-beta involves in high glucose-induced beta ig-h3 expression. Finally, we did proliferation, migration, and adhesion assay to investigate biologic function of beta ig-h3 in VSMCs. RESULTS: Our results demonstrated that TGF-beta induced beta ig-h3 expression in VSMCs in dose dependent manners. High glucose induced TGF expression as well as beta ig-h3 protein. Finally, beta ig-h3 was found to support the proliferation, migration, and adhesion of rat VSMCs. CONCLUSION: These results suggest that high glucose-and TGF-beta-induced beta ig-h3 may play an important role in diabetic angiopathy by regulating proliferation, migration, and adhesion of VSMCs.

The Effects of Troglitazone on Vascular Smooth Muscle Cell Proliferation.: Yun Jae Chung, Kyeong Min Min, Eun Young Oh, Jae Hoon Chung, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim; Korean Diabetes J. 2000;24(3):348-355. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Elevated fasting and postprandial insulin levels are frequently observed in patients with obesity and hypertension as well as type 2 diabetes mellitus. This phenomenon has been suggested as an independent risk factors for atherosclerotic cardiovascular diseases. Troglitazone, an insulin-sensitizing antidiabetic agent, has been shown to inhibit atherosclerotic process, but its mechanism of action is not yet elucidated. This study was undertaken to examine the effects of troglitazone, a peroxisome proliferator- activated receptor- (PPAR ) ligand, on vascular smooth muscle cell proliferation. METHODS: Aortic smooth muscle cells were isolated from Sprague-Dawley rats and the effects of several different agonists (insulin, ET-I, IGF-I) on cellular DNA synthesis were measured and compared with the effects of troglitazone. In addition, the mRNA of PPARgamma gene in rat aortic smooth muscle cells(RASMCs) was detected by RT-PCR methods. RESULTS:1. Insulin, endothelin-I and IGF-I significantly stimulated DNA synthesis in RASMCs (p<0.05). 2. Insulin-induced DNA synthesis was not significantly inhibited by coincubation with wortmannin or LY294002 but inhibited by PD98059. 3. Troglitazone significantly inhibited insulin, endothelin-I and IGF-I-induced DNA synthesis in RASMCs (p<0.05, respectively). 4. PPAR mRNA was detected in RASMCs by RT-PCR and its expression did not significantly increase by troglitazone treatment. CONCLUSION: Troglitazone could inhibit agonist-induced proliferation of vascular smooth muscle cells and might be a useful agent for treatment as well as prevention of atherosclerosis.

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