Endocrinology and Metabolism

Review Article

Diabetes, obesity and metabolism
Glucagon-Like Peptide-1 Based Therapies: A New Horizon in Obesity Management: Jang Won Son, Soo Lim; Endocrinol Metab. 2024;39(2):206-221. Published online April 16, 2024; DOI: https://doi.org/10.3803/EnM.2024.1940

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Abstract PDF PubReader ePub: Obesity is a significant risk factor for health issues like type 2 diabetes and cardiovascular disease. It often proves resistant to traditional lifestyle interventions, prompting a need for more precise therapeutic strategies. This has led to a focus on signaling pathways and neuroendocrine mechanisms to develop targeted obesity treatments. Recent developments in obesity management have been revolutionized by introducing novel glucagon-like peptide-1 (GLP-1) based drugs, such as semaglutide and tirzepatide. These drugs are part of an emerging class of nutrient-stimulated hormone-based therapeutics, acting as incretin mimetics to target G-protein–coupled receptors like GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and glucagon. These receptors are vital in regulating body fat and energy balance. The development of multiagonists, including GLP-1–glucagon and GIP–GLP-1–glucagon receptor agonists, especially with the potential for glucagon receptor activation, marks a significant advancement in the field. This review covers the development and clinical efficacy of various GLP-1-based therapeutics, exploring the challenges and future directions in obesity management.

Original Article

Diabetes, Obesity and Metabolism
Dulaglutide Ameliorates Palmitic Acid-Induced Hepatic Steatosis by Activating FAM3A Signaling Pathway: Jinmi Lee, Seok-Woo Hong, Min-Jeong Kim, Sun Joon Moon, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Won-Young Lee; Endocrinol Metab. 2022;37(1):74-83. Published online February 9, 2022; DOI: https://doi.org/10.3803/EnM.2021.1293

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Background
Dulaglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), has been shown to reduce body weight and liver fat content in patients with type 2 diabetes. Family with sequence similarity 3 member A (FAM3A) plays a vital role in regulating glucose and lipid metabolism. The aim of this study was to determine the mechanisms by which dulaglutide protects against hepatic steatosis in HepG2 cells treated with palmitic acid (PA).
Methods
HepG2 cells were pretreated with 400 μM PA for 24 hours, followed by treatment with or without 100 nM dulaglutide for 24 hours. Hepatic lipid accumulation was determined using Oil red O staining and triglyceride (TG) assay, and the expression of lipid metabolism-associated factor was analyzed using quantitative real time polymerase chain reaction and Western blotting.
Results
Dulaglutide significantly decreased hepatic lipid accumulation and reduced the expression of genes associated with lipid droplet binding proteins, de novo lipogenesis, and TG synthesis in PA-treated HepG2 cells. Dulaglutide also increased the expression of proteins associated with lipolysis and fatty acid oxidation and FAM3A in PA-treated cells. However, exendin-(9-39), a GLP-1R antagonist, reversed the expression of FAM3A, and fatty acid oxidation-associated factors increased due to dulaglutide. In addition, inhibition of FAM3A by siRNA attenuated the reducing effect of dulaglutide on TG content and its increasing effect on regulation of fatty acid oxidation.
Conclusion
These results suggest that dulaglutide could be used therapeutically for improving nonalcoholic fatty liver disease, and its effect could be mediated in part via upregulation of FAM3A expression through a GLP-1R-dependent pathway.

Citations

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GLP-1/GLP-1RAs: New Options for the Drug Treatment of NAFLD
Haoran Jiang, Linquan Zang
Current Pharmaceutical Design.2024; 30(2): 100. CrossRef
GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives
Riccardo Nevola, Raffaella Epifani, Simona Imbriani, Giovanni Tortorella, Concetta Aprea, Raffaele Galiero, Luca Rinaldi, Raffaele Marfella, Ferdinando Carlo Sasso
International Journal of Molecular Sciences.2023; 24(2): 1703. CrossRef
FAM3A mediates the phenotypic switch of human aortic smooth muscle cells stimulated with oxidised low-density lipoprotein by influencing the PI3K-AKT pathway
Lei Yang, Baoshun Du, Shitao Zhang, Maode Wang
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Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH)
Xiaohan Xu, Kyle L. Poulsen, Lijuan Wu, Shan Liu, Tatsunori Miyata, Qiaoling Song, Qingda Wei, Chenyang Zhao, Chunhua Lin, Jinbo Yang
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Review Articles

Diabetes
Cardiorenal Protection in Diabetic Kidney Disease: Jason F. Lee, Ecaterina Berzan, Vikas S. Sridhar, Ayodele Odutayo, David Z.I. Cherney; Endocrinol Metab. 2021;36(2):256-269. Published online April 19, 2021; DOI: https://doi.org/10.3803/EnM.2021.987

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Over the last 5 years there have been many new developments in the management of diabetic kidney disease. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 (SGLT2) inhibitors were initially used for glycemic control, but more recent studies have now shown that their benefits extend to cardiovascular and kidney outcomes. The recent addition of data on the novel mineralocorticoid receptor antagonist (MRA) gives us another approach to further decrease the residual risk of diabetic kidney disease progression. In this review we describe the mechanism of action, key studies, and possible adverse effects related to these three classes of medications. The management of type 2 diabetes now includes an increasing number of medications for the management of comorbidities in a patient population at significant risk of cardiovascular disease and progression of chronic kidney disease. It is from this perspective that we seek to outline the rationale for the sequential and/or combined use of SGLT2 inhibitors, GLP-1 RA and MRAs in patients with type 2 diabetes for heart and kidney protection.

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Ayodele Odutayo, Adeera Levin
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Intrarenal Mechanisms of Sodium-Glucose Cotransporter-2 Inhibitors on Tubuloglomerular Feedback and Natriuresis
Eun Sil Koh, Gheun-Ho Kim, Sungjin Chung
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Ayodele Odutayo, Bruno R. da Costa, Tiago V. Pereira, Vinay Garg, Samir Iskander, Fatimah Roble, Rahim Lalji, Cesar A. Hincapié, Aquila Akingbade, Myanca Rodrigues, Arnav Agarwal, Bishoy Lawendy, Pakeezah Saadat, Jacob A. Udell, Francesco Cosentino, Peter
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Finerenone: A Potential Treatment for Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus
Luis D’Marco, María Jesús Puchades, Lorena Gandía, Claudia Forquet, Elena Giménez-Civera, Nayara Panizo, Javier Reque, Isabel Juan-García, Valmore Bermúdez, José Luis Gorriz
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Sodium-Glucose Cotransporter 2 Inhibitors Mechanisms of Action: A Review
Jorge I. Fonseca-Correa, Ricardo Correa-Rotter
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Diabetes
Best Achievements in Clinical Medicine in Diabetes and Dyslipidemia in 2020: Eun-Jung Rhee, Mee-Kyung Kim, Won-Young Lee; Endocrinol Metab. 2021;36(1):41-50. Published online February 24, 2021; DOI: https://doi.org/10.3803/EnM.2021.106

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Over the last two decades, our understanding of diabetes and treatment strategies have evolved tremendously, from scientific, mechanistic, and human perspectives. The categories of anti-diabetic medications expanded from a few to numerous, enabling clinicians to personalize diabetes care and treatment. Thanks to rapid growth in the field of science and medical engineering, newer treatment options are coming to the market with various advantages and disadvantages to be aware of. Therefore, clinicians should rapidly adopt new trends based on guidelines and data from many clinical trials in the field of diabetes. In the treatment of dyslipidemia, trends and guidelines are changing every year, and novel therapies are being developed. In this review, we would like to summarize the major achievements in clinical medicine in 2020 in the field of diabetes mellitus and dyslipidemia.

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Diabetes
A Review of the Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors on Lean Body Mass in Humans: Jack Alistair Sargeant, Joseph Henson, James Adam King, Thomas Yates, Kamlesh Khunti, Melanie Jane Davies; Endocrinol Metab. 2019;34(3):247-262. Published online September 26, 2019; DOI: https://doi.org/10.3803/EnM.2019.34.3.247

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Weight loss is an important goal in the management of several chronic conditions, including type 2 diabetes mellitus, and pharmacological therapies that aid weight loss are appealing. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) are novel glucose-lowering therapies that have been shown to induce clinically significant reductions in body weight. However, this weight loss may not be attributed solely to fat mass (FM). Given the importance of skeletal muscle and lean body mass (LBM) on cardio-metabolic health and physical function, we reviewed the available literature reporting the effects of GLP-1RAs and SGLT2is on body composition. Results demonstrate that, in most circumstances, the weight loss associated with both therapies predominantly comprises a reduction in FM, although significant heterogeneity exists between studies. In over half of the studies identified, the proportion of LBM reduction ranged between 20% and 50% of total weight lost, which is consistent with diet-induced weight loss and bariatric surgery. No clear differences existed between GLP-1RAs and SGLT2is. Consequently, the loss of LBM and skeletal muscle associated with weight loss induced by GLP-1RAs and SGLT2is warrants attention. Strategies to preserve skeletal muscle and improve physical function, for example through structured exercise, are of great importance.

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Namgok Lecture 2016

New Potential Targets of Glucagon-Like Peptide 1 Receptor Agonists in Pancreatic β-Cells and Hepatocytes: Won-Young Lee; Endocrinol Metab. 2017;32(1):1-5. Published online February 6, 2017; DOI: https://doi.org/10.3803/EnM.2017.32.1.1

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Abstract PDF PubReader

It is well known that both insulin resistance and decreased insulin secretory capacity are important factors in the pathogenesis of type 2 diabetes mellitus (T2DM). In addition to genetic factors, obesity and lipotoxicity can increase the risk of T2DM. Glucagon-like peptide 1 (GLP-1) receptor agonists are novel antidiabetic drugs with multiple effects. They can stimulate glucose-dependent insulin secretion, inhibit postprandial glucagon release, delay gastric emptying, and induce pancreatic β-cell proliferation. They can also reduce the weight of patients with T2DM and relieve lipotoxicity at the cellular level. Many intracellular targets of GLP-1 have been found, but more remain to be identified. Elucidating these targets could be a basis for developing new potential drugs. My colleagues and I have investigated new targets of GLP-1, with a particular focus on pancreatic β-cell lines and hepatic cell lines. Herein, I summarize the recent work from my laboratory, with profound gratitude for receiving the prestigious 2016 Namgok Award.

Citations

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Original Article

Thyroid
Expression of Glucagon-Like Peptide-1 Receptor in Papillary Thyroid Carcinoma and Its Clinicopathologic Significance: Min Jung Jung, Su Kyoung Kwon; Endocrinol Metab. 2014;29(4):536-544. Published online December 29, 2014; DOI: https://doi.org/10.3803/EnM.2014.29.4.536

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Background

Incretin-based therapies are rapidly becoming one of the main glycemic control strategies in diabetes. Considering the large numbers of papillary thyroid carcinomas (PTCs) and possible effects of glucagon-like peptide-1 (GLP-1) on cell proliferation, the expression of GLP-1 receptor (GLP-1R) in PTC is likely to have clinical significance. We performed this study to evaluate the expression of GLP-1R in PTC and the clinical meaning of GLP-1R expression in PTC.

Methods

Fifty-six cases of PTC, four cases of medullary thyroid cancer (MTC), seven cases of nodular hyperplasia and 56 normal thyroid tissue samples were selected for immunostaining for GLP-1R. Clinical parameters were obtained by retrospective review of medical records.

Results

Immunohistochemical staining for GLP-1R showed immunoreactivity in 18 of 56 cases of PTC (32.1%). All four cases of MTC exhibited cytoplasmic GLP-1R expression. Nodular hyperplasia exhibited immunoreactivity in two of seven cases (28.6%). All normal thyroid follicular cells showed negative immunoreactivity. In univariable and multivariable analyses, tumor multifocality was negatively correlated with GLP-1R expression. Extrathyroidal extension showed positive association with GLP-1R expression that was almost significant. Sex, age, tumor size, and lymph node metastasis were not significantly associated with GLP-1R expression.

Conclusion

Some parts of PTC tissues express GLP-1R, and GLP-1R expression in PTC was negatively correlated with tumor multifocality. The long-term influence of pharmacologically increased GLP-1 on thyroid follicular cells and development and progression of tumors originating from thyroid follicular cells should be investigated.

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Response: Expression of Glucagon-Like Peptide-1 Receptor in Papillary Thyroid Carcinoma and Its Clinicopathologic Significance (Endocrinol Metab2014;29:536-44, Min Jung Jung et al.)
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Endocrinology and Metabolism.2015; 30(2): 231. CrossRef

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