Diabetes & Metabolism Journal

Review

Metabolic Risk/Epidemiology
Glucagon-Like Peptide-1: New Regulator in Lipid Metabolism: Tong Bu, Ziyan Sun, Yi Pan, Xia Deng, Guoyue Yuan; Diabetes Metab J. 2024;48(3):354-372. Published online April 1, 2024; DOI: https://doi.org/10.4093/dmj.2023.0277

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Glucagon-like peptide-1 (GLP-1) is a 30-amino acid peptide hormone that is mainly expressed in the intestine and hypothalamus. In recent years, basic and clinical studies have shown that GLP-1 is closely related to lipid metabolism, and it can participate in lipid metabolism by inhibiting fat synthesis, promoting fat differentiation, enhancing cholesterol metabolism, and promoting adipose browning. GLP-1 plays a key role in the occurrence and development of metabolic diseases such as obesity, nonalcoholic fatty liver disease, and atherosclerosis by regulating lipid metabolism. It is expected to become a new target for the treatment of metabolic disorders. The effects of GLP-1 and dual agonists on lipid metabolism also provide a more complete treatment plan for metabolic diseases. This article reviews the recent research progress of GLP-1 in lipid metabolism.

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Iryna Halabitska, Liliia Babinets, Valentyn Oksenych, Oleksandr Kamyshnyi
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The Effect of Tirzepatide on Body Composition in People with Overweight and Obesity: A Systematic Review of Randomized, Controlled Studies
Vincenzo Rochira, Carla Greco, Stefano Boni, Francesco Costantino, Leonardo Dalla Valentina, Eleonora Zanni, Leila Itani, Marwan El Ghoch
Diseases.2024; 12(9): 204. CrossRef
Glucagon-like peptide-1 receptor: mechanisms and advances in therapy
Zhikai Zheng, Yao Zong, Yiyang Ma, Yucheng Tian, Yidan Pang, Changqing Zhang, Junjie Gao
Signal Transduction and Targeted Therapy.2024;[Epub] CrossRef
Recent Advances and Therapeutic Benefits of Glucagon-Like Peptide-1 (GLP-1) Agonists in the Management of Type 2 Diabetes and Associated Metabolic Disorders
John O Olukorode, Dolapo A Orimoloye, Nwachukwu O Nwachukwu, Chidera N Onwuzo, Praise O Oloyede, Temiloluwa Fayemi, Oluwatobi S Odunaike, Petra S Ayobami-Ojo, Nwachi Divine, Demilade J Alo, Chukwurah U Alex
Cureus.2024;[Epub] CrossRef
Incretin hormones: Revolutionizing the treatment landscape for kidney and liver diseases in type 2 diabetes and obesity
Jae Hyun Bae, Young Min Cho
Journal of Diabetes Investigation.2024;[Epub] CrossRef
Interactions between glucagon like peptide 1 (GLP-1) and estrogens regulates lipid metabolism
Jorge F.A. Model, Rafaella S. Normann, Éverton L. Vogt, Maiza Von Dentz, Marjoriane de Amaral, Rui Xu, Tsvetan Bachvaroff, Poli Mara Spritzer, J. Sook Chung, Anapaula S. Vinagre
Biochemical Pharmacology.2024; 230: 116623. CrossRef
Changes in 24-Hour Urine Chemistry in Patients with Nephrolithiasis during Weight Loss with Glucagon-Like Peptide 1–Based Therapies
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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.

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Basic Research
DA-1241, a Novel GPR119 Agonist, Improves Hyperglycaemia by Inhibiting Hepatic Gluconeogenesis and Enhancing Insulin Secretion in Diabetic Mice: Youjin Kim, Si Woo Lee, Hyejin Wang, Ryeong-Hyeon Kim, Hyun Ki Park, Hangkyu Lee, Eun Seok Kang; Diabetes Metab J. 2022;46(2):337-348. Published online January 21, 2022; DOI: https://doi.org/10.4093/dmj.2021.0056

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Background
We investigated the antidiabetic effects of DA-1241, a novel G protein-coupled receptor (GPR) 119 agonist, in vitro and in vivo.
Methods
DA-1241 was administrated to high-fat diet (HFD)-fed C57BL/6J mice for 12 weeks after hyperglycaemia developed. Oral/intraperitoneal glucose tolerance test and insulin tolerance test were performed. Serum insulin and glucagon-like peptide-1 (GLP-1) levels were measured during oral glucose tolerance test. Insulinoma cell line (INS-1E) cells and mouse islets were used to find whether DA-1241 directly stimulate insulin secretion in beta cell. HepG2 cells were used to evaluate the gluconeogenesis and autophagic process. Autophagic flux was evaluated by transfecting microtubule-associated protein 1 light chain 3-fused to green fluorescent protein and monomeric red fluorescent (mRFP-GFP-LC3) expression vector to HepG2 cells.
Results
Although DA-1241 treatment did not affect body weight gain and amount of food intake, fasting blood glucose level decreased along with increase in GLP-1 level. DA-1241 improved only oral glucose tolerance test and showed no effect in intraperitoneal glucose tolerance test. No significant effect was observed in insulin tolerance test. DA-1241 did not increase insulin secretion in INS-1E cell and mouse islets. DA-1241 reduced triglyceride content in the liver thereby improved fatty liver. Additionally, DA-1241 reduced gluconeogenic enzyme expression in HepG2 cells and mouse liver. DA-1241 reduced autophagic flow in HepG2 cells.
Conclusion
These findings suggested that DA-1241 augmented glucose-dependent insulin release via stimulation of GLP-1 secretion, and reduced hepatic gluconeogenesis, which might be associated with autophagic blockage, leading to improved glycaemic control.

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Seung-Ho Lee, Hansu Park, Eun-Kyoung Yang, Bo Ram Lee, Il-Hoon Jung, Tae-Hyoung Kim, Moon Jung Goo, Yuna Chae, Mi-Kyung Kim
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Characteristics of the Latest Therapeutic Agent for Diabetes
Nuri Yun
The Journal of Korean Diabetes.2023; 24(3): 148. CrossRef
DA-1241, a Novel GPR119 Agonist, Improves Hyperglycaemia by Inhibiting Hepatic Gluconeogenesis and Enhancing Insulin Secretion in Diabetic Mice
Youjin Kim, Si Woo Lee, Hyejin Wang, Ryeong-Hyeon Kim, Hyun Ki Park, Hangkyu Lee, Eun Seok Kang
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Drug/Regimen
Glucagon-Like Peptide-1 Receptor Agonist Differentially Affects Brain Activation in Response to Visual Food Cues in Lean and Obese Individuals with Type 2 Diabetes Mellitus: Jae Hyun Bae, Hyung Jin Choi, Kang Ik Kevin Cho, Lee Kyung Kim, Jun Soo Kwon, Young Min Cho; Diabetes Metab J. 2020;44(2):248-259. Published online November 4, 2019; DOI: https://doi.org/10.4093/dmj.2019.0018

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Background

To investigate the effects of a glucagon-like peptide-1 receptor agonist on functional brain activation in lean and obese individuals with type 2 diabetes mellitus (T2DM) in response to visual food cues.

Methods

In a randomized, single-blinded, crossover study, 15 lean and 14 obese individuals with T2DM were administered lixisenatide or normal saline subcutaneously with a 1-week washout period. We evaluated brain activation in response to pictures of high-calorie food, low-calorie food, and nonfood using functional magnetic resonance imaging and measured appetite and caloric intake in participants who were given access to an ad libitum buffet.

Results

Obese individuals with T2DM showed significantly greater activation of the hypothalamus, pineal gland, parietal cortex (high-calorie food vs. low-calorie food, P<0.05), orbitofrontal cortex (high-calorie food vs. nonfood, P<0.05), and visual cortex (food vs. nonfood, P<0.05) than lean individuals with T2DM. Lixisenatide injection significantly reduced the functional activation of the fusiform gyrus and lateral ventricle in obese individuals with T2DM compared with that in lean individuals with T2DM (nonfood vs. high-calorie food, P<0.05). In addition, in individuals who decreased their caloric intake after lixisenatide injection, there were significant interaction effects between group and treatment in the posterior cingulate, medial frontal cortex (high-calorie food vs. low-calorie food, P<0.05), hypothalamus, orbitofrontal cortex, and temporal lobe (food vs. nonfood, P<0.05).

Conclusion

Brain responses to visual food cues were different in lean and obese individuals with T2DM. In addition, acute administration of lixisenatide differentially affected functional brain activation in these individuals, especially in those who decreased their caloric intake after lixisenatide injection.

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Altered Metabolic Phenotypes and Hypothalamic Neuronal Activity Triggered by Sodium-Glucose Cotransporter 2 Inhibition (Diabetes Metab J 2023;47:784-95)
Jae Hyun Bae
Diabetes & Metabolism Journal.2024; 48(1): 157. CrossRef
GLP-1 increases preingestive satiation via hypothalamic circuits in mice and humans
Kyu Sik Kim, Joon Seok Park, Eunsang Hwang, Min Jung Park, Hwa Yun Shin, Young Hee Lee, Kyung Min Kim, Laurent Gautron, Elizabeth Godschall, Bryan Portillo, Kyle Grose, Sang-Ho Jung, So Lin Baek, Young Hyun Yun, Doyeon Lee, Eunseong Kim, Jason Ajwani, Seo
Science.2024; 385(6707): 438. CrossRef
Glucagon-like peptide 1 agonist and effects on reward behaviour: A systematic review
Sebastian Badulescu, Aniqa Tabassum, Gia Han Le, Sabrina Wong, Lee Phan, Hartej Gill, Cristian-Daniel Llach, Roger S. McIntyre, Joshua Rosenblat, Rodrigo Mansur
Physiology & Behavior.2024; 283: 114622. CrossRef
Clinical Consequences of Delayed Gastric Emptying With GLP-1 Receptor Agonists and Tirzepatide
Ryan J Jalleh, Mark P Plummer, Chinmay S Marathe, Mahesh M Umapathysivam, Daniel R Quast, Christopher K Rayner, Karen L Jones, Tongzhi Wu, Michael Horowitz, Michael A Nauck
The Journal of Clinical Endocrinology & Metabolism.2024;[Epub] CrossRef
Diabetes remission and relapse following an intensive metabolic intervention combining insulin glargine/lixisenatide, metformin and lifestyle approaches: Results of a randomised controlled trial
Natalia McInnes, Stephanie Hall, Heather A. Lochnan, Stewart B. Harris, Zubin Punthakee, Ronald J. Sigal, Irene Hramiak, Mohammed Azharuddin, Joanne F. Liutkus, Jean‐François Yale, Farah Sultan, Ada Smith, Rose E. Otto, Diana Sherifali, Yan Yun Liu, Hertz
Diabetes, Obesity and Metabolism.2023; 25(11): 3347. CrossRef
Glucagon-like peptide-1 analog therapy in rare genetic diseases: monogenic obesity, monogenic diabetes, and spinal muscular atrophy
Hussein Zaitoon, Ronit Lubetzky, Achiya Z. Amir, Hadar Moran-Lev, Liora Sagi, Michal Yacobi-Bach, Ophir Borger, Efrat Chorna, Yael Lebenthal, Avivit Brener
Acta Diabetologica.2023; 60(8): 1099. CrossRef
What can functional brain imaging teach us about remission of type 2 diabetes?
Dhruti Hirani, Shahd Alabdulkader, Alexander. D. Miras, Victoria Salem
Diabetic Medicine.2023;[Epub] CrossRef
Fasting oxyntomodulin, glicentin, and gastric inhibitory polypeptide levels are associated with activation of reward‐ and attention‐related brain centres in response to visual food cues in adults with obesity: A cross‐sectional functional MRI study
Nikolaos Perakakis, Olivia M. Farr, Christos S. Mantzoros
Diabetes, Obesity and Metabolism.2021; 23(5): 1202. CrossRef
Aberrant Brain Functional Connectivity Strength and Effective Connectivity in Patients with Type 2 Diabetes Mellitus
Xi Guo, Su Wang, Yu-Chen Chen, Heng-Le Wei, Gang-Ping Zhou, Yu-Sheng Yu, Xindao Yin, Kun Wang, Hong Zhang, Eusebio Chiefari
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Obesity and Metabolic Syndrome
Premeal Consumption of a Protein-Enriched, Dietary Fiber-Fortified Bar Decreases Total Energy Intake in Healthy Individuals: Chang Ho Ahn, Jae Hyun Bae, Young Min Cho; Diabetes Metab J. 2019;43(6):879-892. Published online June 25, 2019; DOI: https://doi.org/10.4093/dmj.2018.0202

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Background

A premeal load of protein can increase satiety and reduce energy intake. Dietary fiber also conveys metabolic benefits by modulating energy intake. We made a protein-enriched, dietary fiber-fortified bar (PFB) and aimed to investigate its effects on food intake and gut hormone secretion in healthy individuals.

Methods

Twenty subjects with normal glucose tolerance were enrolled. On three separate visits, the subjects received, in a randomized order, one of the following: a PFB containing 73 kcal with 10.7 g of protein and 12.7 g of dietary fiber; a usual bar (UB) containing the same calories as the PFB but only 0.9 g of protein and no dietary fiber; or water (control). After 15 minutes, the subjects had ad libitum intake of a test meal. Food consumption, appetite, and plasma gut hormone levels were measured.

Results

Total energy intake, including the bar and the test meal, was significantly reduced with the PFB preload compared to the water (904.4±534.9 kcal vs. 1,075.0±508.0 kcal, P=0.016). With the UB preload, only the intake of the test meal was reduced (P=0.044) but not the total energy intake (P=0.471) than the water. Fullness was also significantly increased after the PFB. In addition, postprandial glucose levels decreased and glucagon-like peptide-1 levels increased with the PFB compared with both the UB and water.

Conclusion

In healthy individuals, a premeal supplementation of PFB reduced total energy intake and decreased postprandial glucose excursion. This finding necessitates long-term studies regarding clinical use in obesity.

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Citrus pectin protects mice from burn injury by modulating intestinal microbiota, GLP-1 secretion and immune response
Ji-Wei Hao, Hong-Sheng Liu, Ling-Ying Liu, Qing-Hong Zhang
International Immunopharmacology.2024; 131: 111912. CrossRef
Effect of Two Different Meal Compositions on 1-hour Plasma Ghrelin Levels in Young Men
Brinnell Annette Caszo, Sangeetha Shyam, Purushotham Krishnappa, Justin Vijay Gnanou
Malaysian Journal of Medicine and Health Sciences.2023; 19(5): 185. CrossRef
Intake of Fibre-Associated Foods and Texture Preferences in Relation to Weight Status Among 9–12 Years Old Children in 6 European Countries
Marlies Hörmann-Wallner, Raphaela Krause, Begoña Alfaro, Hannah Jilani, Monica Laureati, Valérie L. Almli, Mari Sandell, Pernilla Sandvik, Gertrude G. Zeinstra, Lisa Methven
Frontiers in Nutrition.2021;[Epub] CrossRef
Response: Premeal Consumption of a Protein-Enriched, Dietary Fiber-Fortified Bar Decreases Total Energy Intake in Healthy Individuals (Diabetes Metab J 2019;43:879–92)
Chang Ho Ahn, Jae Hyun Bae, Young Min Cho
Diabetes & Metabolism Journal.2020; 44(1): 207. CrossRef
Letter: Premeal Consumption of a Protein-Enriched, Dietary Fiber-Fortified Bar Decreases Total Energy Intake in Healthy Individuals (Diabetes Metab J 2019;43:879–92)
Mi-kyung Kim
Diabetes & Metabolism Journal.2020; 44(1): 203. CrossRef
Spent coffee (Coffea arabicaL.) grounds promote satiety and attenuate energy intake: A pilot study
Rocio Campos‐Vega, Andrea Arreguín‐Campos, Miguel A. Cruz‐Medrano, María Dolores Castillo Bilbao
Journal of Food Biochemistry.2020;[Epub] CrossRef

Pathophysiology
Factors Related to Blood Intact Incretin Levels in Patients with Type 2 Diabetes Mellitus: Soyeon Yoo, Eun-Jin Yang, Gwanpyo Koh; Diabetes Metab J. 2019;43(4):495-503. Published online February 20, 2019; DOI: https://doi.org/10.4093/dmj.2018.0105

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Abstract PDF PubReader: Background
We performed this study to identify factors related to intact incretin levels in patients with type 2 diabetes mellitus (T2DM).
Methods
We cross-sectionally analyzed 336 patients with T2DM. Intact glucagon-like peptide 1 (iGLP-1) and intact glucose-dependent insulinotropic polypeptide (iGIP) levels were measured in a fasted state and 30 minutes after ingestion of a standard mixed meal. The differences between 30 and 0 minute iGLP-1 and iGIP levels were indicated as ΔiGLP-1 and ΔiGIP.
Results
In simple correlation analyses, fasting iGLP-1 was positively correlated with glucose, C-peptide, creatinine, and triglyceride levels, and negatively correlated with estimated glomerular filtration rate. ΔiGLP-1 was positively correlated only with ΔC-peptide levels. Fasting iGIP showed positive correlations with glycosylated hemoglobin (HbA1c) and fasting glucose levels, and negative correlations with ΔC-peptide levels. ΔiGIP was negatively correlated with diabetes duration and HbA1c levels, and positively correlated with Δglucose and ΔC-peptide levels. In multivariate analyses adjusting for age, sex, and covariates, fasting iGLP-1 levels were significantly related to fasting glucose levels, ΔiGLP-1 levels were positively related to ΔC-peptide levels, fasting iGIP levels were related to fasting C-peptide levels, and ΔiGIP levels were positively related to ΔC-peptide and Δglucose levels.
Conclusion
Taken together, intact incretin levels are primarily related to C-peptide and glucose levels. This result suggests that glycemia and insulin secretion are the main factors associated with intact incretin levels in T2DM patients.

Clinical Diabetes & Therapeutics
Asian Subpopulations May Exhibit Greater Cardiovascular Benefit from Long-Acting Glucagon-Like Peptide 1 Receptor Agonists: A Meta-Analysis of Cardiovascular Outcome Trials: Yu Mi Kang, Yun Kyung Cho, Jiwoo Lee, Seung Eun Lee, Woo Je Lee, Joong-Yeol Park, Ye-Jee Kim, Chang Hee Jung, Michael A. Nauck; Diabetes Metab J. 2019;43(4):410-421. Published online December 27, 2018; DOI: https://doi.org/10.4093/dmj.2018.0070

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Background

Based on reported results of three large cardiovascular outcome trials (CVOTs) of glucagon-like peptide 1 receptor agonists (GLP-1 RAs), we aimed to investigate the overall effect of GLP-1 RAs on major adverse cardiovascular events (MACEs) and to identify subpopulations exhibiting the greatest cardiovascular (CV) benefit.

Methods

Three CVOTs reporting effects of long-acting GLP-1 RAs were included: LEADER (liraglutide), SUSTAIN-6 (semaglutide), and EXSCEL (exenatide once weekly). In all studies, the primary endpoint was three-point MACE, comprising CV death, non-fatal myocardial infarction, and non-fatal stroke. Overall effect estimates were calculated as hazard ratios and 95% confidence intervals (CIs) using the random-effects model; subgroup analyses reported in the original studies were similarly analyzed.

Results

Overall, statistically significant risk reductions in MACE and CV death were observed. Subgroup analysis indicated a significant racial difference with respect to CV benefit (P for interaction <0.001), and more substantial risk reductions were observed in subjects of African origin (relative risk [RR], 0.78; 95% CI, 0.60 to 0.99) and in Asians (RR, 0.35; 95% CI, 0.09 to 1.32). However, post hoc analysis (Bonferroni method) revealed that only Asians exhibited a significantly greater CV benefit from treatment, compared with white subjects (P<0.0001).

Conclusion

Long-acting GLP-1 RAs reduced risks of MACE and CV deaths in high-risk patients with type 2 diabetes mellitus. Our findings of a particularly effective reduction in CV events with GLP-1 RA in Asian populations merits further exploration and dedicated trials in specific populations.

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Effects of a 6-Month Exenatide Therapy on HbA1c and Weight in Korean Patients with Type 2 Diabetes: A Retrospective Cohort Study: Juyoung Shin, Jin-Sun Chang, Hun-Sung Kim, Sun-Hee Ko, Bong-Yun Cha, Ho-Young Son, Kun-Ho Yoon, Jae-Hyoung Cho; Diabetes Metab J. 2012;36(5):364-370. Published online October 18, 2012; DOI: https://doi.org/10.4093/dmj.2012.36.5.364

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Background

While many studies have shown the good efficacy and safety of exenatide in patients with diabetes, limited information is available about exenatide in clinical practice in Korean populations. Therefore, this retrospective cohort study was designed to analyze the effects of exenatide on blood glucose level and body weight in Korean patients with type 2 diabetes mellitus.

Methods

We reviewed the records of the patients with diabetes who visited Seoul St. Mary's Hospital and for whom exenatide was prescribed from June 2009 to October 2011. After excluding subjects based on their race/ethnicity, medical history, whether or not they changed more than 2 kinds of oral hypoglycemic agents with exenatide treatment, loss to follow-up, or whether they stopped exenatide therapy within 6 months, a total of 52 subjects were included in the final analysis.

Results

The mean glycated hemoglobin (HbA1c) level and weight remarkably decreased from 8.5±1.7% to 6.7±1.0% (P<0.001) and from 82.3±15.8 kg to 78.6±16.3 kg (P<0.001), respectively. The multiple regression analysis indicated that the reduction in HbA1c level was significantly associated with a shorter duration of diabetes, a higher baseline HbA1c level, and greater weight reduction, whereas weight loss had no significant correlation with other factors. No severe adverse events were observed.

Conclusion

These results suggest that a 6-month exenatide injection therapy significantly improved patients' HbA1c levels and body weights without causing serious adverse effects in Korean patients with type 2 diabetes.

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Reviews

GLP-1 Receptor Agonist and Non-Alcoholic Fatty Liver Disease: Jinmi Lee, Seok-Woo Hong, Eun-Jung Rhee, Won-Young Lee; Diabetes Metab J. 2012;36(4):262-267. Published online August 20, 2012; DOI: https://doi.org/10.4093/dmj.2012.36.4.262

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Non-alcoholic fatty liver disease (NAFLD), one of the most common liver diseases, is caused by the disruption of hepatic lipid homeostasis. It is associated with insulin resistance as seen in type 2 diabetes mellitus. Glucagon-like peptide-1 (GLP-1) is an incretin that increases insulin sensitivity and aids glucose metabolism. In recent in vivo and in vitro studies, GLP-1 presents a novel therapeutic approach against NAFLD by increasing fatty acid oxidation, decreasing lipogenesis, and improving hepatic glucose metabolism. In this report, we provide an overview of the role and mechanism of GLP-1 in relieving NAFLD.

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Understanding the Cardiovascular Effects of Incretin: Ji Sung Yoon, Hyoung Woo Lee; Diabetes Metab J. 2011;35(5):437-443. Published online October 31, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.5.437

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Abstract PDF PubReader

Cardiovascular disease (CVD), a leading cause of death in patients with diabetes mellitus, has several pathogenic mechanisms that are well established. However, the traditional hypoglycemic agents do not have proven positive effects on macrovascular disease. Novel therapeutic agents target the incretin pathway including the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonists and the dipeptidyl peptidase-4 inhibitors. The glucose-regulatory actions of these agents function by increasing insulin secretion and suppressing glucagon. They also act to increase weight loss not only by inhibiting gastric emptying, but also by reducing appetite. Although GLP-1 and GLP-1R agonists have demonstrated beneficial effects on myocardium and vascular endothelium including coronary and peripheral mouse vessels, they also have anti-inflammatory and anti-atherogenic actions. These agents also have positive effects on the lipid profile and blood pressure. Although these cardioprotective actions seem to be beyond the effects of glucose control and weight loss, they are mediated through GLP-1R- or GLP-1R-independent actions of cleaved GLP-1 (9-36). Larger randomized controlled trials are necessary to elucidate the clinical promise of these beneficial CVD effects.

Citations

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Original Article

Insulin Secretion and Incretin Hormone Concentration in Women with Previous Gestational Diabetes Mellitus: Sung Hoon Yu, Bongjun Cho, Yejin Lee, Eunhye Kim, Sung Hee Choi, Soo Lim, Ka Hee Yi, Young Joo Park, Kyong Soo Park, Hak Chul Jang; Diabetes Metab J. 2011;35(1):58-64. Published online February 28, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.1.58

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Background

We examined the change in the levels of incretin hormone and effects of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) on insulin secretion in women with previous gestational diabetes (pGDM).

Methods

A 75-g oral glucose tolerance test (OGTT) was conducted on 34 women with pGDM. In addition, 11 women with normal glucose tolerance, matched for age, height and weight, were also tested. The insulin, GIP, GLP-1, and glucagon concentrations were measured, and their anthropometric and biochemical markers were also measured.

Results

Among 34 women with pGDM, 18 had normal glucose tolerance, 13 had impaired glucose tolerance (IGT) and 1 had diabetes. No significant differences were found in GLP-1 concentration between the pGDM and control group. However, a significantly high level of glucagon was present in the pGDM group at 30 minutes into the OGTT. The GIP concentration was elevated at 30 minutes and 60 minutes in the pGDM group. With the exception of the 30-minute timepoint, women with IGT had significantly high blood glucose from 0 to 120 minutes. However, there was no significant difference in insulin or GLP-1 concentration. The GIP level was significantly high from 0 to 90 minutes in patients diagnosed with IGT.

Conclusion

GLP-1 secretion does not differ between pGDM patients and normal women. GIP was elevated, but that does not seem to induce in increase in insulin secretion. Therefore, we conclude that other factors such as heredity and environment play important roles in the development of type 2 diabetes.

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Review

Triple Combination Therapy Using Metformin, Thiazolidinedione, and a GLP-1 Analog or DPP-IV Inhibitor in Patients with Type 2 Diabetes Mellitus: Sun Woo Kim; Korean Diabetes J. 2010;34(6):331-337. Published online December 31, 2010; DOI: https://doi.org/10.4093/kdj.2010.34.6.331

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Although there is no HbA1c threshold for cardiovascular risk, the American Diabetic Association-recommended goal of HbA1c < 7.0% appears to be unacceptably high. To achieve an optimal HbA1c level goal of 6.0% or less, a high dosage of sulfonylureas and insulin would be required; the trade-off would be the common adverse effects of hypoglycemia and weight gain. In contrast, hypoglycemia is uncommon with insulin sensitizers and GLP-1 analogs, allowing the physician to titrate these drugs to maximum dosage to reduce HbA1c levels below 6.0% and they have been shown to preserve β-cell function. Lastly, weight gain is common with sulfonylurea and insulin therapy, whereas GLP-1 analogs induce weight loss and offset the weight gain associated with TZDs. A treatment paradigm shift is recommended in which combination therapy is initiated with diet/exercise, metformin (which has antiatherogenic effects and improves hepatic insulin sensitivity), a TZD (which improves insulin sensitivity and preserves β-cell function with proven durability), and a GLP-1 analog (which improves β, α-cell function and promotes weight loss) or a dipeptidyl peptidase IV inhibitor in patients with type 2 diabetes mellitus.

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Original Article

Genetic Polymorphism of Glucagon-Like Peptide 1 Receptor in Korean Type 2 Diabetes Mellitus.: Kyung Wook Lee, Meihua Jiang, Shanji Piao, Eun A Kim, Seong Bin Hong, Moon Suk Nam, Yong Seong Kim, Kyong Soo Park, Hyun Chul Lee; Korean Diabetes J. 2005;29(1):30-38. Published online January 1, 2005

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Abstract PDF: BACKGROUND
Glucagon-like peptide-1 (GLP-1) is a hormone secreted by intestinal L-cells, which stimulates insulin secretion from cells. The biological action of GLP-1 is mediated by the glucagon-like peptide-1 receptor (GLP-1R), which is 463 amino acids in size, with 7 transmembrane domains. Because GLP-1 plays an important modulatory role in regulating glucose-stimulated insulin, the GLP-1R could be a candidate gene contributing to impaired -cell function and the development of this genetically heterogeneous disorder. Recently, four GLP-1R SNPs were identified in Caucasian diabetic individuals, and for the SNP at the Leu- 260Phe (A/C) position, statistically significant differences were detected in the distribution of genotypes between type 2 diabetic and nondiabetic subjects. We replicated the genetic association between the SNP at the leu260Phe (A/C) position in the GLP-1R gene and Korean type 2 diabetes mellitus. METHODS: The Leu260Phe polymorphism in the GLP-1R gene was determined using a PCR- RFLP method (the genotypes were determined according to the results of polymerase chain reaction products after digestion and the digestive enzyme was BbsI) in 419 Korean type 2 diabetic patients and 345 nondiabetic subjects. RESULTS: In contrast to the Caucasian report, there was no significant difference in the frequencies of alleles, and genotypes between Korean type 2 diabetic and nondiabetic subjects. When analyzed according to gender, BMI and age of onset, the genotype distribution of type 2 diabetic subjects was not significantly different from nondiabetic subjects. CONCLUSION: The Leu260Phe polymorphism in the GLP-1R gene was not associated with type 2 diabetes mellitus, and we were unable to replicate the genetic association between this polymorphism and Korean type 2 diabetes mellitus

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