Diabetes & Metabolism Journal

Review

Basic and Translational Research
Glucagon-Like Peptide-1 and Hypothalamic Regulation of Satiation: Cognitive and Neural Insights from Human and Animal Studies: Joon Seok Park, Kyu Sik Kim, Hyung Jin Choi; Diabetes Metab J. 2025;49(3):333-347. Published online May 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0106

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Abstract PDF PubReader ePub: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as blockbuster drugs for treating metabolic diseases. Glucagon-like peptide-1 (GLP-1) plays a pivotal role in glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying, and acting on the central nervous system to regulate satiation and satiety. This review summarizes the discovery of GLP-1 and the development of GLP-1RAs, with a particular focus on their central mechanisms of action. Human neuroimaging studies demonstrate that GLP-1RAs influence brain activity during food cognition, supporting a role in pre-ingestive satiation. Animal studies on hypothalamic feed-forward regulation of hunger suggest that cognitive hypothalamic mechanisms may also contribute to satiation control. We highlight the brain mechanisms of GLP-1RA-induced satiation and satiety, including cognitive impacts, with an emphasis on animal studies of hypothalamic glucagon-like peptide-1 receptor (GLP-1R) and GLP-1R-expressing neurons. Actions in non-hypothalamic regions are also discussed. Additionally, we review emerging combination drugs and oral GLP-1RA formulations aimed at improving efficacy and patient adherence. In conclusion, the dorsomedial hypothalamus (DMH)—a key GLP-1RA target—mediates pre-ingestive cognitive satiation, while other hypothalamic GLP-1R neurons regulate diverse aspects of feeding behavior, offering potential therapeutic targets for obesity treatment.

Original Articles

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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14 Web of Science
15 Crossref

Abstract PDF Supplementary Material PubReader

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.

Citations

Citations to this article as recorded by

Effect and mechanism of GLP-1 on cognitive function in diabetes mellitus
Xiaoke Dou, Lei Zhao, Jing Li, Yaqiu Jiang
Frontiers in Neuroscience.2025;[Epub] CrossRef
Are Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists Central Nervous System (CNS) Penetrant: A Narrative Review
Juliana West, Maggie Li, Sabrina Wong, Gia Han Le, Kayla M. Teopiz, Kyle Valentino, Christine E. Dri, Roger S. McIntyre
Neurology and Therapy.2025;[Epub] CrossRef
Neurovascular decoupling of frontoparietal cortex-putamen-cerebellum network in type 2 diabetes patient: Potential biomarker for abnormal eating patterns
Ying Yu, Bo Hu, Xin-Wen Yu, Yan-Yan Cui, Xin-Yu Cao, Min-Hua Ni, Si-Ning Li, Pan Dai, Qian Sun, Xiao-Yan Bai, Yao Tong, Xiao-Rui Jing, Ai-Li Yang, Sheng-Ru Liang, Li-Juan Du, Shuo Guo, Lin-Feng Yan, Bin Gao, Guang-Bin Cui
Diabetes Research and Clinical Practice.2025; 224: 112175. CrossRef
Regulation of the interaction between carboxymethyl starch and whey protein isolate by tannin: Effects on their colonic targeting and stimulation of satiety hormone secretion
Jinming Tan, Yingying Li, Zhibing Zhang, Xiaoxi Li
Food Research International.2025; 217: 116839. CrossRef
Glucagon-Like Peptide-1 and Hypothalamic Regulation of Satiation: Cognitive and Neural Insights from Human and Animal Studies
Joon Seok Park, Kyu Sik Kim, Hyung Jin Choi
Diabetes & Metabolism Journal.2025; 49(3): 333. CrossRef
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; 110(1): 1. CrossRef
Physiology and Pharmacology of Effects of GLP-1-based Therapies on Gastric, Biliary and Intestinal Motility
Ryan J Jalleh, Chinmay S Marathe, Christopher K Rayner, Karen L Jones, Mahesh M Umapathysivam, Tongzhi Wu, Daniel R Quast, Mark P Plummer, Michael A Nauck, Michael Horowitz
Endocrinology.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
Journal of Diabetes Research.2021; 2021: 1. CrossRef

Association between Genetic Polymorphisms in Hepatocyte Nuclear Factor 4alpha and Type 2 Diabetes in Koreans.: Eun Jung Lee, Soo Heon Kwak, Sun Wook Jo, Hyung Jin Choi, Hyoung Doo Shin, Min Kyong Moon, Young Min Cho, Hak Chul Jang, Kyong Soo Park, Houng Kyu Lee; Korean Diabetes J. 2006;30(1):10-16. Published online January 1, 2006; DOI: https://doi.org/10.4093/jkda.2006.30.1.10

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Abstract PDF: BACKGROUND
Hepatocyte nuclear factor-4alpha (HNF-4alpha) is a member of transcription factor network which is essential for the development and function of the beta cell. Furthermore mutations in the HNF-4alpha gene have been known to cause maturity-onset diabetes of the young. Therefore we aimed to examine the association between polymorphisms in the HNF-4alpha gene and the risk of type 2 diabetes (T2DM) and its related phenotypes in the Korean population. METHODS: Two single nucleotide polymorphisms (SNPs) in the HNF-4alpha gene, g.4681C>T and HNF-4alpha g.12352C>T (Thr139Ile), were genotyped in unrelated T2DM (n=760) and non-diabetic subjects (n=303). The genetic associations between these SNPs and the risk of T2DM and metabolic phenotypes were analyzed. RESULTS: There was no significant association between genetic polymorphisms in the HNF-4alpha and the risk of T2DM. However HNF-4alpha g.4681C>T increased total cholesterol in the recessive model (P = 0.02) and showed marginal association with fasting plasma glucose (P = 0.049) in the additive model. CONCLUSION: There was no significant association between genetic polymorphisms and the risk of T2DM in the Korean populations. But HNF-4alpha g.4681C>T was associated with higher level of total cholesterol and fasting plasma glucose.

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