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Qin YF, Zhang WH, Zhang HN, Li YW, Huang WQ, Xie JL, Yang S, Li LN, Cui C, Pei Q, Huang J, Yang GP. A phase 1, randomized, double-blind, placebo-controlled trial investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of KN056 (a recombinant human GLP-1 variant Fc fusion protein) in healthy Chinese participants. Expert Opin Investig Drugs 2025; 34:329-337. [PMID: 40328758 DOI: 10.1080/13543784.2025.2500303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 04/15/2025] [Indexed: 05/08/2025]
Abstract
BACKGROUND This randomized clinical pharmacology trial investigated the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of KN056 following single-dose subcutaneous administration in healthy Chinese participants. METHODS Thirty healthy male subjects were randomized to receive a single dose of KN056 (0.5, 1.0, 3.0, 6.0, or 12.0 mg) or placebo. PK and PD parameters, as well as safety and tolerability, were assessed. RESULTS KN056 exposure increased proportionally with dose, with a half-life ranging from 141 to 188 hours. KN056 was well-tolerated, with gastrointestinal adverse events being the most common, particularly at the highest dose (12.0 mg). In the oral glucose tolerance test, KN056 dose-dependently decreased the AUC on the glucose versus time (gAUC) from baseline within 144 hours post-dosing. Specifically, the maximum reduction was 29.9% (occurring at the 72-hour mark). Body weight decreased within seven days of administration, correlating with dose levels, with a mean reduction of -1.68 kg in the 12.0 mg group; however, no significant change in body weight was observed by the end of the study. CONCLUSIONS KN056 demonstrated favorable PK, PD, and safety profiles in healthy Chinese participants, supporting its potential for once-weekly dosing.
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Affiliation(s)
- Yuan-Fang Qin
- Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Wen-Hua Zhang
- Department of Ophthalmology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Hao-Nan Zhang
- Suzhou Alphamab Co, Ltd, Suzhou, Jiangsu Province, China
| | - Yu-Wei Li
- Suzhou Alphamab Co, Ltd, Suzhou, Jiangsu Province, China
| | - Wen-Qiao Huang
- Suzhou Alphamab Co, Ltd, Suzhou, Jiangsu Province, China
| | - Jin-Lian Xie
- Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Shuang Yang
- Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Lan-Ni Li
- Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Chang Cui
- Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Qi Pei
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Jie Huang
- Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Guo-Ping Yang
- Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, China
- XiangYa school of Pharmaceutical Sciences, Central South University, Changsha, China
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Unal S. Comment on: Prescribing semaglutide for weight loss in non-diabetic, obese patients is associated with an increased risk of erectile dysfunction: a TriNetX database study. Int J Impot Res 2025; 37:342. [PMID: 39122866 DOI: 10.1038/s41443-024-00960-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 07/15/2024] [Accepted: 07/30/2024] [Indexed: 08/12/2024]
Affiliation(s)
- Selman Unal
- Department of Urology, Urgup State Hospital, Nevsehir, Turkey.
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Ferguson J, Fisher O, Talbot M, Rigas G. Effectiveness of Adjuvant Semaglutide Following Bariatric Metabolic Surgery. Obes Surg 2025; 35:694-700. [PMID: 39982604 PMCID: PMC11906545 DOI: 10.1007/s11695-025-07703-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 01/16/2025] [Accepted: 01/18/2025] [Indexed: 02/22/2025]
Abstract
BACKGROUND Obesity is a relapsing condition and response to anti-obesity therapies appears to be normally distributed. Therefore, some patients undergoing metabolic bariatric surgery (MBS) will demonstrate a partial response to therapy. When prescribing therapies to patients living with obesity (PwO) the median total weight loss (TWL) gives a good indication of the likely utility of prescription for that individual. GLP-1 agonists (GLP1a) offer patients a reasonable prospect of clinically significant weight loss even if they have been previously treated with MBS. METHODS A retrospective review of prospectively collected data in a single bariatric clinic was performed. Patients with insufficient weight loss at any time point were offered semaglutide therapy with doses titrated depending on response to treatment, tolerability, availability and affordability. Duration of therapy, highest dose tolerated, anthropometric measures and reported side effects were recorded. Reasons for discontinuation were noted where possible; however, discontinuation due to medication unavailability was not reliably captured in the dataset. RESULTS The median dose tolerated was 1 mg s/c per week, and 78% tolerated ≤ 1 mg as the maximum achieved dose. The median TWL was 7.5% and side effects were uncommon. Most patients took therapy for > 6 months, but continued therapy > 1 year was uncommon. CONCLUSION Overall 'real-world' utility of semaglutide after MBS may potentially be hampered by supply and cost issues more than issues associated with effectiveness or side effect profile.
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Yang Y, Yamane S, Harada N, Ikeguchi-Ogura E, Yamamoto K, Wada N, Fauzi M, Murakami T, Yabe D, Hayashi Y, Inagaki N. Voltage-gated calcium channel α 2δ-1 subunit is involved in the regulation of glucose-stimulated GLP-1 secretion in mice. Am J Physiol Gastrointest Liver Physiol 2025; 328:G243-G251. [PMID: 39918794 DOI: 10.1152/ajpgi.00279.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 10/01/2024] [Accepted: 02/03/2025] [Indexed: 02/26/2025]
Abstract
Glucagon-like peptide-1 (GLP-1) is an incretin produced by enteroendocrine preproglucagon (PPG)-expressing cells in response to nutrient ingestion that potentiates insulin secretion. The voltage-gated Ca2+ channel has been reported previously to be involved in glucose-stimulated GLP-1 secretion; in this study, we show that PPG-cells in upper and lower small intestine substantially express the voltage-gated Ca2+ channel α2δ-1 subunit (CaVα2δ-1). In vitro experiments using NCI-H716 cells demonstrate that inhibition of CaVα2δ-1 by gabapentin (GBP), an inhibitory ligand of the α2δ subunit, attenuates glucose-stimulated intracellular calcium elevation and reduces GLP-1 secretion. In addition, systemic administration of gabapentin significantly reduces glucose-stimulated GLP-1 secretion without affecting blood glucose levels in wild-type mice. Furthermore, knockout mice of intestine-specific Cacna2d1, a gene encoding CaVα2δ-1, exhibit reduced GLP-1 secretion in response to oral glucose administration regardless of sex. These results demonstrate that CaVα2δ-1 expressed in PPG-cells plays an important role in glucose-stimulated GLP-1 secretion and represents a potential target in the treatment of diabetes and obesity.NEW & NOTEWORTHY In this study, we establish high expression of the voltage-gated Ca2+ channel α2δ-1 subunit (CaVα2δ-1) subunit in enteroendocrine glucagon-like peptide-1 (GLP-1) producing cells and elucidate its role in GLP-1 secretion, providing a more detailed understanding of the mechanism of GLP-1 secretion.
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Affiliation(s)
- Yuhan Yang
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shunsuke Yamane
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Norio Harada
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Endocrinology and Metabolism, School of Medical Sciences, University of Fukui, Fukui, Japan
| | - Eri Ikeguchi-Ogura
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kana Yamamoto
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Naoki Wada
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Muhammad Fauzi
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takaaki Murakami
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Daisuke Yabe
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshitaka Hayashi
- Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Medical Research Institute Kitano Hospital, P.I.I.F. Tazuke-kofukai, Osaka, Japan
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Rocha GR, de Melo FF. Glucagon-like peptide-1 and impaired counterregulatory responses to hypoglycemia in type 1 diabetes. World J Diabetes 2025; 16:99928. [PMID: 39959274 PMCID: PMC11718485 DOI: 10.4239/wjd.v16.i2.99928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 10/25/2024] [Accepted: 11/04/2024] [Indexed: 12/30/2024] Open
Abstract
This letter comments on a study by Jin et al, published recently in the World Journal of Diabetes. Hypoglycemia is a significant complication of diabetes, with primary defense mechanisms involving the stimulation of glucagon secretion in α-cells and the inhibition of insulin secretion in pancreatic β-cells, which are often compromised in type 1 diabetes mellitus (T1DM) and advanced type 2 diabetes mellitus. Recurrent hypoglycemia predisposes the development of impaired hypoglycemia awareness, a condition underpinned by complex pathophysiological processes, encompassing central nervous system adaptations and several hormonal interactions, including a potential role for glucagon-like peptide-1 (GLP-1) in paracrine and endocrine vias. Experimental evidence indicates that GLP-1 may impair hypoglycemic counterregulation by disrupting the sympathoadrenal system and promoting somatostatin release in pancreatic δ-cells, which inhibits glucagon secretion from neighboring α-cells. However, current trials evaluating GLP-1 receptor agonists (GLP-1 RAs) in T1DM patients have shown promising benefits in reducing insulin requirements and body weight, without increasing the risk of hypoglycemia. Further research is essential to elucidate the specific roles of GLP-1 and GLP-1 RAs in modulating glucagon secretion and the sympathetic-adrenal reflex, and their impact on hypoglycemia unawareness in T1DM patients.
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Affiliation(s)
- Gabriel Reis Rocha
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45065-430, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45065-430, Bahia, Brazil
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Krieger JP, Daniels D, Lee S, Mastitskaya S, Langhans W. Glucagon-Like Peptide-1 Links Ingestion, Homeostasis, and the Heart. Compr Physiol 2025; 15:e7. [PMID: 39887844 PMCID: PMC11790259 DOI: 10.1002/cph4.7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 11/02/2024] [Accepted: 11/05/2024] [Indexed: 02/01/2025]
Abstract
Glucagon-like peptide-1 (GLP-1), a hormone released from enteroendocrine cells in the distal small and large intestines in response to nutrients and other stimuli, not only controls eating and insulin release, but is also involved in drinking control as well as renal and cardiovascular functions. Moreover, GLP-1 functions as a central nervous system peptide transmitter, produced by preproglucagon (PPG) neurons in the hindbrain. Intestinal GLP-1 inhibits eating by activating vagal sensory neurons directly, via GLP-1 receptors (GLP-1Rs), but presumably also indirectly, by triggering the release of serotonin from enterochromaffin cells. GLP-1 enhances glucose-dependent insulin release via a vago-vagal reflex and by direct action on beta cells. Finally, intestinal GLP-1 acts on the kidneys to modulate electrolyte and water movements, and on the heart, where it provides numerous benefits, including anti-inflammatory, antiatherogenic, and vasodilatory effects, as well as protection against ischemia/reperfusion injury and arrhythmias. Hindbrain PPG neurons receive multiple inputs and project to many GLP-1R-expressing brain areas involved in reward, autonomic functions, and stress. PPG neuron-derived GLP-1 is involved in the termination of large meals and is implicated in the inhibition of water intake. This review details GLP-1's roles in these interconnected systems, highlighting recent findings and unresolved issues, and integrating them to discuss the physiological and pathological relevance of endogenous GLP-1 in coordinating these functions. As eating poses significant threats to metabolic, fluid, and immune homeostasis, the body needs mechanisms to mitigate these challenges while sustaining essential nutrient intake. Endogenous GLP-1 plays a crucial role in this "ingestive homeostasis."
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Affiliation(s)
- Jean-Philippe Krieger
- Jean-Philippe Krieger, Institute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zurich, Winterthurerstr. 260, 8057 Zurich
| | - Derek Daniels
- Department of Biological Sciences and the Center for Ingestive Behavior Research, University at Buffalo, the State University of New York, Buffalo NY 14260 USA
| | - Shin Lee
- Shin J. Lee, Neurimmune AG, Wagistrasse 18, 8952 Schlieren, Switzerland
| | - Svetlana Mastitskaya
- Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Wolfgang Langhans
- Physiology and Behavior Laboratory, Dept. of Health Sciences and Technology, ETH Zurich, 8603 Schwerzenbach, Switzerland
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Zarei M, Sahebi Vaighan N, Farjoo MH, Talebi S, Zarei M. Incretin-based therapy: a new horizon in diabetes management. J Diabetes Metab Disord 2024; 23:1665-1686. [PMID: 39610543 PMCID: PMC11599551 DOI: 10.1007/s40200-024-01479-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Accepted: 07/22/2024] [Indexed: 11/30/2024]
Abstract
Diabetes mellitus, a metabolic syndrome characterized by hyperglycemia and insulin dysfunction, often leads to serious complications such as neuropathy, nephropathy, retinopathy, and cardiovascular disease. Incretins, gut peptide hormones released post-nutrient intake, have shown promising therapeutic effects on these complications due to their wide-ranging biological impacts on various body systems. This review focuses on the role of incretin-based therapies, particularly Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, in managing diabetes and its complications. We also discuss the potential of novel agents like semaglutide, a recently approved oral compound, and dual/triple agonists targeting GLP-1/GIP, GLP-1/glucagon, and GLP-1/GIP/glucagon receptors, which are currently under investigation. The review aims to provide a comprehensive understanding of the beneficial impacts of natural incretins and the therapeutic potential of incretin-based therapies in diabetes management.
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Affiliation(s)
- Malek Zarei
- Department of Pharmacology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Navideh Sahebi Vaighan
- Department of Pharmacology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Hadi Farjoo
- Department of Pharmacology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soosan Talebi
- Department of Pharmacology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Zarei
- Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
- John B. Little Center for Radiation Sciences, Harvard T.H Chan School of Public Health, Boston, MA USA
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Sangwung P, Ho JD, Siddall T, Lin J, Tomas A, Jones B, Sloop KW. Class B1 GPCRs: insights into multireceptor pharmacology for the treatment of metabolic disease. Am J Physiol Endocrinol Metab 2024; 327:E600-E615. [PMID: 38984948 PMCID: PMC11559640 DOI: 10.1152/ajpendo.00371.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 06/14/2024] [Accepted: 07/01/2024] [Indexed: 07/11/2024]
Abstract
The secretin-like, class B1 subfamily of seven transmembrane-spanning G protein-coupled receptors (GPCRs) consists of 15 members that coordinate important physiological processes. These receptors bind peptide ligands and use a distinct mechanism of activation that is driven by evolutionarily conserved structural features. For the class B1 receptors, the C-terminus of the cognate ligand is initially recognized by the receptor via an N-terminal extracellular domain that forms a hydrophobic ligand-binding groove. This binding enables the N-terminus of the ligand to engage deep into a large volume, open transmembrane pocket of the receptor. Importantly, the phylogenetic basis of this ligand-receptor activation mechanism has provided opportunities to engineer analogs of several class B1 ligands for therapeutic use. Among the most accepted of these are drugs targeting the glucagon-like peptide-1 (GLP-1) receptor for the treatment of type 2 diabetes and obesity. Recently, multifunctional agonists possessing activity at the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, such as tirzepatide, and others that also contain glucagon receptor activity, have been developed. In this article, we review members of the class B1 GPCR family with focus on receptors for GLP-1, GIP, and glucagon, including their signal transduction and receptor trafficking characteristics. The metabolic importance of these receptors is also highlighted, along with the benefit of polypharmacologic ligands. Furthermore, key structural features and comparative analyses of high-resolution cryogenic electron microscopy structures for these receptors in active-state complexes with either native ligands or multifunctional agonists are provided, supporting the pharmacological basis of such therapeutic agents.
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Affiliation(s)
- Panjamaporn Sangwung
- Molecular Pharmacology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States
| | - Joseph D Ho
- Department of Structural Biology, Lilly Biotechnology Center, San Diego, California, United States
| | - Tessa Siddall
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Jerry Lin
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Alejandra Tomas
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Ben Jones
- Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Kyle W Sloop
- Diabetes, Obesity and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States
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Gabe MBN, Breitschaft A, Knop FK, Hansen MR, Kirkeby K, Rathor N, Adrian CL. Effect of oral semaglutide on energy intake, appetite, control of eating and gastric emptying in adults living with obesity: A randomized controlled trial. Diabetes Obes Metab 2024; 26:4480-4489. [PMID: 39082206 DOI: 10.1111/dom.15802] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 06/21/2024] [Accepted: 06/30/2024] [Indexed: 09/19/2024]
Abstract
AIM To investigate the effects of once-daily oral semaglutide 50 mg on energy intake, appetite, control of eating and gastric emptying. METHODS A clinical pharmacology, double-blind study was conducted in 61 adults with obesity randomized to once-daily oral semaglutide (dose-escalated to 50 mg) or placebo for 20 weeks. Energy intake was measured during an ad libitum lunch, and participant-reported appetite ratings and Control of Eating Questionnaire responses were assessed. Gastric emptying was measured using paracetamol absorption following a standardized breakfast. RESULTS The relative change from baseline in ad libitum energy intake at week 20 (primary endpoint) was -39.2% points (95% confidence interval -59.0%, -19.4%) with semaglutide compared with placebo. Body weight was reduced by 9.8% with semaglutide and by 1.5% with placebo. Semaglutide reduced hunger, increased fullness and satiety, and was associated with fewer food cravings and better control of eating versus placebo. No statistically significant difference in gastric emptying was observed at week 20. CONCLUSIONS In participants with obesity, once-daily oral semaglutide 50 mg reduced energy intake, body weight and appetite, and improved control of eating. There was no evidence of delayed gastric emptying at week 20, as measured through paracetamol absorption.
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Affiliation(s)
| | | | - Filip Krag Knop
- Novo Nordisk A/S, Søborg, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Quast DR, Lancaster D, Xie C, Bound MJ, Grivell J, Jones KL, Horowitz M, Meier JJ, Wu T, Rayner CK, Nauck MA. Randomised comparison of intravenous and subcutaneous routes of glucagon-like peptide-1 administration for lowering plasma glucose in hyperglycaemic subjects with type 2 diabetes. Diabetes Obes Metab 2024; 26:3897-3905. [PMID: 38951936 DOI: 10.1111/dom.15736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 05/27/2024] [Accepted: 06/05/2024] [Indexed: 07/03/2024]
Abstract
AIM To perform a direct, double-blind, randomised, crossover comparison of subcutaneous and intravenous glucagon-like peptide-1 (GLP-1) in hyperglycaemic subjects with type 2 diabetes naïve to GLP-1-based therapy. MATERIALS AND METHODS Ten fasted, hyperglycaemic subjects (1 female, age 63 ± 10 years [mean ± SD], glycated haemoglobin 73.5 ± 22.0 mmol/mol [8.9% ± 2.0%], both mean ± SD) received subcutaneous GLP-1 and intravenous saline, or intravenous GLP-1 and subcutaneous saline. Infusion rates were doubled every 120 min (1.2, 2.4, 4.8 and 9.6 pmol·kg-1·min-1 for subcutaneous, and 0.3, 0.6, 1.2 and 2.4 pmol·kg-1·min-1 for intravenous). Plasma glucose, total and intact GLP-1, insulin, C-peptide, glucagon and gastrointestinal symptoms were evaluated over 8 h. The results are presented as mean ± SEM. RESULTS Plasma glucose decreased more with intravenous (by ~8.0 mmol/L [144 mg/dL]) than subcutaneous GLP-1 (by ~5.6 mmol/L [100 mg/dL]; p < 0.001). Plasma GLP-1 increased dose-dependently, but more with intravenous than subcutaneous for both total (∆max 154.2 ± 3.9 pmol/L vs. 85.1 ± 3.8 pmol/L; p < 0.001), and intact GLP-1 (∆max 44.2 ± 2.2 pmol/L vs. 12.8 ± 2.2 pmol/L; p < 0.001). Total and intact GLP-1 clearance was higher for subcutaneous than intravenous GLP-1 (p < 0.001 and p = 0.002, respectively). The increase in insulin secretion was greater, and glucagon was suppressed more with intravenous GLP-1 (p < 0.05 each). Gastrointestinal symptoms did not differ (p > 0.05 each). CONCLUSIONS Subcutaneous GLP-1 administration is much less efficient than intravenous GLP-1 in lowering fasting plasma glucose, with less stimulation of insulin and suppression of glucagon, and much less bioavailability, even at fourfold higher infusion rates.
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Affiliation(s)
- Daniel R Quast
- Adelaide Medical School and Centre of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
- Diabetes, Endocrinology and Metabolism Section, Department of Internal Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Dara Lancaster
- Adelaide Medical School and Centre of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
| | - Cong Xie
- Adelaide Medical School and Centre of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
| | - Michelle J Bound
- Adelaide Medical School and Centre of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
| | - Jacqueline Grivell
- Adelaide Medical School and Centre of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
| | - Karen L Jones
- Adelaide Medical School and Centre of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
| | - Michael Horowitz
- Adelaide Medical School and Centre of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia
| | - Juris J Meier
- Department of Internal Medicine, Augusta-Hospital, Bochum, Germany
| | - Tongzhi Wu
- Adelaide Medical School and Centre of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
| | - Christopher K Rayner
- Adelaide Medical School and Centre of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia
| | - Michael A Nauck
- Diabetes, Endocrinology and Metabolism Section, Department of Internal Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
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Elimihele TA, Mangrola AM, Oshomoji O, Wilson NB, Nnamani I, Ashong B, Billings S, Getu DK, Kumar S, Maliakkal B. Confounding Factors in the Association Between Glucagon-Like Peptide-1 Receptor Agonist Use and Retained Gastric Contents in Asymptomatic Patients Undergoing Upper Gastrointestinal Endoscopy: A Retrospective Study. Cureus 2024; 16:e69152. [PMID: 39398811 PMCID: PMC11467768 DOI: 10.7759/cureus.69152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/10/2024] [Indexed: 10/15/2024] Open
Abstract
Introduction The use of glucagon-like peptide-1 receptor agonists (GLP-1 RA) has gained acceptance in managing diabetic and non-diabetic patients, thanks to its benefits in treating obesity and improving cardiovascular outcomes. The potential ability of GLP-1 RA to cause retained gastric contents (RGC) which can lead to aspiration has led to the recommendation to withhold GLP-1 RA for at least one week prior to elective surgeries and procedures, including upper endoscopies and colonoscopies. However, many co-medications and conditions associated can contribute to delayed gastric emptying (DGE) and these need to be controlled to establish a clear association and incidence, which has been largely missing in most studies and reports. Our aim was to assess clinically significant delayed gastric emptying (CSDGE) related to GLP-1 RA in a "real world" situation by controlling for some common confounding factors. Method We carried out an eight-year retrospective single-center study to assess the relationship between CSDGE and the use of GLP-1 RA among asymptomatic patients undergoing upper endoscopies while controlling for common confounding factors. Result Out of the 3415 patients who had esophagogastroduodenoscopy (EGD) with or without colonoscopy (Ew/woC) during the eight-year period, 129 eligible patients were found to have CSDGE. The use of GLP-1 RA was associated with the lowest percentage frequency distribution of CSDGE, at 2%, and opiate accounted for more percentage frequency distribution, at 35%. The odds ratio for patients on GLP-1 RA who developed CSDGE was 2.5 (95% CI 0.75-8.29). All patients who had CSDGE while on GLP-1 RA were also on other medications or had conditions associated with DGE. Conclusion Our result confirmed the possible effect of confounding factors in the association between CSDGE and GLP-1 RA among asymptomatic patients undergoing Ew/woC. While the need to ensure patients' safety cannot be overemphasized, the proper approach currently favors assessing patients on a case-by-case basis while we await the results of large prospective controlled studies.
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Affiliation(s)
- Thomas A Elimihele
- Department of Internal Medicine, Meharry Medical College, Nashville, USA
| | - Anjali M Mangrola
- Department of Internal Medicine, Meharry Medical College, Nashville, USA
| | - Oluwatobi Oshomoji
- Department of Internal Medicine, Meharry Medical College, Nashville, USA
| | - Nateshia B Wilson
- Department of Internal Medicine, Meharry Medical College, Nashville, USA
| | - Ikenna Nnamani
- Department of Internal Medicine, Meharry Medical College, Nashville, USA
| | - Bryan Ashong
- Department of Internal Medicine, Meharry Medical College, Nashville, USA
| | - Sunteasja Billings
- Department of Internal Medicine, Meharry Medical College, Nashville, USA
| | - Daniel K Getu
- Department of Population Health/Analytics, Nashville General Hospital, Nashville, USA
| | - Sachin Kumar
- Department of Internal Medicine, Spartan Health Sciences University School of Medicine, Vieux Fort, LCA
| | - Benedict Maliakkal
- Department of Gastroenterology and Hepatology, Nashville General Hospital, Nashville, USA
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12
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Palatini Jackson KM, Mhawish R, Komarnytsky S. Bitter Phytochemicals Acutely Lower Blood Glucose Levels by Inhibition of Glucose Absorption in the Gut. ENDOCRINES 2024; 5:304-322. [DOI: 10.3390/endocrines5030022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
For early hominids, frequent encounters with plant foods necessitated the ability to discern bitter poisons and adjust the activity of the gastrointestinal system in anticipation of carbohydrate-rich meals. Plants bitters were also used historically to manage a variety of metabolic and digestive disorders despite an immense structural diversity of bitter phytochemicals without a common molecular target. Our study confirms these observations in a standardized C57BL/6J prediabetic mouse model using 24 model compounds by demonstrating acute lower peak blood glucose values and improved glucose tolerance following intragastric, but not intraperitoneal, treatment. The administration of the synthetic bitter compound denatonium benzoate yielded similar results that were attenuated by co-application of the allosteric inhibitor of the bitter TAS2R receptors. We also show that these effects occur dose-dependently; associate with reduced glucose uptake, increased intracellular [Ca2+] fluxes, and enhanced GLP-1 expression; and are attenuated by the TAS2R inhibitor in the neuroendocrine STC-1 intestinal cells. These findings support the view that inhibition of glucose transport from the intestinal lumen to the blood by TAS2R bitter receptor signaling in the gut may represent a common mechanism in the acute response to oral ingestion of bitter phytochemicals.
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Affiliation(s)
| | - Reham Mhawish
- Plants for Human Health Institute, North Carolina State University, 600 Laureate Way, Kannapolis, NC 28081, USA
| | - Slavko Komarnytsky
- Plants for Human Health Institute, North Carolina State University, 600 Laureate Way, Kannapolis, NC 28081, USA
- Department of Food, Bioprocessing, and Nutrition Sciences, North Carolina State University, 400 Dan Allen Drive, Raleigh, NC 27695, USA
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13
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Liu QK. Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists. Front Endocrinol (Lausanne) 2024; 15:1431292. [PMID: 39114288 PMCID: PMC11304055 DOI: 10.3389/fendo.2024.1431292] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 07/08/2024] [Indexed: 08/10/2024] Open
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two incretins that bind to their respective receptors and activate the downstream signaling in various tissues and organs. Both GIP and GLP-1 play roles in regulating food intake by stimulating neurons in the brain's satiety center. They also stimulate insulin secretion in pancreatic β-cells, but their effects on glucagon production in pancreatic α-cells differ, with GIP having a glucagonotropic effect during hypoglycemia and GLP-1 exhibiting glucagonostatic effect during hyperglycemia. Additionally, GIP directly stimulates lipogenesis, while GLP-1 indirectly promotes lipolysis, collectively maintaining healthy adipocytes, reducing ectopic fat distribution, and increasing the production and secretion of adiponectin from adipocytes. Together, these two incretins contribute to metabolic homeostasis, preventing both hyperglycemia and hypoglycemia, mitigating dyslipidemia, and reducing the risk of cardiovascular diseases in individuals with type 2 diabetes and obesity. Several GLP-1 and dual GIP/GLP-1 receptor agonists have been developed to harness these pharmacological effects in the treatment of type 2 diabetes, with some demonstrating robust effectiveness in weight management and prevention of cardiovascular diseases. Elucidating the underlying cellular and molecular mechanisms could potentially usher in the development of new generations of incretin mimetics with enhanced efficacy and fewer adverse effects. The treatment guidelines are evolving based on clinical trial outcomes, shaping the management of metabolic and cardiovascular diseases.
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Affiliation(s)
- Qiyuan Keith Liu
- MedStar Medical Group, MedStar Montgomery Medical Center, Olney, MD, United States
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14
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Ghazanfar H, Javed N, Qasim A, Sosa F, Altaf F, Khan S, Mahasamudram J, Jyala A, Kandhi SD, Shin D, Mantri N, Sun H, Hanumanthu S, Patel H, Makker J, Balar B, Dev A, Chilimuri S. Is it necessary to stop glucagon-like peptide-1 receptor agonists prior to endoscopic procedure? A retrospective study. World J Gastroenterol 2024; 30:3221-3228. [PMID: 39086638 PMCID: PMC11287410 DOI: 10.3748/wjg.v30.i26.3221] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 05/14/2024] [Accepted: 06/24/2024] [Indexed: 07/09/2024] Open
Abstract
BACKGROUND Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are effective in diabetes and obesity, reducing hyperglycemia by increasing insulin release and delaying gastric emptying. However, they can cause gastroparesis, raising concerns about aspiration during procedures. Recent guidelines advise discontinuing GLP-1 RA before surgery to reduce the risk of pulmonary aspiration. AIM To evaluate the effect of GLP-1 RAs on gastric residual contents during endoscopic procedures. METHODS A retrospective chart review at BronxCare Health System, New York, from January 2019 to October 2023, assessed gastric residue and aspiration in GLP-1 RA patients undergoing endoscopic procedures. Two groups were compared based on dietary status before the procedure. Data included demographics, symptoms of gastroparesis, opiate use, hemoglobin A1c, GLP-1 agonist indication, endoscopic details, and aspiration occurrence. IBM SPSS was used for analysis, calculating means, standard deviations, and applying Pearson's chi-square and t-tests for associations, with P < 0.05 as being significant. RESULTS During the study, 306 patients were included, with 41.2% on a clear liquid/low residue diet and 58.8% on a regular diet before endoscopy. Most patients (63.1%) were male, with a mean age of 60 ± 12 years. The majority (85.6%) were on GLP-1 RAs for diabetes, and 10.1% reported digestive symptoms before endoscopy. Among those on a clear liquid diet, 1.5% had residual food at endoscopy compared to 10% on a regular diet, which was statistically significant (P = 0.03). Out of 31 patients with digestive symptoms, 13% had residual food, all from the regular diet group (P = 0.130). No complications were reported during or after the procedures. CONCLUSION The study reflects a significant rise in GLP-1 RA use for diabetes and obesity. A 24-hour liquid diet seems safe for endoscopic procedures without aspiration. Patients with upper gastrointestinal symptoms might have a higher residual food risk, though not statistically significant. Further research is needed to assess risks based on diabetes duration, gastroparesis, and GLP-1 RA dosing, aiming to minimize interruptions in therapy during procedures.
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Affiliation(s)
- Haider Ghazanfar
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Nismat Javed
- Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Abeer Qasim
- Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Franklin Sosa
- Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Faryal Altaf
- Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Shazia Khan
- Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Jaydeep Mahasamudram
- Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Abhilasha Jyala
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Sameer Datta Kandhi
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Dongmin Shin
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Nikhitha Mantri
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Haozhe Sun
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Siddarth Hanumanthu
- Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Harish Patel
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Jasbir Makker
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Bhavna Balar
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Anil Dev
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
| | - Sridhar Chilimuri
- Division of Gastroenterology, Department of Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, Bronx, NY 10457, United States
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15
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Fediuk DJ, Gorman DN, Stoddard SA, Zhang Y, Ogden AG, Winton JA, Saxena AR. Effect of Renal Impairment on the Pharmacokinetics of a Single Oral Dose of Danuglipron in Participants With Type 2 Diabetes. J Clin Pharmacol 2024; 64:449-460. [PMID: 37840155 DOI: 10.1002/jcph.2371] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 10/11/2023] [Indexed: 10/17/2023]
Abstract
Danuglipron (PF-06882961) is an oral, small-molecule glucagon-like peptide-1 receptor agonist in development for the treatment of type 2 diabetes (T2D) and obesity. Impaired renal function is prevalent in patients with T2D. This Phase 1, open-label study evaluated the effect of renal impairment on the pharmacokinetics, safety, and tolerability of danuglipron (20 mg) in healthy participants with normal renal function (estimated glomerular filtration rate [eGFR] unnormalized for body surface area: ≥90 mL/min), in participants with T2D and normal renal function (eGFR ≥90 mL/min), and in participants with T2D and mild (eGFR 60-89 mL/min), moderate (eGFR 30-59 mL/min), or severe (eGFR <30 mL/min) renal impairment (N = 39). Log-linear regression analyses and analyses of variance showed no evidence of a clinically significant effect of reduced renal function on danuglipron pharmacokinetics. Renal clearance of unchanged danuglipron was minimal (<1% across all renal function groups). Danuglipron pharmacokinetics were similar between healthy participants and participants with T2D and normal renal function. A single 20-mg oral dose of danuglipron was generally safe and well tolerated in all participant groups. In participants with T2D, renal impairment had no clinically meaningful effect on the pharmacokinetic, safety, and tolerability profiles of danuglipron, indicating that dose adjustment of danuglipron will not be required when administered to patients with T2D and reduced renal function.
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Affiliation(s)
- Daryl J Fediuk
- Clinical Pharmacology and Bioanalytics, Pfizer Worldwide Research, Development and Medical, Groton, CT, USA
| | - Donal N Gorman
- Global Biometrics and Data Management, Pfizer Global Product Development, Cambridge, UK
| | - Stephanie-An Stoddard
- Early Clinical Development, Clinical Sciences, Pfizer Worldwide Research, Development and Medical, Cambridge, MA, USA
| | - Yizhong Zhang
- Clinical Pharmacology and Bioanalytics, Pfizer Worldwide Research, Development and Medical, Groton, CT, USA
| | - Adam G Ogden
- Clinical Pharmacology and Bioanalytics, Pfizer Worldwide Research, Development and Medical, Groton, CT, USA
| | - Jennifer A Winton
- Clinical Pharmacology and Bioanalytics, Pfizer Worldwide Research, Development and Medical, Groton, CT, USA
| | - Aditi R Saxena
- Internal Medicine Research Unit, Pfizer Worldwide Research, Development and Medical, Cambridge, MA, USA
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16
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Pelluri R, Kongara S, Nagasubramanian VR, Mahadevan S, Chimakurthy J. Effect of Teneligliptin 20 mg Twice Daily on Glucagon-Like Peptide-1 Levels and Its Influence on Non-Glycemic Components in Non-Diabetic Obese Individuals. Metab Syndr Relat Disord 2024; 22:90-96. [PMID: 38165660 DOI: 10.1089/met.2023.0218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2024] Open
Abstract
Background and Aims: Teneligliptin is an oral antidiabetic agent, it can persevere glucagon-like peptide-1 (GLP-1) by inhibiting dipeptidyl peptidase enzyme. In addition, it has rare incidence of hypoglycemia. Hence, this study aimed to test the effect of teneligliptin 20 mg twice daily along with low carbohydrate diet and physical exercise on change of body weight and insulin resistance in nondiabetic obese subjects. Materials and Methods: It is a prospective, randomized, double-blind, placebo-controlled, parallel group study carried out at outpatient department of an endocrinology hospital over the period of 48 weeks. Teneligliptin 20 mg twice daily 30 min before food (low carbohydrate diet [LCD]) with regular physical exercise, and control group was kept with placebo twice daily 30 min before food LCD with regular physical exercise. This study was registered in clinical trial registry of India [CTRI/2020/02/023329]. Results: A total of 150 nondiabetic obese subjects were randomized into test (n = 75) and control groups (n = 75). At the end of 48 weeks there was significant improvement in GLP-1, simplified nutrition assessment questionnaire (SNAQ) score, homeostasis model assessment of insulin resistance (HOMA-IR), triglycerides (TG), and body weight. The mean difference and 95% confidence interval of GLP-1 (pg/mL) was 76.42 (44.42-148.41) (P = 0.37); SNAQ score, -1.64 (-2.48 to -0.81) (P = 0.000); HOMA-IR, -0.9 (-0.59 to -0.38) (P = 0.000); TG (mg/dL) -29.37 (-44.46 to -14.07) (P = 0.000); reduction of body weight (kilograms) -3.09 (-6.11 to -0.07) (P = 0.043). Conclusion: Findings of this study reveals that teneligliptin-treated group showed significant improvement in GLP-1 levels, reduced insulin resistance, body weight, TG, appetite, and metabolic syndrome. Teneligliptin is well tolerated, except in upper respiratory tract infections. CTR number: CTRI/2020/02/023329.
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Affiliation(s)
- Ranakishor Pelluri
- Department of Pharmacy Practice, Sri Ramachandra Institute of Higher Education Research, (Deemed to be University), Chennai, India
- Department of Endocrinology and Metabolism, Endolife Speciality Hospital, Guntur, India
- Department of Pharmaceutical Sciences, Vignan's Foundation for Science Technology and Research, (Deemed to be University), Guntur, India
| | - Srikanth Kongara
- Department of Endocrinology and Metabolism, Endolife Speciality Hospital, Guntur, India
| | | | - Shriraam Mahadevan
- Department of Endocrinology and Metabolism, Sri Ramachandra Institute of Higher Education and Research, (Deemed to be University), Chennai, India
| | - Jithendra Chimakurthy
- Department of Pharmaceutical Sciences, Vignan's Foundation for Science Technology and Research, (Deemed to be University), Guntur, India
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17
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Li X, Petrov MS. Dietary Fibre for the Prevention of Post-Pancreatitis Diabetes Mellitus: A Review of the Literature and Future Research Directions. Nutrients 2024; 16:435. [PMID: 38337719 PMCID: PMC10857198 DOI: 10.3390/nu16030435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/30/2024] [Accepted: 01/30/2024] [Indexed: 02/12/2024] Open
Abstract
Post-pancreatitis diabetes mellitus-the most common sequela of pancreatitis-leads to poorer glycaemic control compared with type 2 diabetes. Because post-pancreatitis diabetes mellitus is an exemplar of secondary diabetes (with a clear underlying cause), much post-pancreatitis diabetes mellitus is preventable or treatable early. Earlier literature established the important role of dietary fibre in reducing plasma glucose in individuals with type 2 diabetes. The present review benchmarks available evidence on the role of habitual dietary fibre intake in pancreatitis and post-pancreatitis diabetes mellitus. It also paves the way for future research on the use of dietary fibre in the post-pancreatitis setting.
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Affiliation(s)
| | - Maxim S. Petrov
- School of Medicine, University of Auckland, Auckland 1023, New Zealand
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18
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Otvos L, Wade JD. Big peptide drugs in a small molecule world. Front Chem 2023; 11:1302169. [PMID: 38144886 PMCID: PMC10740154 DOI: 10.3389/fchem.2023.1302169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 11/24/2023] [Indexed: 12/26/2023] Open
Abstract
A quarter of a century ago, designer peptide drugs finally broke through the glass ceiling. Despite the resistance by big pharma, biotechnology companies managed to develop injectable peptide-based drugs, first against orphan or other small volume diseases, and later for conditions affecting large patient populations such as type 2 diabetes. Even their lack of gastrointestinal absorption could be utilized to enable successful oral dosing against chronic constipation. The preference of peptide therapeutics over small molecule competitors against identical medical conditions can be achieved by careful target selection, intrachain and terminal amino acid modifications, appropriate conjugation to stability enhancers and chemical space expansion, innovative delivery and administration techniques and patient-focused marketing strategies. Unfortunately, however, pharmacoeconomical considerations, including the strength of big pharma to develop competing small molecule drugs, have somewhat limited the success of otherwise smart peptide-based therapeutics. Yet, with increasing improvement in peptide drug modification and formulation, these are continuing to gain significant, and growing, acceptance as desirable alternatives to small molecule compounds.
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Affiliation(s)
- Laszlo Otvos
- Institute of Medical Microbiology, Semmelweis University, Budapest, Hungary
- OLPE Pharmaceutical Consultants, Audubon, PA, United States
| | - John D. Wade
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
- School of Chemistry, University of Melbourne, Parkville, VIC, Australia
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19
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Salgado-Delgado RC, Espinosa-Tanguma R, Valdés Abadía B, Ramírez-Plascencia OD, Escobar C, Saderi N. Feeding during the resting phase causes gastrointestinal tract dysfunction and desynchronization of metabolic and neuronal rhythms in rats. Neurogastroenterol Motil 2023; 35:e14687. [PMID: 37815021 DOI: 10.1111/nmo.14687] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 09/15/2023] [Accepted: 09/25/2023] [Indexed: 10/11/2023]
Abstract
BACKGROUND Disrupted circadian rhythms may result from a misalignment between the environmental cycles (due to shift work, sleep restriction, feeding at an unusual time of day) and endogenous rhythms or by physiological aging. Among the numerous adverse effects, disrupted rhythms affect the brain-gut axis, contributing to the pathogenesis of several diseases in the gastrointestinal tract, for example, abdominal pain, constipation, gastric dyspepsia, inflammatory bowel disease, irritable bowel syndrome, and others. METHODS This study evaluated the rat gastric emptying, gastrointestinal motility, a clock gene, gut hormones, and the neuron activity on the nucleus of tractus solitarius (NTS), area postrema (AP), and the dorsal motor nucleus of the vagus (DMV) in rats with restricted food access to the rest phase for 4 weeks. KEY RESULTS Our results show that food restricted to the rest light period disturbed the expression pattern of a series of transcripts, including metabolic and circadian regulation. Also, the secretion of gastrointestinal hormones, gastric emptying, intestinal motility, and NTS, AP, and DMV activity were altered. CONCLUSIONS & INFERENCES These data indicate the importance of the time of the day food is ingested on the regulation of energy balance and the endocrine activity of the stomach and small intestine, emphasizing the importance of food as a powerful circadian synchronizer and an essential factor for the triggering of gastrointestinal diseases and metabolic problems. These findings offer a novel clue regarding the obesity-promoting effect attributed to feeding time and open the possibility of treating this and other intestinal disorders.
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Affiliation(s)
| | - Ricardo Espinosa-Tanguma
- Facultad de Medicina, Departamento de Fisiología y Biofísica, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
| | - Belkis Valdés Abadía
- Facultad de Medicina, Departamento de Fisiología y Biofísica, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
| | | | - Carolina Escobar
- Facultad de Medicina, Departamento de Anatomía, Universidad Nacional Autónoma de México, Mexico, Mexico
| | - Nadia Saderi
- Facultad de Ciencias, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
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20
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Aspnes GE, Bagley SW, Coffey SB, Conn EL, Curto JM, Edmonds DJ, Genovino J, Griffith DA, Ingle G, Jiao W, Limberakis C, Mathiowetz AM, Piotrowski DW, Rose CR, Ruggeri RB, Wei L. 6-Azaspiro[2.5]octanes as small molecule agonists of the human glucagon-like peptide-1 receptor. Bioorg Med Chem Lett 2023; 94:129454. [PMID: 37591316 DOI: 10.1016/j.bmcl.2023.129454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 07/05/2023] [Accepted: 08/14/2023] [Indexed: 08/19/2023]
Abstract
Activation of the glucagon-like peptide-1 (GLP-1) receptor stimulates insulin release, lowers plasma glucose levels, delays gastric emptying, increases satiety, suppresses food intake, and affords weight loss in humans. These beneficial attributes have made peptide-based agonists valuable tools for the treatment of type 2 diabetes mellitus and obesity. However, efficient, and consistent delivery of peptide agents generally requires subcutaneous injection, which can reduce patient utilization. Traditional orally absorbed small molecules for this target may offer improved patient compliance as well as the opportunity for co-formulation with other oral therapeutics. Herein, we describe an SAR investigation leading to small-molecule GLP-1 receptor agonists that represent a series that parallels the recently reported clinical candidate danuglipron. In the event, identification of a benzyloxypyrimidine lead, using a sensitized high-throughput GLP-1 agonist assay, was followed by optimization of the SAR using substituent modifications analogous to those discovered in the danuglipron series. A new series of 6-azaspiro[2.5]octane molecules was optimized into potent GLP-1 agonists. Information gleaned from cryogenic electron microscope structures was used to rationalize the SAR of the optimized compounds.
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Affiliation(s)
- Gary E Aspnes
- Pfizer Medicine Design, Cambridge, MA 02139, United States
| | | | | | - Edward L Conn
- Pfizer Medicine Design, Groton, CT 06340, United States
| | - John M Curto
- Pfizer Medicine Design, Groton, CT 06340, United States
| | | | | | | | | | - Wenhua Jiao
- Pfizer Medicine Design, Groton, CT 06340, United States
| | | | | | | | - Colin R Rose
- Pfizer Medicine Design, Groton, CT 06340, United States
| | | | - Liuqing Wei
- Pfizer Medicine Design, Groton, CT 06340, United States
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21
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Panfili E, Frontino G, Pallotta MT. GLP-1 receptor agonists as promising disease-modifying agents in WFS1 spectrum disorder. FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2023; 4:1171091. [PMID: 37333802 PMCID: PMC10275359 DOI: 10.3389/fcdhc.2023.1171091] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 05/22/2023] [Indexed: 06/20/2023]
Abstract
WFS1 spectrum disorder (WFS1-SD) is a rare monogenic neurodegenerative disorder whose cardinal symptoms are childhood-onset diabetes mellitus, optic atrophy, deafness, diabetes insipidus, and neurological signs ranging from mild to severe. The prognosis is poor as most patients die prematurely with severe neurological disabilities such as bulbar dysfunction and organic brain syndrome. Mutation of the WFS1 gene is recognized as the prime mover of the disease and responsible for a dysregulated ER stress signaling, which leads to neuron and pancreatic β-cell death. There is no currently cure and no treatment that definitively arrests the progression of the disease. GLP-1 receptor agonists appear to be an efficient way to reduce elevated ER stress in vitro and in vivo, and increasing findings suggest they could be effective in delaying the progression of WFS1-SD. Here, we summarize the characteristics of GLP-1 receptor agonists and preclinical and clinical data obtained by testing them in WFS1-SD as a feasible strategy for managing this disease.
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Affiliation(s)
- Eleonora Panfili
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Giulio Frontino
- Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Hospital, Milano, Italy
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22
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Wibawa IDN, Mariadi IK, Somayana G, Krisnawardani Kumbara CIY, Sindhughosa DA. Diabetes and fatty liver: Involvement of incretin and its benefit for fatty liver management. World J Diabetes 2023; 14:549-559. [PMID: 37273247 PMCID: PMC10237000 DOI: 10.4239/wjd.v14.i5.549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 02/02/2023] [Accepted: 04/11/2023] [Indexed: 05/15/2023] Open
Abstract
Fatty liver disease is defined as liver condition characterized by hepatic steatosis, closely related to pathological conditions in type 2 diabetes and obesity. The high prevalence of fatty liver disease in obese patients with type 2 diabetes reached 70%, reflecting the importance of these conditions with fatty liver. Although the exact pathological mechanism of fatty liver disease, specifically non-alcoholic fatty liver disease (NAFLD) remains not completely revealed, insulin resistance is suggested as the major mechanism that bridged the development of NAFLD. Indeed, loss of the incretin effect leads to insulin resistance. Since incretin is closely related to insulin resistance and the resistance of insulin associated with the development of fatty liver disease, this pathway suggested a potential me-chanism that explains the association between type 2 diabetes and NAFLD. Furthermore, recent studies indicated that NAFLD is associated with impaired glucagon-like peptide-1, resulting in decreased incretin effect. Nevertheless, improving the incretin effect becomes a reasonable approach to manage fatty liver disease. This review elucidates the involvement of incretin in fatty liver disease and recent studies of incretin as the management for fatty liver disease.
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Affiliation(s)
- I Dewa Nyoman Wibawa
- Department of Internal Medicine, Gastroentero-hepatology Division, Udayana University, Faculty of Medicine, Denpasar 80233, Bali, Indonesia
| | - I Ketut Mariadi
- Department of Internal Medicine, Gastroentero-hepatology Division, Udayana University, Faculty of Medicine, Denpasar 80233, Bali, Indonesia
| | - Gde Somayana
- Department of Internal Medicine, Gastroentero-hepatology Division, Udayana University, Faculty of Medicine, Denpasar 80233, Bali, Indonesia
| | | | - Dwijo Anargha Sindhughosa
- Internal Medicine Resident, Udayana University, Faculty of Medicine, Denpasar 80233, Bali, Indonesia
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23
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Caiazzo R, Marciniak C, Rémond A, Baud G, Pattou F. Future of bariatric surgery beyond simple weight loss: Metabolic surgery. J Visc Surg 2023; 160:S55-S62. [PMID: 36774271 DOI: 10.1016/j.jviscsurg.2023.01.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Anatomical modifications implemented during bariatric surgery not only result in weight loss, but also lead to metabolic corrections that translate into better glycemia stability and improvement in cardiovascular and liver disorders. The logical extension of surgical indications beyond mere reduction of the body mass index (BMI) (i.e. patients with<35kg/m2) is a hot topic today in France and worldwide. Metabolic surgeries make use of multiple modalities (endoscopic, mini-invasive, invasive) that should be carried out by trained physicians and within the same type of multidisciplinary formation as that for bariatric surgery. The aim of this update is to describe the physiological mechanisms that result in the benefits of bariatric surgery, the various procedures currently available and the perspectives for this new field in visceral and digestive surgery.
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Affiliation(s)
- R Caiazzo
- General and Endocrine Surgery Department, Inuversity Hospital of Lille, Lille, France.
| | - C Marciniak
- General and Endocrine Surgery Department, Inuversity Hospital of Lille, Lille, France
| | - A Rémond
- General and Endocrine Surgery Department, Inuversity Hospital of Lille, Lille, France
| | - G Baud
- General and Endocrine Surgery Department, Inuversity Hospital of Lille, Lille, France
| | - F Pattou
- General and Endocrine Surgery Department, Inuversity Hospital of Lille, Lille, France
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24
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de Laat MA, Fitzgerald DM, Harris PA, Bailey SR. A glucagon-like peptide-1 receptor antagonist reduces the insulin response to a glycemic meal in ponies. J Anim Sci 2023; 101:skad389. [PMID: 38066683 PMCID: PMC10724109 DOI: 10.1093/jas/skad389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 12/05/2023] [Indexed: 12/18/2023] Open
Abstract
High plasma concentrations of insulin can cause acute laminitis. Ponies and horses with insulin dysregulation (ID) exhibit marked hyperinsulinemia in response to dietary hydrolyzable carbohydrates. Glucagon-like peptide-1 (GLP-1), an incretin hormone released from the gastrointestinal tract, enhances insulin release, and is increased postprandially in ponies with ID. The aim of this study was to determine whether blocking the GLP-1 receptor reduces the insulin response to a high glycemic meal. Five adult ponies were adapted to a cereal meal and then given two feed challenges 24 h apart of a meal containing 3 g/kg BW micronized maize. Using a randomized cross-over design all ponies received both treatments, where one of the feeds was preceded by the IV administration of a GLP-1 receptor blocking peptide, Exendin-3 (9-39) amide (80 µg/kg), and the other feed by a sham treatment of peptide diluent only. Blood samples were taken before feeding and peptide administration, and then at 30-min intervals via a jugular catheter for 6 h for the measurement of insulin, glucose, and active GLP-1. The peptide and meal challenge caused no adverse effects, and the change in plasma glucose in response to the meal was not affected (P = 0.36) by treatment: peak concentration 9.24 ± 1.22 and 9.14 ± 1.08 mmol/L without and with the antagonist, respectively. Similarly, there was no effect (P = 0.35) on plasma active GLP-1 concentrations: peak concentration 14.3 ± 1.36 pM and 13.7 ± 1.97 pM without and with the antagonist, respectively. However, the antagonist caused a significant decrease in the area under the curve for insulin (P = 0.04), and weak evidence (P = 0.06) of a reduction in peak insulin concentration (456 ± 147 μIU/mL and 370 ± 146 μIU/mL without and with the antagonist, respectively). The lower overall insulin response to the maize meal after treatment with the antagonist demonstrates that blocking the GLP-1 receptor partially reduced insulin production in response to a high starch, high glycemic index, diet. Using a different methodological approach to published studies, this study also confirmed that GLP-1 does contribute to the excessive insulin production in ponies with ID.
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Affiliation(s)
- Melody A de Laat
- Faculty of Science, Queensland University of Technology, Brisbane, QLD, Australia
| | | | - Patricia A Harris
- Equine Studies Group, Waltham Petcare Science Institute, Melton Mowbray, UK
| | - Simon R Bailey
- Melbourne Veterinary School, The University of Melbourne, Parkville, VIC, Australia
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25
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Tong Y, Huang JQ, Chen Y, Tu M, Wang W. Impact of glucagon-like peptide 1 receptor agonist liraglutide and dipeptidyl peptidase-4 inhibitor sitagliptin on bowel cleaning and gastrointestinal symptoms in type 2 diabetes. Front Pharmacol 2023; 14:1176206. [PMID: 37089939 PMCID: PMC10115949 DOI: 10.3389/fphar.2023.1176206] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 03/29/2023] [Indexed: 04/25/2023] Open
Abstract
Objective: Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4i) profoundly affect the gastrointestinal motor system, which may increase the incidence of inadequate bowel cleaning and gastrointestinal symptoms. Hence, this observational study mainly aimed to assess the influence of GLP-1 RAs liraglutide and DPP-4i sitagliptin on bowel preparation in type 2 diabetes (T2DM). Method: This observational study consecutively enrolled T2DM scheduled for a colonoscopy. Participants were prospectively separated into the liraglutide group (n = 120), sitagliptin group (n = 120), and control group (n = 120) based on the current hypoglycemic regimen. 3L split-dose polyethylene glycol regimens were used for bowel preparation. Experienced gastrointestinal endoscopists conducted colonoscopies. Lawrance Bowel-Preparation Tolerability Questionnaire and Boston Bowel Preparation Scale (BBPS) were conducted to assess bowel cleaning quality, tolerability, and safety. Results: The incidence of inadequate bowel cleaning was 17.5% in the liraglutide group, 20.5% in the sitagliptin group, and 21.7% in the control group. The difference among the three groups was not statistically significant (p = 0.927). Meanwhile, there were no significant differences in the mean BBPS, cecal intubation time, and polyp-detecting rates among the three groups (all p > 0.0.05). Nausea, vomiting, and bloating scores were increased in the liraglutide group compared with the other two groups (p < 0.05), whereas most were mild or very mild. Subgroup analyses showed that the incidence of inadequate bowel cleaning in T2DM with diabetic peripheral neuropathy (DPN) was increased in the liraglutide group compared with the sitagliptin group (61.3% vs. 32.1%, p = 0.022) and control group (61.3% vs. 32.8%, p = 0.025). Conclusion: GLP-1RA liraglutide or DPP-4i sitagliptin did not significantly increase the incidence of inadequate bowel cleaning and gastrointestinal symptoms during bowel preparation. Liraglutide may increase the incidence of inadequate bowel preparation in patients with DPN. This study reveal that more attention and aggressive bowel preparation regimens should be given to the T2DM with DPN. Clinical Trial Registration: (https://www.chictr.org.cn/index.aspx), identifier (ChiCTR2200056148).
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Affiliation(s)
| | | | | | - Mei Tu
- *Correspondence: Wei Wang, ; Mei Tu,
| | - Wei Wang
- *Correspondence: Wei Wang, ; Mei Tu,
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26
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Sridhar A, Khan D, Abdelaal M, Elliott JA, Naughton V, Flatt PR, Le Roux CW, Docherty NG, Moffett CR. Differential effects of RYGB surgery and best medical treatment for obesity-diabetes on intestinal and islet adaptations in obese-diabetic ZDSD rats. PLoS One 2022; 17:e0274788. [PMID: 36137097 PMCID: PMC9499270 DOI: 10.1371/journal.pone.0274788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 09/05/2022] [Indexed: 11/19/2022] Open
Abstract
Modification of gut-islet secretions after Roux-En-Y gastric bypass (RYBG) surgery contributes to its metabolic and anti-diabetic benefits. However, there is limited knowledge on tissue-specific hormone distribution post-RYGB surgery and how this compares with best medical treatment (BMT). In the present study, pancreatic and ileal tissues were excised from male Zucker-Diabetic Sprague Dawley (ZDSD) rats 8-weeks after RYGB, BMT (daily oral dosing with metformin 300mg/kg, fenofibrate 100mg/kg, ramipril 1mg/kg, rosuvastatin 10mg/kg and subcutaneous liraglutide 0.2mg/kg) or sham operation (laparotomy). Insulin, glucagon, somatostatin, PYY, GLP-1 and GIP expression patterns were assessed using immunocytochemistry and analyzed using ImageJ. After RYGB and BMT, body weight and plasma glucose were decreased. Intestinal morphometry was unaltered by RYGB, but crypt depth was decreased by BMT. Intestinal PYY cells were increased by both interventions. GLP-1- and GIP-cell counts were unchanged by RYGB but BMT increased ileal GLP-1-cells and decreased those expressing GIP. The intestinal contents of PYY and GLP-1 were significantly enhanced by RYGB, whereas BMT decreased ileal GLP-1. No changes of islet and beta-cell area or proliferation were observed, but the extent of beta-cell apoptosis and islet integrity calculated using circularity index were improved by both treatments. Significantly decreased islet alpha-cell areas were observed in both groups, while beta- and PYY-cell areas were unchanged. RYGB also induced a decrease in islet delta-cell area. PYY and GLP-1 colocalization with glucagon in islets was significantly decreased in both groups, while co-staining of PYY with glucagon was decreased and that with somatostatin increased. These data characterize significant cellular islet and intestinal adaptations following RYGB and BMT associated with amelioration of obesity-diabetes in ZDSD rats. The differential responses observed and particularly those within islets, may provide important clues to the unique ability of RYGB to cause diabetes remission.
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Affiliation(s)
- Ananyaa Sridhar
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, United Kingdom
| | - Dawood Khan
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, United Kingdom
- * E-mail:
| | - Mahmoud Abdelaal
- Diabetes Complications Research Centre, School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Jessie A. Elliott
- Department of Surgery, Trinity Centre for Health Sciences and St. James’s Hospital, Dublin, Ireland
| | - Violetta Naughton
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, United Kingdom
| | - Peter R. Flatt
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, United Kingdom
| | - Carel W. Le Roux
- Diabetes Complications Research Centre, School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Neil G. Docherty
- Diabetes Complications Research Centre, School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Charlotte R. Moffett
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, United Kingdom
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Teysseire F, Flad E, Bordier V, Budzinska A, Weltens N, Rehfeld JF, Beglinger C, Van Oudenhove L, Wölnerhanssen BK, Meyer-Gerspach AC. Oral Erythritol Reduces Energy Intake during a Subsequent ad libitum Test Meal: A Randomized, Controlled, Crossover Trial in Healthy Humans. Nutrients 2022; 14:nu14193918. [PMID: 36235571 PMCID: PMC9571225 DOI: 10.3390/nu14193918] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 09/16/2022] [Accepted: 09/19/2022] [Indexed: 11/16/2022] Open
Abstract
The impact of oral erythritol on subsequent energy intake is unknown. The aim was to assess the effect of oral erythritol compared to sucrose, sucralose, or tap water on energy intake during a subsequent ad libitum test meal and to examine the release of cholecystokinin (CCK) in response to these substances. In this randomized, crossover trial, 20 healthy volunteers received 50 g erythritol, 33.5 g sucrose, or 0.0558 g sucralose dissolved in tap water, or tap water as an oral preload in four different sessions. Fifteen minutes later, a test meal was served and energy intake was assessed. At set time points, blood samples were collected to quantify CCK concentrations. The energy intake (ad libitum test meal) was significantly lower after erythritol compared to sucrose, sucralose, or tap water (p < 0.05). Before the start of the ad libitum test meal, erythritol led to a significant increase in CCK compared to sucrose, sucralose, or tap water (p < 0.001). Oral erythritol given alone induced the release of CCK before the start of the ad libitum test meal and reduced subsequent energy intake compared to sucrose, sucralose, or tap water. These properties make erythritol a useful sugar alternative.
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Affiliation(s)
- Fabienne Teysseire
- St. Clara Research Ltd. at St. Claraspital, 4002 Basel, Switzerland
- Faculty of Medicine, University of Basel, 4001 Basel, Switzerland
| | - Emilie Flad
- St. Clara Research Ltd. at St. Claraspital, 4002 Basel, Switzerland
- Faculty of Medicine, University of Basel, 4001 Basel, Switzerland
| | - Valentine Bordier
- St. Clara Research Ltd. at St. Claraspital, 4002 Basel, Switzerland
- Faculty of Medicine, University of Basel, 4001 Basel, Switzerland
| | - Aleksandra Budzinska
- Translational Research Center for Gastrointestinal Disorders, Laboratory for Brain-Gut Axis Studies, Department of Chronic Diseases and Metabolism, Catholic University of Leuven, 3000 Leuven, Belgium
- Leuven Brain Institute, Catholic University of Leuven, 3000 Leuven, Belgium
| | - Nathalie Weltens
- Translational Research Center for Gastrointestinal Disorders, Laboratory for Brain-Gut Axis Studies, Department of Chronic Diseases and Metabolism, Catholic University of Leuven, 3000 Leuven, Belgium
- Leuven Brain Institute, Catholic University of Leuven, 3000 Leuven, Belgium
| | - Jens F. Rehfeld
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, 1172 Copenhagen, Denmark
| | | | - Lukas Van Oudenhove
- Translational Research Center for Gastrointestinal Disorders, Laboratory for Brain-Gut Axis Studies, Department of Chronic Diseases and Metabolism, Catholic University of Leuven, 3000 Leuven, Belgium
- Leuven Brain Institute, Catholic University of Leuven, 3000 Leuven, Belgium
- Cognitive and Affective Neuroscience Lab, Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH 03755, USA
| | - Bettina K. Wölnerhanssen
- St. Clara Research Ltd. at St. Claraspital, 4002 Basel, Switzerland
- Faculty of Medicine, University of Basel, 4001 Basel, Switzerland
| | - Anne Christin Meyer-Gerspach
- St. Clara Research Ltd. at St. Claraspital, 4002 Basel, Switzerland
- Faculty of Medicine, University of Basel, 4001 Basel, Switzerland
- Correspondence: ; Tel.: +41-61-685-85
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Muangchan N, Khiewvan B, Chatree S, Pongwattanapakin K, Kunlaket N, Dokmai T, Chaikomin R. Riceberry rice ( Oryza sativa L.) slows gastric emptying and improves the postprandial glycaemic response. Br J Nutr 2022; 128:424-432. [PMID: 34503597 DOI: 10.1017/s0007114521003494] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Postprandial glycaemia is a key determinant of overall glycaemic control. One mechanism by which dietary strategies can reduce postprandial glycaemic excursions is by slowing gastric emptying. This study aimed to evaluate the acute effect of ingesting riceberry rice (RR) compared with that of ingesting white rice (WR) on gastric emptying rate (GER), plasma glucose and glucose-regulating hormones, including insulin, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), in healthy subjects. A randomised, open-label, within-subject, crossover study was performed in six healthy men. GER was measured by scintigraphy over 240 min, and plasma concentrations of glucose, insulin, GLP-1 and GIP were measured at multiple time points over 180 min. This study revealed that RR slows GER with a reduction in postprandial plasma glucose concentrations compared with WR. Plasma insulin and GLP-1 concentrations did not differ between RR and WR. However, plasma GIP concentrations were markedly increased after WR ingesting v. after RR ingestion. We conclude that RR attenuates postprandial glycaemia by slowing GER without altering plasma insulin or GLP-1. Plasma GIP concentrations are likely related to differences in GER and carbohydrate absorption. We propose that dietary fibre-enriched foods, including RR, could contribute to improvement in postprandial glycaemia via delayed gastric emptying.
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Affiliation(s)
- Nipaporn Muangchan
- Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, 85 Satholamark Rd., Warin Chamrap, Ubon Ratchathani34190, Thailand
| | - Benjapa Khiewvan
- Division of Nuclear Medicine, Department of Radiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, 2 Wanglang Rd., Bangkoknoi, Bangkok10700, Thailand
| | - Saimai Chatree
- Faculty of Medicine and Public Health, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, 906 Kamphaeng Phet 6 Rd., Lak Si, Bangkok10210, Thailand
| | - Kitchaya Pongwattanapakin
- Department of Physiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, 2 Wanglang Rd., Bangkoknoi, Bangkok10700, Thailand
| | - Nattinee Kunlaket
- Department of Physiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, 2 Wanglang Rd., Bangkoknoi, Bangkok10700, Thailand
| | - Traiphop Dokmai
- Department of Physiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, 2 Wanglang Rd., Bangkoknoi, Bangkok10700, Thailand
| | - Reawika Chaikomin
- Department of Physiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, 2 Wanglang Rd., Bangkoknoi, Bangkok10700, Thailand
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Ito K, Satoh S, Kondo Y, Tamura H, Hasebe M, Terauchi Y. Effect of dulaglutide and long-acting insulin combination therapy in patients with type 2 diabetes: a retrospective observational study. Diabetol Int 2022; 14:51-57. [PMID: 36636162 PMCID: PMC9829941 DOI: 10.1007/s13340-022-00592-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 06/15/2022] [Indexed: 01/16/2023]
Abstract
Objective The study aimed to evaluate the long-term effects of combination therapy comprising dulaglutide and long-acting insulin, on glycemic control in patients with type 2 diabetes. Methods This retrospective observational study included 20 patients with type 2 diabetes who underwent blood glucose management with intensive insulin therapy for a limited period. All patients were switched from intensive insulin therapy to combination therapy comprising dulaglutide and long-acting insulin. Hemoglobin A1c was evaluated before and 4, 12, and 24 weeks after starting combination therapy. Continuous glucose monitoring was conducted before and 1 and 24 weeks after starting combination therapy. Results Hemoglobin A1c levels were significantly reduced after 4, 12, and 24 weeks of combination therapy (- 2.2% ± 0.4%, P < 0.0001; - 3.7% ± 0.8%, P = 0.0003; and - 3.6% ± 0.8%, P = 0.0005, respectively). Glycemic variability (% coefficient of variation) was significantly decreased after 1 and 24 weeks of combination therapy (- 5.7% ± 2.1%, P = 0.011; and - 8.7% ± 2.4%, P = 0.003, respectively) and the percentage of readings and time > 250 mg/dL at 24 weeks was significantly improved (- 2.2% ± 0.8%, P = 0.019). Conclusion Combination therapy with dulaglutide and long-acting insulin resulted in better blood glucose control than intensive insulin therapy, which persisted for 24 weeks. Combination therapy also reduced blood glucose fluctuations and the number of self-injections needed. Supplementary Information The online version contains supplementary material available at 10.1007/s13340-022-00592-z.
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Affiliation(s)
- Kohei Ito
- Chigasaki Municipal Hospital, Chigasaki, 253-0042 Japan
| | - Shinobu Satoh
- Chigasaki Municipal Hospital, Chigasaki, 253-0042 Japan
| | - Yoshinobu Kondo
- Department of Endocrinology and Diabetes, Yokohama City University Medical Center, Yokohama, Japan
| | - Haruka Tamura
- Chigasaki Municipal Hospital, Chigasaki, 253-0042 Japan
| | | | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
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30
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Griffith DA, Edmonds DJ, Fortin JP, Kalgutkar AS, Kuzmiski JB, Loria PM, Saxena AR, Bagley SW, Buckeridge C, Curto JM, Derksen DR, Dias JM, Griffor MC, Han S, Jackson VM, Landis MS, Lettiere D, Limberakis C, Liu Y, Mathiowetz AM, Patel JC, Piotrowski DW, Price DA, Ruggeri RB, Tess DA. A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor. J Med Chem 2022; 65:8208-8226. [PMID: 35647711 PMCID: PMC9234956 DOI: 10.1021/acs.jmedchem.1c01856] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe the discovery of the orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nanomolar potency. Incorporation of a carboxylic acid moiety provided considerable GLP-1R potency gains with improved off-target pharmacology and reduced metabolic clearance, ultimately resulting in the identification of danuglipron. Danuglipron increased insulin levels in primates but not rodents, which was explained by receptor mutagensis studies and a cryogenic electron microscope structure that revealed a binding pocket requiring a primate-specific tryptophan 33 residue. Oral administration of danuglipron to healthy humans produced dose-proportional increases in systemic exposure (NCT03309241). This opens an opportunity for oral small-molecule therapies that target the well-validated GLP-1R for metabolic health.
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Affiliation(s)
- David A Griffith
- Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States
| | - David J Edmonds
- Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States
| | - Jean-Philippe Fortin
- Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States
| | - Amit S Kalgutkar
- Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States
| | - J Brent Kuzmiski
- Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States
| | - Paula M Loria
- Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States
| | - Aditi R Saxena
- Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States
| | - Scott W Bagley
- Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States
| | - Clare Buckeridge
- Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States
| | - John M Curto
- Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States
| | - David R Derksen
- Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States
| | - João M Dias
- Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States
| | - Matthew C Griffor
- Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States
| | - Seungil Han
- Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States
| | - V Margaret Jackson
- Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States
| | - Margaret S Landis
- Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States
| | - Daniel Lettiere
- Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States
| | - Chris Limberakis
- Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States
| | - Yuhang Liu
- Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States
| | - Alan M Mathiowetz
- Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States
| | | | - David W Piotrowski
- Pfizer Worldwide Research, Development, and Medical, Groton, Connecticut 06340, United States
| | - David A Price
- Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States
| | - Roger B Ruggeri
- Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States
| | - David A Tess
- Pfizer Worldwide Research, Development, and Medical, Cambridge, Massachusetts 02139, United States
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Ranđelović S, Bipat R. A Review of Coumarins and Coumarin-Related Compounds for Their Potential Antidiabetic Effect. Clin Med Insights Endocrinol Diabetes 2022; 14:11795514211042023. [PMID: 35173509 PMCID: PMC8842344 DOI: 10.1177/11795514211042023] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 08/05/2021] [Indexed: 12/21/2022] Open
Abstract
Background and aims: Worldwide, type 2 diabetes mellitus accounts for a considerable burden of disease, with an estimated global cost of >800 billion USD annually. For this reason, the search for more effective and efficient therapeutic anti-diabetic agents is continuing. Coumarins are naturally derived and synthetic molecules with a wide variety of biological actions. The most common application of these molecules in medicine is for their thrombostatic activity. This study aims to give an overview of the current knowledge about the applicability of these chemical products in the therapeutic strategy against diabetes and its complications. Methods: For this purpose, we searched internet databases for publications and abstracts in English that investigated the effects of coumarins or coumarin-like agents with potential anti-diabetic activity. Results: The result is that a variety of these agents have proven in in vitro, in silico, and simple animal models to possess properties that may reduce the glucose absorption rate in the intestines, increase the level of insulin, increase the cellular uptake of glucose or reduce the gluconeogenesis. In addition, some of these agents also reduced the level of glycation of peptides in diabetic animal models and showed antioxidant properties. Conclusion: In conclusion, we can summarize that coumarins and their related derivatives may be potential antidiabetic agents. Useful formulations with appropriate pharmacokinetic and pharmacodynamic properties must be developed and tested for their efficacy and toxicity in comprehensive animal models before they can enter clinical trials.
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Affiliation(s)
- Sara Ranđelović
- Department of Chemistry, Faculty of Sciences and Mathematics, University of Niš, Niš, Serbia
| | - Robbert Bipat
- Department of Physiology, Faculty of Medical Science, Anton de Kom University of Suriname, Paramaribo, Suriname
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Pelle MC, Provenzano M, Zaffina I, Pujia R, Giofrè F, Lucà S, Andreucci M, Sciacqua A, Arturi F. Role of a Dual Glucose-Dependent Insulinotropic Peptide (GIP)/Glucagon-like Peptide-1 Receptor Agonist (Twincretin) in Glycemic Control: From Pathophysiology to Treatment. Life (Basel) 2021; 12:29. [PMID: 35054422 PMCID: PMC8779403 DOI: 10.3390/life12010029] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/18/2021] [Accepted: 12/21/2021] [Indexed: 02/06/2023] Open
Abstract
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two gut hormones, defined incretins, responsible for the amplification of insulin secretion after oral glucose intake. Unlike GLP-1, GIP has little acute effect on insulin secretion and no effect on food intake; instead it seems that the GIP may be an obesity-promoting hormone. In patients with type2 diabetes mellitus (T2DM) some studies found a downregulation of GIP receptors on pancreatic β cells caused by hyperglycemic state, but the glucagonotropic effect persisted. Agonists of the receptor for the GLP-1 have proven successful for the treatment of diabetes, since they reduce the risk for cardiovascular and renal events, but the possible application of GIP as therapy for T2DM is discussed. Moreover, the latest evidence showed a synergetic effect when GIP was combined with GLP-1 in monomolecular co-agonists. In fact, compared with the separate infusion of each hormone, the combination increased both insulin response and glucagonostatic response. In accordance with theseconsiderations, a dual GIP/GLP-1receptor agonist, i.e., Tirzepatide, known as a "twincretin" had been developed. In the pre-clinical trials, as well as Phase 1-3 clinical trials, Tirzepatideshowedpotent glucose lowering and weight loss effects within an acceptable safety.
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Affiliation(s)
- Maria Chiara Pelle
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (M.C.P.); (I.Z.); (R.P.); (F.G.); (S.L.); (A.S.)
| | - Michele Provenzano
- Department of Health Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (M.P.); (M.A.)
| | - Isabella Zaffina
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (M.C.P.); (I.Z.); (R.P.); (F.G.); (S.L.); (A.S.)
| | - Roberta Pujia
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (M.C.P.); (I.Z.); (R.P.); (F.G.); (S.L.); (A.S.)
| | - Federica Giofrè
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (M.C.P.); (I.Z.); (R.P.); (F.G.); (S.L.); (A.S.)
| | - Stefania Lucà
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (M.C.P.); (I.Z.); (R.P.); (F.G.); (S.L.); (A.S.)
| | - Michele Andreucci
- Department of Health Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (M.P.); (M.A.)
| | - Angela Sciacqua
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (M.C.P.); (I.Z.); (R.P.); (F.G.); (S.L.); (A.S.)
| | - Franco Arturi
- Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (M.C.P.); (I.Z.); (R.P.); (F.G.); (S.L.); (A.S.)
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Riyaphan J, Pham DC, Leong MK, Weng CF. In Silico Approaches to Identify Polyphenol Compounds as α-Glucosidase and α-Amylase Inhibitors against Type-II Diabetes. Biomolecules 2021; 11:1877. [PMID: 34944521 PMCID: PMC8699780 DOI: 10.3390/biom11121877] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 12/08/2021] [Accepted: 12/09/2021] [Indexed: 01/01/2023] Open
Abstract
Type-II diabetes mellitus (T2DM) results from a combination of genetic and lifestyle factors, and the prevalence of T2DM is increasing worldwide. Clinically, both α-glucosidase and α-amylase enzymes inhibitors can suppress peaks of postprandial glucose with surplus adverse effects, leading to efforts devoted to urgently seeking new anti-diabetes drugs from natural sources for delayed starch digestion. This review attempts to explore 10 families e.g., Bignoniaceae, Ericaceae, Dryopteridaceae, Campanulaceae, Geraniaceae, Euphorbiaceae, Rubiaceae, Acanthaceae, Rutaceae, and Moraceae as medicinal plants, and folk and herb medicines for lowering blood glucose level, or alternative anti-diabetic natural products. Many natural products have been studied in silico, in vitro, and in vivo assays to restrain hyperglycemia. In addition, natural products, and particularly polyphenols, possess diverse structures for exploring them as inhibitors of α-glucosidase and α-amylase. Interestingly, an in silico discovery approach using natural compounds via virtual screening could directly target α-glucosidase and α-amylase enzymes through Monte Carto molecular modeling. Autodock, MOE-Dock, Biovia Discovery Studio, PyMOL, and Accelrys have been used to discover new candidates as inhibitors or activators. While docking score, binding energy (Kcal/mol), the number of hydrogen bonds, or interactions with critical amino acid residues have been taken into concerning the reliability of software for validation of enzymatic analysis, in vitro cell assay and in vivo animal tests are required to obtain leads, hits, and candidates in drug discovery and development.
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Affiliation(s)
| | - Dinh-Chuong Pham
- Biomaterials and Nanotechnology Research Group, Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam;
| | - Max K. Leong
- Department of Chemistry, National Dong Hwa University, Hualien 97401, Taiwan
| | - Ching-Feng Weng
- Functional Physiology Section, Department of Basic Medical Science, Xiamen Medical College, Xiamen 361023, China
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Okamoto A, Yokokawa H, Nagamine T, Fukuda H, Hisaoka T, Naito T. Efficacy and safety of semaglutide in glycemic control, body weight management, lipid profiles and other biomarkers among obese type 2 diabetes patients initiated or switched to semaglutide from other GLP-1 receptor agonists. J Diabetes Metab Disord 2021; 20:2121-2128. [PMID: 34900848 PMCID: PMC8630305 DOI: 10.1007/s40200-021-00899-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 09/07/2021] [Indexed: 12/25/2022]
Abstract
Purpose Evidence of the efficacy and safety of semaglutide among patients with type 2 diabetes who were initiated on or were switched to semaglutide from other GLP-1 RAs remains limited. The objective of this study was to investigate the short-term effects of switching to semaglutide from other GLP-1 RAs. Methods This retrospective cohort study evaluated patients with type 2 diabetes who were initiated on or were switched to semaglutide due to poor diabetes control with other GLP-1 RAs or other medications, or obesity. HbA1c, body weight, serum creatinine, serum uric acid, parameters of lipid metabolism, and parameters of liver function were measured before and 6 months after administration of semaglutide. Results A total of 50 patients were registered in the study. After switching to semaglutide (n = 43), HbA1c and body weight significantly decreased (p < 0.01, p < 0.01), respectively. The same findings were observed in semaglutide-naïve patients (p = 0.04, p < 0.02) (n = 7). Serum uric acid, total cholesterol, triglycerides, and urinary albumin-creatinine ratio decreased significantly as well (p = 0.04, p = 0.04, p = 0.02, p = 0.04), whereas serum creatinine did not change significantly (p = 0.51). Conclusions Semaglutide showed excellent efficacy, even in patients switched from other GLP-1 RAs. Semaglutide appears to be a promising agent for blood glucose and body weight control in obese type 2 diabetes mellitus patients and could be more potent in treating type 2 diabetes than existing GLP-1 RAs.
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Affiliation(s)
- Aki Okamoto
- OKM Okamoto Internal Medicine Clinic, Tokyo, Japan
| | - Hirohide Yokokawa
- Department of General Medicine, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Tomoko Nagamine
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Nippon Medical School, Tokyo, Japan
| | - Hiroshi Fukuda
- Department of General Medicine, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Teruhiko Hisaoka
- Department of General Medicine, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Toshio Naito
- Department of General Medicine, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan
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Przezak A, Bielka W, Pawlik A. Incretins in the Therapy of Diabetic Kidney Disease. Int J Mol Sci 2021; 22:ijms222212312. [PMID: 34830194 PMCID: PMC8617946 DOI: 10.3390/ijms222212312] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/09/2021] [Accepted: 11/12/2021] [Indexed: 12/17/2022] Open
Abstract
Diabetic kidney disease is a microvascular complication that occurs in patients with diabetes. It is strongly associated with increased risk of kidney replacement therapy and all-cause mortality. Incretins are peptide hormones derived from the gastrointestinal tract, that besides causing enhancement of insulin secretion after oral glucose intake, participate in many other metabolic processes. Antidiabetic drug classes, such as dipeptidyl peptidase 4 inhibitors and glucagon-like peptide receptor agonists, which way of action is based on incretins facility, not only show glucose-lowering properties but also have nephroprotective functions. The aim of this article is to present the latest information about incretin-based therapy and its influence on diabetic kidney disease appearance and progression, point its potential mechanisms of kidney protection and focus on future therapeutic possibilities bound with these two antidiabetic drug classes.
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36
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Smith KR, Moran TH. Gastrointestinal peptides in eating-related disorders. Physiol Behav 2021; 238:113456. [PMID: 33989649 PMCID: PMC8462672 DOI: 10.1016/j.physbeh.2021.113456] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 04/19/2021] [Accepted: 05/04/2021] [Indexed: 12/13/2022]
Abstract
Food intake is tightly controlled by homeostatic signals sensitive to metabolic need for the regulation of body weight. This review focuses on the peripherally-secreted gastrointestinal peptides (i.e., ghrelin, cholecystokinin, glucagon-like peptide 1, and peptide tyrosine tyrosine) that contribute to the control of appetite and discusses how these peptides or the signals arising from their release are disrupted in eating-related disorders across the weight spectrum, namely anorexia nervosa, bulimia nervosa, and obesity, and whether they are normalized following weight restoration or weight loss treatment. Further, the role of gut peptides in the pathogenesis and treatment response in human weight conditions as identified by rodent models are discussed. Lastly, we review the incretin- and hormone-based pharmacotherapies available for the treatment of obesity and eating-related disorders.
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Affiliation(s)
- Kimberly R Smith
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
| | - Timothy H Moran
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
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Nauck MA, Quast DR, Wefers J, Pfeiffer AFH. The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update. Diabetes Obes Metab 2021; 23 Suppl 3:5-29. [PMID: 34310013 DOI: 10.1111/dom.14496] [Citation(s) in RCA: 191] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/13/2021] [Accepted: 07/13/2021] [Indexed: 11/27/2022]
Abstract
The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have their main physiological role in augmenting insulin secretion after their nutrient-induced secretion from the gut. A functioning entero-insular (gut-endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to "isoglycaemic" intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP-1 have additive effects on insulin secretion. Local production of GIP and/or GLP-1 in islet α-cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP-1 suppresses, and GIP increases glucagon secretion, both in a glucose-dependent manner. GIP plays a greater physiological role as an incretin. In type 2-diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP-1. While insulinotropic effects of GLP-1 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP-1 have additional biological functions: GLP-1 at pharmacological concentrations reduces appetite, food intake, and-in the long run-body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP-1 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP-1, play a role in bone remodelling. GLP-1, but not GIP slows gastric emptying, which reduces post-meal glycaemic increments. For both GIP and GLP-1, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP/GLP-1 receptor co-agonists like tirzepatide have superior efficacy compared to selective GLP-1 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long-term interaction of GIP and GLP-1 receptor signalling. A GLP-1 receptor antagonist (exendin [9-39]) and, more recently, a GIP receptor agonist (GIP [3-30] NH2 ) and, hopefully, longer-acting GIP receptor agonists for human use will be helpful tools to shed light on the open questions. A detailed knowledge of incretin physiology and pathophysiology will be a prerequisite for designing more effective incretin-based diabetes drugs.
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Affiliation(s)
- Michael A Nauck
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - Daniel R Quast
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - Jakob Wefers
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - Andreas F H Pfeiffer
- Charité - Universitätsmedizin Berlin, Klinik für Endokrinologie, Stoffwechsel- und Ernährungsmedizin, Berlin, Germany
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Campos C, Unger J. Primary care management of type 2 diabetes: a comparison of the efficacy and safety of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Postgrad Med 2021; 133:843-853. [PMID: 34416133 DOI: 10.1080/00325481.2021.1971461] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 inhibitors (DPP4is) exert their effects via the incretin system, which augments glucose-dependent insulin secretion in response to nutrient intake (the 'incretin effect'). Both classes are well-established pharmacologic options for the management of glycemic control in individuals with type 2 diabetes (T2D) after failure of first-line metformin; however, they have inherent differences in their mechanisms of action that are reflected in their clinical safety and efficacy profiles. GLP-1RAs have high glycemic efficacy and are associated with weight loss and, in some cases, cardioprotective effects, with a side-effect profile of predominantly transient gastrointestinal adverse events. Most GLP-1RAs are administered as subcutaneous injection, although an oral formulation of one GLP-1RA, semaglutide, has recently become available. DPP4is provide moderate glycemic control, are weight-neutral, and do not offer any cardiovascular benefits, but are generally well tolerated. DPP4is are all administered orally. This narrative review aims to provide guidance for a primary care audience on the similarities and differences between GLP-1RA and DPP4i therapies, with a focus on their mechanism of action, clinical safety, efficacy, and real-world effectiveness. The role of incretin-based therapies in the T2D treatment paradigm, including key considerations for guiding treatment decisions, will also be discussed.
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Affiliation(s)
- Carlos Campos
- Department of Family Medicine, University of Texas Health Science Center, San Antonio, USA
| | - Jeff Unger
- Unger Primary Care Concierge Medical Group, Rancho Cucamonga, USA
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Metabolic Phenotypes and Step by Step Evolution of Type 2 Diabetes: A New Paradigm. Biomedicines 2021; 9:biomedicines9070800. [PMID: 34356863 PMCID: PMC8301386 DOI: 10.3390/biomedicines9070800] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/02/2021] [Accepted: 07/05/2021] [Indexed: 01/18/2023] Open
Abstract
Unlike bolus insulin secretion mechanisms, basal insulin secretion is poorly understood. It is essential to elucidate these mechanisms in non-hyperinsulinaemia healthy persons. This establishes a baseline for investigation into pathologies where these processes are dysregulated, such as in type 2 diabetes (T2DM), cardiovascular disease (CVD), certain cancers and dementias. Chronic hyperinsulinaemia enforces glucose fueling, depleting the NAD+ dependent antioxidant activity that increases mitochondrial reactive oxygen species (mtROS). Consequently, beta-cell mitochondria increase uncoupling protein expression, which decreases the mitochondrial ATP surge generation capacity, impairing bolus mediated insulin exocytosis. Excessive ROS increases the Drp1:Mfn2 ratio, increasing mitochondrial fission, which increases mtROS; endoplasmic reticulum-stress and impaired calcium homeostasis ensues. Healthy individuals in habitual ketosis have significantly lower glucagon and insulin levels than T2DM individuals. As beta-hydroxybutyrate rises, hepatic gluconeogenesis and glycogenolysis supply extra-hepatic glucose needs, and osteocalcin synthesis/release increases. We propose insulin’s primary role is regulating beta-hydroxybutyrate synthesis, while the role of bone regulates glucose uptake sensitivity via osteocalcin. Osteocalcin regulates the alpha-cell glucagon secretory profile via glucagon-like peptide-1 and serotonin, and beta-hydroxybutyrate synthesis via regulating basal insulin levels. Establishing metabolic phenotypes aids in resolving basal insulin secretion regulation, enabling elucidation of the pathological changes that occur and progress into chronic diseases associated with ageing.
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Quitadamo P, Zenzeri L, Mozzillo E, Giorgio V, Rocco A, Franzese A, Nardone G, Staiano A. Plasma dosage of ghrelin, IGF-1, GLP- 1 and leptin related to gastric emptying and esophageal pH-impedance in children with obesity. J Endocrinol Invest 2021; 44:1275-1281. [PMID: 32960416 DOI: 10.1007/s40618-020-01425-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Accepted: 09/14/2020] [Indexed: 01/11/2023]
Abstract
PURPOSE The main aim of the study was to assess the relationship between leptin, ghrelin, insulin-like growth factor 1 (IGF-1), and glucagon-like peptide 1 (GLP-1) blood levels and gastric motility in children with obesity compared to healthy children. Secondary aims were to assess the possible association between these hormones and obesity, reflux impedance parameters, reflux symptoms, other GI disorders, and quality-of-life scores within the same groups. METHODS Children with obesity plus GERD symptoms and 2 control groups of children with obesity without GERD and healthy lean children aged 4-17 years underwent an auxological evaluation, an assessment of gastro-intestinal symptoms and quality of life, hormonal dosages, and an evaluation of gastric emptying time (GET) through 13C-octanoic acid breath test. RESULTS No significant association was found between hormones and gastric motility. Leptin and ghrelin levels were significantly associated with obesity parameters. No significant differences were found between GET and hormones of the patients with obesity, either with or without GERD. CONCLUSION Although we found an association between auxological parameters and both leptin and ghrelin levels, this association did not imply an effect on the upper GI motility. Therefore, our hypothesis that alterations of these hormones in children with obesity could affect gastric emptying, triggering GERD, was not supported by our data.
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Affiliation(s)
- P Quitadamo
- Department of Translational Medical Science, Section of Pediatrics, "Federico II" University of Naples, Naples, Italy.
- Department of Pediatrics, A.O.R.N. Santobono-Pausilipon, Via Mario Fiore 6, 80129, Naples, Italy.
| | - L Zenzeri
- Department of Pediatrics, University of Perugia, Perugia, Italy
| | - E Mozzillo
- Department of Translational Medical Science, Section of Pediatrics, "Federico II" University of Naples, Naples, Italy
| | - V Giorgio
- UOC Pediatria, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - A Rocco
- Department of Gastroenterology, "Federico II" University of Naples, Naples, Italy
| | - A Franzese
- Department of Translational Medical Science, Section of Pediatrics, "Federico II" University of Naples, Naples, Italy
| | - G Nardone
- Department of Gastroenterology, "Federico II" University of Naples, Naples, Italy
| | - A Staiano
- Department of Translational Medical Science, Section of Pediatrics, "Federico II" University of Naples, Naples, Italy
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Furbetta N, Comandatore A, Gianardi D, Palmeri M, Di Franco G, Guadagni S, Caprili G, Bianchini M, Fatucchi LM, Picchi M, Bastiani L, Biancofiore G, Di Candio G, Morelli L. Perioperative Nutritional Aspects in Total Pancreatectomy: A Comprehensive Review of the Literature. Nutrients 2021; 13:1765. [PMID: 34067286 PMCID: PMC8224756 DOI: 10.3390/nu13061765] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/18/2021] [Accepted: 05/20/2021] [Indexed: 02/05/2023] Open
Abstract
Total pancreatectomy (TP) is a highly invasive procedure often performed in patients affected by anorexia, malabsorption, cachexia, and malnutrition, which are risk factors for bad surgical outcome and even may cause enhanced toxicity to chemo-radiotherapy. The role of nutritional therapies and the association between nutritional aspects and the outcome of patients who have undergone TP is described in some studies. The aim of this comprehensive review is to summarize the available recent evidence about the influence of nutritional factors in TP. Preoperative nutritional and metabolic assessment, but also intra-operative and post-operative nutritional therapies and their consequences, are analyzed in order to identify the aspects that can influence the outcome of patients undergoing TP. The results of this review show that preoperative nutritional status, sarcopenia, BMI and serum albumin are prognostic factors both in TP for pancreatic cancer to support chemotherapy, prevent recurrence and prolong survival, and in TP with islet auto-transplantation for chronic pancreatitis to improve postoperative glycemic control and obtain better outcomes. When it is possible, enteral nutrition is always preferable to parenteral nutrition, with the aim to prevent or reduce cachexia. Nowadays, the nutritional consequences of TP, including diabetes control, are improved and become more manageable.
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Affiliation(s)
- Niccolò Furbetta
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (N.F.); (A.C.); (D.G.); (M.P.); (G.D.F.); (S.G.); (G.C.); (M.B.); (L.M.F.); (M.P.); (G.D.C.)
| | - Annalisa Comandatore
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (N.F.); (A.C.); (D.G.); (M.P.); (G.D.F.); (S.G.); (G.C.); (M.B.); (L.M.F.); (M.P.); (G.D.C.)
| | - Desirée Gianardi
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (N.F.); (A.C.); (D.G.); (M.P.); (G.D.F.); (S.G.); (G.C.); (M.B.); (L.M.F.); (M.P.); (G.D.C.)
| | - Matteo Palmeri
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (N.F.); (A.C.); (D.G.); (M.P.); (G.D.F.); (S.G.); (G.C.); (M.B.); (L.M.F.); (M.P.); (G.D.C.)
| | - Gregorio Di Franco
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (N.F.); (A.C.); (D.G.); (M.P.); (G.D.F.); (S.G.); (G.C.); (M.B.); (L.M.F.); (M.P.); (G.D.C.)
| | - Simone Guadagni
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (N.F.); (A.C.); (D.G.); (M.P.); (G.D.F.); (S.G.); (G.C.); (M.B.); (L.M.F.); (M.P.); (G.D.C.)
| | - Giovanni Caprili
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (N.F.); (A.C.); (D.G.); (M.P.); (G.D.F.); (S.G.); (G.C.); (M.B.); (L.M.F.); (M.P.); (G.D.C.)
| | - Matteo Bianchini
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (N.F.); (A.C.); (D.G.); (M.P.); (G.D.F.); (S.G.); (G.C.); (M.B.); (L.M.F.); (M.P.); (G.D.C.)
| | - Lorenzo Maria Fatucchi
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (N.F.); (A.C.); (D.G.); (M.P.); (G.D.F.); (S.G.); (G.C.); (M.B.); (L.M.F.); (M.P.); (G.D.C.)
| | - Martina Picchi
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (N.F.); (A.C.); (D.G.); (M.P.); (G.D.F.); (S.G.); (G.C.); (M.B.); (L.M.F.); (M.P.); (G.D.C.)
| | - Luca Bastiani
- Institute of Clinical Physiology, National Council of Research, 56124 Pisa, Italy;
| | | | - Giulio Di Candio
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (N.F.); (A.C.); (D.G.); (M.P.); (G.D.F.); (S.G.); (G.C.); (M.B.); (L.M.F.); (M.P.); (G.D.C.)
| | - Luca Morelli
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (N.F.); (A.C.); (D.G.); (M.P.); (G.D.F.); (S.G.); (G.C.); (M.B.); (L.M.F.); (M.P.); (G.D.C.)
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Cai Z, Yuan S, Zhong Y, Deng L, Li J, Tan X, Feng J. Amelioration of Endothelial Dysfunction in Diabetes: Role of Takeda G Protein-Coupled Receptor 5. Front Pharmacol 2021; 12:637051. [PMID: 33995040 PMCID: PMC8113688 DOI: 10.3389/fphar.2021.637051] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 02/22/2021] [Indexed: 12/25/2022] Open
Abstract
Diabetes mellitus (DM) eventually leads to chronic vascular complications, resulting in cardiovascular diseases. DM-associated endothelial dysfunction (ED) plays an important role in the development of chronic vascular complications. Low endothelial nitric oxide synthase (eNOS) activity, inflammation, and oxidative stress all contribute to ED. The G protein-coupled receptor Takeda G protein-coupled receptor 5 (TGR5) is a membrane receptor for bile acids that plays an important role in the regulation of glucose metabolism. Recent studies have shown that TGR5 is involved in the regulation of various mediators of ED, which suggests that TGR5 may represent a target for the treatment of DM-associated ED. In this review, we summarize the principal mechanisms of DM-associated ED, then propose TGR5 as a novel therapeutic target on the basis of its mechanistic involvement, and suggest potential directions for future research.
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Affiliation(s)
- Zhengyao Cai
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Suxin Yuan
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Yi Zhong
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Li Deng
- Department of Rheumatology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jiafu Li
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Xiaoqiu Tan
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Jian Feng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
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Rezaie P, Bitarafan V, Horowitz M, Feinle-Bisset C. Effects of Bitter Substances on GI Function, Energy Intake and Glycaemia-Do Preclinical Findings Translate to Outcomes in Humans? Nutrients 2021; 13:1317. [PMID: 33923589 PMCID: PMC8072924 DOI: 10.3390/nu13041317] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/07/2021] [Accepted: 04/15/2021] [Indexed: 12/25/2022] Open
Abstract
Bitter substances are contained in many plants, are often toxic and can be present in spoiled food. Thus, the capacity to detect bitter taste has classically been viewed to have evolved primarily to signal the presence of toxins and thereby avoid their consumption. The recognition, based on preclinical studies (i.e., studies in cell cultures or experimental animals), that bitter substances may have potent effects to stimulate the secretion of gastrointestinal (GI) hormones and modulate gut motility, via activation of bitter taste receptors located in the GI tract, reduce food intake and lower postprandial blood glucose, has sparked considerable interest in their potential use in the management or prevention of obesity and/or type 2 diabetes. However, it remains to be established whether findings from preclinical studies can be translated to health outcomes, including weight loss and improved long-term glycaemic control. This review examines information relating to the effects of bitter substances on the secretion of key gut hormones, gastric motility, food intake and blood glucose in preclinical studies, as well as the evidence from clinical studies, as to whether findings from animal studies translate to humans. Finally, the evidence that bitter substances have the capacity to reduce body weight and/or improve glycaemic control in obesity and/or type 2 diabetes, and potentially represent a novel strategy for the management, or prevention, of obesity and type 2 diabetes, is explored.
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Affiliation(s)
| | | | | | - Christine Feinle-Bisset
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide 5005, Australia; (P.R.); (V.B.); (M.H.)
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Fujiwara Y, Yamane S, Harada N, Ikeguchi-Ogura E, Usui R, Nakamura T, Iwasaki K, Suzuki K, Yabe D, Hayashi Y, Inagaki N. Carbonic anhydrase 8 (CAR8) negatively regulates GLP-1 secretion from enteroendocrine cells in response to long-chain fatty acids. Am J Physiol Gastrointest Liver Physiol 2021; 320:G617-G626. [PMID: 33533304 DOI: 10.1152/ajpgi.00312.2020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 01/30/2021] [Indexed: 01/31/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) is an incretin secreted from enteroendocrine preproglucagon (PPG)-expressing cells (traditionally known as L cells) in response to luminal nutrients that potentiates insulin secretion. Augmentation of endogenous GLP-1 secretion might well represent a novel therapeutic target for diabetes treatment in addition to the incretin-associated drugs currently in use. In this study, we found that PPG cells substantially express carbonic anhydrase 8 (CAR8), which has been reported to inhibit inositol 1,4,5-trisphosphate (IP3) binding to the IP3 receptor and subsequent Ca2+ efflux from the endoplasmic reticulum in neuronal cells. In vitro experiments using STC-1 cells demonstrated that Car8 knockdown increases long-chain fatty acid (LCFA)-stimulated GLP-1 secretion. This effect was reduced in the presence of phospholipase C (PLC) inhibitor; in addition, Car8 knockdown increased the intracellular Ca2+ elevation caused by α-linolenic acid, indicating that CAR8 exerts its effect on GLP-1 secretion via the PLC/IP3/Ca2+ pathway. Car8wdl null mutant mice showed significant increase in GLP-1 response to oral corn oil administration compared with that in wild-type littermates, with no significant change in intestinal GLP-1 content. These results demonstrate that CAR8 negatively regulates GLP-1 secretion from PPG cells in response to LCFAs, suggesting the possibility of augmentation of postprandial GLP-1 secretion by CAR8 inhibition.NEW & NOTEWORTHY This study focused on the physiological significance of carbonic anhydrase 8 (CAR8) in GLP-1 secretion from enteroendocrine preproglucagon (PPG)-expressing cells. We found an inhibitory role of CAR8 in LCFA-induced GLP-1 secretion in vitro and in vivo, suggesting a novel therapeutic approach to diabetes and obesity through augmentation of postprandial GLP-1 secretion by CAR8 inhibition.
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Affiliation(s)
- Yuta Fujiwara
- Department of Diabetes, Endocrinology, and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shunsuke Yamane
- Department of Diabetes, Endocrinology, and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Norio Harada
- Department of Diabetes, Endocrinology, and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Eri Ikeguchi-Ogura
- Department of Diabetes, Endocrinology, and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ryota Usui
- Department of Diabetes, Endocrinology, and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshihiro Nakamura
- Department of Diabetes, Endocrinology, and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kanako Iwasaki
- Department of Diabetes, Endocrinology, and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kazuyo Suzuki
- Department of Diabetes, Endocrinology, and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Daisuke Yabe
- Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yoshitaka Hayashi
- Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology, and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Gastric Sensory and Motor Functions and Energy Intake in Health and Obesity-Therapeutic Implications. Nutrients 2021; 13:nu13041158. [PMID: 33915747 PMCID: PMC8065811 DOI: 10.3390/nu13041158] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/18/2021] [Accepted: 03/26/2021] [Indexed: 01/19/2023] Open
Abstract
Sensory and motor functions of the stomach, including gastric emptying and accommodation, have significant effects on energy consumption and appetite. Obesity is characterized by energy imbalance; altered gastric functions, such as rapid gastric emptying and large fasting gastric volume in obesity, may result in increased food intake prior to reaching usual fullness and increased appetite. Thus, many different interventions for obesity, including different diets, anti-obesity medications, bariatric endoscopy, and surgery, alter gastric functions and gastrointestinal motility. In this review, we focus on the role of the gastric and intestinal functions in food intake, pathophysiology of obesity, and obesity management.
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Thottapillil A, Kouser S, Kukkupuni SK, Vishnuprasad CN. An 'Ayurveda-Biology' platform for integrative diabetes management. JOURNAL OF ETHNOPHARMACOLOGY 2021; 268:113575. [PMID: 33181283 DOI: 10.1016/j.jep.2020.113575] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 10/27/2020] [Accepted: 11/05/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Diabetes is a multifactorial disease with complex multi-organ-multi-target crosstalk in the body. Currently, the theoretical assumptions framing the diabetes management strategies are reductionist and largely focus on reducing hyperglycemia through targeted molecular drugs. While they effectively reduce hyperglycemia, they are inadequate to address the multifactorial etiopathology, chronicity and systemic complications of diabetes. Therefore, a holistic and systemic approach is essential for its successful management. We hypothesize an integrative diabetes management strategy, combining holistic principles of diabetes management with its molecular understandings, would be more appropriate to fill this gap. The holistic disease management principles of Ayurveda, the Indian system of medicine, can play a pivotal role in this context. This narrative review discusses the scope of a trans-disciplinary ' Ayurveda-Biology ' approach for deepening the holistic understanding of the pathophysiology of diabetes as well as designing novel integrative strategies for managing diabetes and restoring whole body glucose homeostasis. METHODOLOGY The article analyses the Ayurveda scheme of diabetes management and correlates it with the molecular understanding of its pathophysiology and management. The sources of information used in this article include classical texts of Ayurveda , medical books, published research articles and scientific databases like PubMed, Google Scholar, Science-Direct, etc. RESULTS: While Ayurveda and modern biomedicine uses different epistemology and ontology for describing diabetes, both the systems recognize the central role of gut and gut derived factors in postprandial glucose disposal and whole body glucose homeostasis. Essentially, the principles of both Ayurveda and modern biomedicine overlap at a gut centred view of diabetes management; and Gastro-intestinal mediated glucose disposal , a holistic concept of glucose metabolism, is emerging as a converging node for designing innovative integrative diabetes management strategies. CONCLUSIONS An integrative disease management strategy, combining holistic and reductionist perspectives of traditional medicine and biology respectively, would be the prerogative for successful management of diabetes. Creating an ' Ayurveda-Biology' knowledge framework integrating the patient centred holistic management principles of Ayurveda and the molecular approaches of modern biology can give better insights into the biology of whole body glucose homeostasis and offer novel strategies for cost effective, holistic and multi-targeted management of diabetes.
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Affiliation(s)
- Anjana Thottapillil
- Centre for Ayurveda Biology and Holistic Nutrition, The University of Transdisciplinary Health Sciences and Technology (TDU), No.74/2, Jarakabande Kaval Post: Attur, Via Yelahanka, Bangalore, 560 106, India
| | - Sania Kouser
- Centre for Ayurveda Biology and Holistic Nutrition, The University of Transdisciplinary Health Sciences and Technology (TDU), No.74/2, Jarakabande Kaval Post: Attur, Via Yelahanka, Bangalore, 560 106, India
| | - Subrahmanya Kumar Kukkupuni
- Centre for Ayurveda Biology and Holistic Nutrition, The University of Transdisciplinary Health Sciences and Technology (TDU), No.74/2, Jarakabande Kaval Post: Attur, Via Yelahanka, Bangalore, 560 106, India
| | - Chethala N Vishnuprasad
- Centre for Ayurveda Biology and Holistic Nutrition, The University of Transdisciplinary Health Sciences and Technology (TDU), No.74/2, Jarakabande Kaval Post: Attur, Via Yelahanka, Bangalore, 560 106, India.
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Saxena AR, Banerjee A, Corbin KD, Parsons SA, Smith SR. Energy intake as a short-term biomarker for weight loss in adults with obesity receiving liraglutide: A randomized trial. Obes Sci Pract 2021; 7:281-290. [PMID: 34123395 PMCID: PMC8170575 DOI: 10.1002/osp4.486] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 12/23/2020] [Accepted: 01/23/2021] [Indexed: 12/02/2022] Open
Abstract
Background and Objective Obesity is a chronic disease associated with many serious comorbidities. Pharmacologic therapies are approved for the treatment of obesity; however, short‐term biomarkers to predict weight loss are not well understood. This study aimed to determine the ability of single‐meal energy intake (EI) to predict weight loss in participants with obesity treated with liraglutide. Methods In this randomized, double‐blind, placebo‐controlled study, participants received subcutaneous liraglutide (titrated to 3.0 mg/day) or placebo once daily, with inpatient assessments at baseline and weeks 3 and 6. The primary endpoint was change from baseline (CFB) in EI during consecutive ad libitum lunch meals at weeks 3 and 6. Secondary endpoints included CFB in 24‐ and 48‐h EI, weight, appetite scores, and gastric emptying measures. Results Sixty‐one participants were randomized (n = 32, liraglutide; n = 29, placebo). The least squares mean (LSM) difference (95% CI; p‐value) in CFB in EI during ad libitum lunch meals between the liraglutide and placebo groups was −236 (−322, −149; p < 0.0001) kcal at week 3 and –244 (−339, −148, p < 0.0001) kcal at week 6. The liraglutide group experienced significant weight loss at weeks 3 and 6, compared with placebo. Weight loss was significantly correlated with EI, but not with appetite score or gastric emptying. Conclusions EI during a single meal is a robust clinical predictor of weight changes in participants with obesity. Future clinical trials can utilize EI at a single meal as a predictor of weight loss.
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Affiliation(s)
- Aditi R Saxena
- Worldwide Research and Development Pfizer Inc Cambridge Massachusetts USA
| | - Anindita Banerjee
- Worldwide Research and Development Pfizer Inc Cambridge Massachusetts USA
| | - Karen D Corbin
- AdventHealth Translational Research Institute Orlando Florida USA
| | | | - Steven R Smith
- AdventHealth Translational Research Institute Orlando Florida USA
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Yoon JY, Arau RT. The Efficacy and Safety of Endoscopic Sleeve Gastroplasty as an Alternative to Laparoscopic Sleeve Gastrectomy. Clin Endosc 2021; 54:17-24. [PMID: 33478194 PMCID: PMC7939770 DOI: 10.5946/ce.2021.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 01/05/2021] [Indexed: 12/13/2022] Open
Abstract
Endoscopic sleeve gastroplasty (ESG) is a therapeutic endoscopic technique for reducing the size of the gastric reservoir in obese patients, using a full-thickness endoscopic suturing device. The effectiveness of ESG in weight loss is significantly greater than that of high-intensity diet and lifestyle therapy and lower than that of laparoscopic sleeve gastrectomy (LSG). The efficacy at 12 months after ESG in terms of percentage of total body weight loss and excess body weight loss was approximately 16% and 60%, respectively. The well-known predictive factors for increased weight loss by ESG are good compliance with regular monitoring and post-procedure care involving a multidisciplinary team approach. Although the underlying mechanism of weight loss induced by ESG is debatable, delayed gastric emptying and early satiation are some of the proposed mechanisms. The pooled rate of adverse events after ESG reported in several meta-analysis studies ranged from 1.5% to 2.3% and the incidence of new-onset gastroesophageal reflux disease after ESG was negligible, indicating that ESG has a superior safety profile to LSG. Moreover, ESG reduced the risk of obesity-related metabolic comorbidities, evidenced by the reduction in HbA1c level, systolic blood pressure, triglyceride level, and risk of hepatic steatosis and fibrosis; it even improved the quality of life. ESG could be considered safe and qualify as an alternative treatment to LSG.
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Affiliation(s)
- Jin Young Yoon
- Division of Gastroenterology, Department of Internal Medicine, Kyung Hee University Hospital, Seoul, Korea
| | - Román Turró Arau
- Department of Bariatric Endoscopy, Centro Medico Teknon, Barcelona, Spain
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Dimitriadis GD, Maratou E, Kountouri A, Board M, Lambadiari V. Regulation of Postabsorptive and Postprandial Glucose Metabolism by Insulin-Dependent and Insulin-Independent Mechanisms: An Integrative Approach. Nutrients 2021; 13:E159. [PMID: 33419065 PMCID: PMC7825450 DOI: 10.3390/nu13010159] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 12/18/2020] [Accepted: 12/24/2020] [Indexed: 12/18/2022] Open
Abstract
Glucose levels in blood must be constantly maintained within a tight physiological range to sustain anabolism. Insulin regulates glucose homeostasis via its effects on glucose production from the liver and kidneys and glucose disposal in peripheral tissues (mainly skeletal muscle). Blood levels of glucose are regulated simultaneously by insulin-mediated rates of glucose production from the liver (and kidneys) and removal from muscle; adipose tissue is a key partner in this scenario, providing nonesterified fatty acids (NEFA) as an alternative fuel for skeletal muscle and liver when blood glucose levels are depleted. During sleep at night, the gradual development of insulin resistance, due to growth hormone and cortisol surges, ensures that blood glucose levels will be maintained within normal levels by: (a) switching from glucose to NEFA oxidation in muscle; (b) modulating glucose production from the liver/kidneys. After meals, several mechanisms (sequence/composition of meals, gastric emptying/intestinal glucose absorption, gastrointestinal hormones, hyperglycemia mass action effects, insulin/glucagon secretion/action, de novo lipogenesis and glucose disposal) operate in concert for optimal regulation of postprandial glucose fluctuations. The contribution of the liver in postprandial glucose homeostasis is critical. The liver is preferentially used to dispose over 50% of the ingested glucose and restrict the acute increases of glucose and insulin in the bloodstream after meals, thus protecting the circulation and tissues from the adverse effects of marked hyperglycemia and hyperinsulinemia.
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Affiliation(s)
- George D. Dimitriadis
- Sector of Medicine, Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece
| | - Eirini Maratou
- Department of Clinical Biochemistry, Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece;
- Department of Clinical Biochemistry, Medical School, “Attikon” University Hospital, Rimini 1, 12462 Chaidari, Greece
| | - Aikaterini Kountouri
- Research Institute and Diabetes Center, 2nd Department of Internal Medicine, “Attikon” University Hospital, 1 Rimini Street, 12542 Haidari, Greece; (A.K.); (V.L.)
| | - Mary Board
- St. Hilda’s College, University of Oxford, Cowley, Oxford OX4 1DY, UK;
| | - Vaia Lambadiari
- Research Institute and Diabetes Center, 2nd Department of Internal Medicine, “Attikon” University Hospital, 1 Rimini Street, 12542 Haidari, Greece; (A.K.); (V.L.)
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Hearn EB, Sherman JJ. Injection-Site Nodules Associated With Once-Weekly Subcutaneous Administration of Semaglutide. Diabetes Spectr 2021; 34:73-75. [PMID: 33627997 PMCID: PMC7887535 DOI: 10.2337/ds20-0033] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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