New Perspectives in Modulating the Entero-Insular Axis in Pediatric Obesity
Abstract
1. Introduction
2. The Secretion of Incretins
3. Particularities of the Incretin Axis in Children
4. Glucagon Like Peptide-1 Receptor Agonists in the Treatment of Obesity in Children
4.1. Data Analysis and Extraction Strategy
4.2. Liraglutide
4.3. Semaglutide
4.4. Exenatide
5. Discussion
6. Future Directions
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
BMI | Body mass index |
GLP-1 | Glucagon-like peptide-1 |
GIP | Gastric inhibitory polypeptide |
DPP-4 | Dipeptidyl peptidase 4 |
cAMP | Cyclic adenosine monophosphate |
HOMA-IR | Homeostasis Model Assessment of Insulin Resistance |
OGTT | Oral glucose tolerance test |
TM | Transmembrane |
BID | Twice per day |
NA | Not available |
GI | Gastrointestinal |
AE | Adverse event |
ADA | American Diabetes Association |
TEAE | Treatment-emergent adverse event |
References
- Ibrahim, S.; Akram, Z.; Noreen, A.; Baig, M.T.; Sheikh, S.; Huma, A.; Jabeen, A.; Lodhi, M.; Khan, S.A.; Hudda, A.; et al. Overweight and Obesity Prevalence and Predictors in People Living in Karachi. J. Pharm. Res. Int. 2021, 33, 194–202. [Google Scholar] [CrossRef]
- Safaei, M.; Sundararajan, E.A.; Driss, M.; Boulila, W.; Shapi’i, A. A systematic literature review on obesity: Understanding the causes & consequences of obesity and reviewing various machine learning approaches used to predict obesity. Comput. Biol. Med. 2021, 136, 104754. [Google Scholar]
- Williams, E.P.; Mesidor, M.; Winters, K.; Dubbert, P.M.; Wyatt, S.B. Overweight and Obesity: Prevalence, Consequences, and Causes of a Growing Public Health Problem. Curr. Obes. Rep. 2015, 4, 363–370. [Google Scholar] [CrossRef] [PubMed]
- Çakmur, H. Introductory Chapter: Unbearable Burden of the Diseases-Obesity; IntechOpen: London, UK, 2020. [Google Scholar]
- Bischoff, S.C.; Boirie, Y.; Cederholm, T.; Chourdakis, M.; Cuerda, C.; Delzenne, N.M.; Deutz, N.E.; Fouque, D.; Genton, L.; Gil, C.; et al. Towards a multidisciplinary approach to understand and manage obesity and related diseases. Clin. Nutr. 2017, 36, 917–938. [Google Scholar] [CrossRef]
- Zetu, C.; Popa, S.; Golli, A.L.; Condurache, A.; Munteanu, R. Long-term improvement of dyslipidaemia, hyperuricemia and metabolic syndrome in patients undergoing laparoscopic sleeve gastrectomy. Arch. Endocrinol. Metab. 2021, 64, 704–709. [Google Scholar] [CrossRef] [PubMed]
- Mirza, N.; Phan, T.L.; Tester, J.; Fals, A.; Fernandez, C.; Datto, G.; Estrada, E.; Eneli, I. Expert exchange workgroup on children aged 5 and younger with severe obesity: A narrative review of medical and genetic risk factors. Child. Obes. 2018, 14, 443–452. [Google Scholar] [CrossRef]
- Shashaj, B.; Bedogni, G.; Graziani, M.P.; Tozzi, A.E.; DiCorpo, M.L.; Morano, D.; Tacconi, L.; Veronelli, P.; Contoli, B.; Manco, M. Origin of cardiovascular risk in overweight preschool children: A cohort study of cardiometabolic risk factors at the onset of obesity. JAMA Pediatr. 2014, 168, 917–924. [Google Scholar] [CrossRef]
- O’Hara, V.; Browne, N.; Fathima, S.; Sorondo, B.; Bayleran, J.; Johnston, S.; Hastey, K. Obesity Cardiometabolic Comorbidity Prevalence in Children in a Rural Weight-Management Program. Glob. Pediatr. Health 2017, 4, 2333794X17729303. [Google Scholar] [CrossRef]
- Woo, J.G.; Zhang, N.; Fenchel, M.; Jacobs, D.R., Jr.; Hu, T.; Urbina, E.M.; Burns, T.L.; Raitakari, O.; Steinberger, J.; Bazzano, L.; et al. Prediction of adult class II/III obesity from childhood BMI: The i3C consortium. Int. J. Obes. 2020, 44, 1164–1172. [Google Scholar] [CrossRef]
- Kim, J.; Lee, I.; Lim, S. Overweight or obesity in children aged 0 to 6 and the risk of adult metabolic syndrome: A systematic review and meta-analysis. J. Clin. Nurs. 2017, 26, 3869–3880. [Google Scholar] [CrossRef]
- Bendor, C.D.; Bardugo, A.; Pinhas-Hamiel, O.; Afek, A.; Twig, G. Cardiovascular morbidity, diabetes and cancer risk among children and adolescents with severe obesity. Cardiovasc. Diabetol. 2020, 19, 79. [Google Scholar] [CrossRef] [PubMed]
- Tester, J.M.; Phan, T.T.; Tucker, J.M.; Leung, C.W.; Dreyer Gillette, M.L.; Sweeney, B.R.; Kirk, S.; Tindall, A.; Olivo-Marston, S.E.; Eneli, I.U. Characteristics of children 2 to 5 years of age with severe obesity. Pediatrics 2018, 141, e20173228. [Google Scholar] [CrossRef] [PubMed]
- Vargas, C.M.; Stines, E.M.; Granado, H.S. Health-equity issues related to childhood obesity: A scoping review. J. Public Health Dent. 2017, 77, S32–S42. [Google Scholar] [CrossRef] [PubMed]
- Mamun, A.A.; Mannan, M.; Doi, S.A.R. Gestational weight gain in relation to offspring obesity over the life course: A systematic review and bias-adjusted meta-analysis. Obes. Rev. 2014, 15, 338–347. [Google Scholar] [CrossRef]
- Diesel, J.C.; Eckhardt, C.L.; Day, N.L.; Brooks, M.M.; Arslanian, S.A.; Bodnar, L.M. Is gestational weight gain associated with offspring obesity at 36 months? Pediatr. Obes. 2015, 10, 305–310. [Google Scholar] [CrossRef]
- Centers for Disease Control and Prevention. Body Mass Index (BMI). Available online: https://www.cdc.gov/bmi/child-teen-calculator/bmi-categories.html (accessed on 5 October 2022).
- Ward, Z.J.; Long, M.W.; Resch, S.C.; Giles, C.M.; Cradock, A.L.; Gortmaker, S.L. Simulation of growth trajectories of childhood obesity into adulthood. N. Engl. J. Med. 2017, 377, 2145–2153. [Google Scholar] [CrossRef]
- Moradi, M.; Mozaffari, H.; Askari, M.; Azadbakht, L. Association between overweight/obesity with depression, anxiety, low self-esteem, and body dissatisfaction in children and adolescents: A systematic review and meta-analysis of observational studies. Crit. Rev. Food Sci. Nutr. 2021, 62, 555–570. [Google Scholar] [CrossRef]
- Medical Home Initiatives for Children with Special Needs Project Advisory Committee; American Academy of Pediatrics. The medical home. Pediatrics 2002, 110 Pt 1, 184–186. [Google Scholar] [CrossRef]
- Spear, B.A.; Barlow, S.E.; Ervin, C.; Ludwig, D.S.; Saelens, B.E.; Schetzina, K.E.; Taveras, E.M. Recommendations for treatment of child and adolescent overweight and obesity. Pediatrics 2007, 120 (Suppl. 4), S254–S288. [Google Scholar] [CrossRef]
- Bean, M.K.; Caccavale, L.J.; Adams, E.L.; Burnette, C.B.; LaRose, J.G.; Raynor, H.A.; Wickham, E.P., 3rd; Mazzeo, S.E. Parent involvement in adolescent obesity treatment: A systematic review. Pediatrics 2020, 146, e20193315. [Google Scholar] [CrossRef]
- Hampl, S.E.; Hassink, S.G.; Skinner, A.C.; Armstrong, S.C.; Barlow, S.E.; Bolling, C.F.; Avila Edwards, K.C.; Eneli, I.; Hamre, R.; Joseph, M.M.; et al. Clinical Practice Guideline for the Evaluation and Treatment of Children and Adolescents with Obesity. Pediatrics 2023, 151, e2022060640. [Google Scholar] [CrossRef] [PubMed]
- Bayliss, W.M.; Starling, E.H. On the causation of the so-called ‘peripheral reflex secretion’ of the pancreas. Proc. R. Soc. Lond. Biol. 1902, 69, 352–353. [Google Scholar]
- Moore, B.; Edie, E.S.; Abram, J.H. On the treatment of Diabetus mellitus by acid extract of Duodenal Mucous Membrane. Biochem. J. 1906, 1, 28. [Google Scholar] [CrossRef]
- Baggio, L.L.; Drucker, D.J. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007, 132, 2131–2157. [Google Scholar] [CrossRef]
- Mortensen, K.; Christensen, L.L.; Holst, J.J.; Orskov, C. GLP-1 and GIP are colocalized in a subset of endocrine cells in the small intestine. Regul. Pept. 2003, 114, 189–196. [Google Scholar] [CrossRef]
- Buchan, A.M.; Polak, J.M.; Capella, C.; Solcia, E.; Pearse, A.G. Electronimmunocytochemical evidence for the K cell localization of gastric inhibitory polypeptide (GIP) in man. Histochemistry 1978, 56, 37–44. [Google Scholar] [CrossRef]
- Nauck, M.A.; El-Ouaghlidi, A.; Gabrys, B.; Hücking, K.; Holst, J.J.; Deacon, C.F.; Gallwitz, B.; Schmidt, W.E.; Meier, J.J. Secretion of incretin hormones (GIP and GLP-1) and incretin effect after oral glucose in first-degree relatives of patients with type 2 diabetes. Regul. Pept. 2004, 122, 209–217. [Google Scholar] [CrossRef]
- Rountree, D.B.; Ulshen, M.H.; Selub, S.; Fuller, C.R.; Bloom, S.R.; Ghatei, M.A.; Lund, P.K. Nutrient-independent increases in proglucagon and ornithine decarboxylase messenger RNAs after jejunoileal resection. Gastroenterology 1992, 103, 462–468. [Google Scholar] [CrossRef]
- Hoyt, E.C.; Lund, P.K.; Winesett, D.E.; Fuller, C.R.; Ghatei, M.A.; Bloom, S.R.; Ulshen, M.H. Effects of fasting, refeeding, and intraluminal triglyceride on proglucagon expression in jejunum and ileum. Diabetes 1996, 45, 434–439. [Google Scholar] [CrossRef]
- Reimer, R.A.; McBURNEY, M.I. Dietary fiber modulates intestinal proglucagon messenger ribonucleic acid and postprandial secretion of glucagon-like peptide-1 and insulin in rats. Endocrinology 1996, 137, 3948–3956. [Google Scholar] [CrossRef]
- Brubaker, P.L. The glucagon-like peptides: Pleiotropic regulators of nutrient homeostasis. Ann. N. Y. Acad. Sci. 2006, 1070, 10–26. [Google Scholar] [CrossRef] [PubMed]
- Theodorakis, M.J.; Carlson, O.; Michopoulos, S. Human duodenal enteroendocrine cells: Source of both incretin peptides, GLP-1 and GIP. Am. J. Physiol. 2006, 290, E550–E559. [Google Scholar] [CrossRef] [PubMed]
- Thornberry, N.A.; Gallwitz, B. Mechanism of action of inhibitors of dipeptidyl-peptidase-4 (DPP-4). Best Pract. Res. Clin. Endocrinol. Metab. 2009, 23, 479–486. [Google Scholar] [CrossRef] [PubMed]
- Unger, R.H.; Ohneda, A.; Valverde, I.; Eisentraut, A.M.; Exton, J. Characterization of the responses of circulating glucagon-like immunoreactivity to intraduodenal and intravenous administration of glucose. J. Clin. Investig. 1968, 47, 48–65. [Google Scholar] [CrossRef]
- Herrmann, C.; Göke, R.; Richter, G.; Fehmann, H.C.; Arnold, R.; Göke, B. Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients. Digestion 1995, 56, 117–126. [Google Scholar] [CrossRef]
- Roberge, J.N.; Brubaker, P.L. Secretion of proglucagon-derived peptides in response to intestinal luminal nutrients. Endocrinology 1991, 128, 3169–3174. [Google Scholar] [CrossRef]
- Lauritsen, K.B.; Moody, A.J.; Christensen, K.C.; Lindkaer Jensen, S. Gastric inhibitory polypeptide (GIP) and insulin release after small-bowel resection in man. Scand. J. Gastroenterol. 1980, 15, 833–840. [Google Scholar]
- Deacon, C.F.; Nauck, M.A.; Meier, J.; Hücking, K.; Holst, J.J. Degradation of endogenous and exogenous gastric inhibitory polypeptide in healthy and in type 2 diabetic subjects as revealed using a new assay for the intact peptide. J. Clin. Endocrinol. Metab. 2000, 85, 3575–3581. [Google Scholar]
- Nauck, M.A.; Meier, J.J. The incretin effect in healthy individuals and those with type 2 diabetes: Physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol. 2016, 4, 525–536. [Google Scholar] [CrossRef]
- Meier, J.J.; Nauck, M.A.; Kranz, D.; Holst, J.J.; Deacon, C.F.; Gaeckler, D.; Schmidt, W.E.; Gallwitz, B. Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Diabetes 2004, 53, 654–662. [Google Scholar] [CrossRef]
- Deacon, C.F.; Danielsen, P.; Klarskov, L.; Olesen, M.; Holst, J.J. Dipeptidyl peptidase IV inhibition reduces the degradation and clearance of GIP and potentiates its insulinotropic and antihyperglycemic effects in anesthetized pigs. Diabetes 2001, 50, 1588–1597. [Google Scholar] [CrossRef]
- Vilsbøll, T.; Agersø, H.; Lauritsen, T.; Deacon, C.F.; Aaboe, K.; Madsbad, S.; Krarup, T.; Holst, J.J. The elimination rates of intact GIP as well as its primary metabolite, GIP 3-42, are similar in type 2 diabetic patients and healthy subjects. Regul. Pept. 2006, 137, 168–172. [Google Scholar] [CrossRef]
- Kieffer, T.J.; McIntosh, C.H.; Pederson, R.A. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 1995, 136, 3585–3596. [Google Scholar] [CrossRef]
- Hansen, L.; Deacon, C.F.; Ørskov, C.; Holst, J.J. Glucagon-like peptide-1-(7–36) amide is transformed to glucagon-like peptide-1-(9–36) amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology 1999, 140, 5356–5363. [Google Scholar] [CrossRef] [PubMed]
- Moon, M.J.; Park, S.; Kim, D.K.; Cho, E.B.; Hwang, J.I.; Vaudry, H.; Seong, J.Y. Structural and molecular conservation of glucagon-like Peptide-1 and its receptor confers selective ligand-receptor interaction. Front. Endocrinol. 2012, 3, 141. [Google Scholar] [CrossRef] [PubMed]
- Zhou, Q.; Zhao, F.; Zhang, Y.; Yang, D.; Wang, M.W. Structural pharmacology and mechanisms of GLP-1R signaling. Trends Pharmacol. Sci. 2025, 46, 422–436. [Google Scholar] [CrossRef] [PubMed]
- Bensignor, M.O.; Bramante, C.T.; Bomberg, E.M.; Fox, C.K.; Hale, P.M.; Kelly, A.S.; Mamadi, R.; Prabhu, N.; Harder-Lauridsen, N.M.; Gross, A.C. Evaluating potential predictors of weight loss response to liraglutide in adolescents with obesity: A post hoc analysis of the randomized, placebo-controlled SCALE Teens trial. Pediatr. Obes. 2023, 18, e13061. [Google Scholar] [CrossRef]
- Flint, A.; Raben, A.; Astrup, A.; Holst, J.J. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J. Clin. Investig. 1998, 101, 515–520. [Google Scholar] [CrossRef]
- Valassi, E.; Scacchi, M.; Cavagnini, F. Neuroendocrine control of food intake. Nutr. Metab. Cardiovasc. Dis. 2008, 18, 158–168. [Google Scholar] [CrossRef]
- Davies, M.J.; Bergenstal, R.; Bode, B.; Kushner, R.F.; Lewin, A.; Skjøth, T.V.; Andreasen, A.H.; Jensen, C.B.; DeFronzo, R.A.; NN8022-1922 Study Group. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: The SCALE diabetes randomized clinical trial. JAMA 2015, 314, 687–699. [Google Scholar] [CrossRef]
- Mcintyre, N.; Holdsworth, C.D.; Turner, D.F. New interpretation of oral glucose tolerance. Lancet 1964, 284, 20–21. [Google Scholar] [CrossRef]
- Elrick, H.; Stimmler, L.; Hlad, C.J., Jr. Plasma insulin response to oral and intravenous glucose administration. J. Clin. Investig. 1964, 24, 1076–1082. [Google Scholar]
- Nyberg, J.; Anderson, M.F.; Meister, B.; Alborn, A.M.; Ström, A.K.; Brederlau, A.; Illerskog, A.C.; Nilsson, O.; Kieffer, T.J.; Hietala, M.A.; et al. Glucose-dependent insulinotropic polypeptide is expressed in adult hippocampus and induces progenitor cell proliferation. J. Neurosci. Off. J. Soc. Neurosci. 2005, 25, 1816–1825. [Google Scholar] [CrossRef] [PubMed]
- Creutzfeldt, W.; Ebert, R.; Willms, B.; Frerichs, H.; Brown, J.C. Gastric inhibitory polypeptide (GIP) and insulin in obesity: Increased response to stimulation and defective feedback control of serum levels. Diabetologia 1978, 14, 15–24. [Google Scholar] [CrossRef]
- Salera, M.; Giacomoni, P.; Pironi, L.; Cornia, G.; Capelli, M.; Marini, A.; Benfenati, F.; Miglioli, M.; Barbara, L. Gastric inhibitory polypeptide release after oral glucose: Relationship to glucose intolerance, diabetes mellitus, and obesity. J. Clin. Endocrinol. Metab. 1982, 55, 329–336. [Google Scholar] [CrossRef]
- Vilsbøll, T.; Krarup, T.; Deacon, C.F.; Madsbad, S.; Holst, J.J. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 2001, 50, 609–613. [Google Scholar] [CrossRef]
- Ranganath, L.R.; Beety, J.M.; Morgan, L.M.; Wright, J.W.; Howland, R.; Marks, V. Attenuated GLP-1 secretion in obesity: Cause or consequence? Gut 1996, 38, 916–919. [Google Scholar] [CrossRef]
- Ranganath, L.; Norris, F.; Morgan, L.; Wright, J.; Marks, V. Inhibition of carbohydrate-mediated glucagon-like peptide-I (7–36) amide secretion by circulating non-esterified fatty acids. Clin. Sci. 1999, 96, 335–342. [Google Scholar] [CrossRef]
- Vaag, A.A.; Holst, J.J.; Vølund, A.; Beck-Nielsen, H. Gut incretin hormones in identical twins discordant for non-insulin-dependent diabetes mellitus (NIDDM)—Evidence for decreased glucagon-like peptide 1 secretion during oral glucose ingestion in NIDDM twins. Eur. J. Endocrinol. 1996, 135, 425–432. [Google Scholar] [CrossRef]
- Mojsov, S.; Weir, G.C.; Habener, J.F. Insulinotropin: Glucagon-like peptide I (7–37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J. Clin. Investig. 1987, 79, 616–619. [Google Scholar] [CrossRef]
- Kreymann, B.; Ghatei, M.A.; Williams, G.; Bloom, S.R. Glucagon-like peptide-1 7–36: A physiological incretin in man. Lancet 1987, 330, 1300–1304. [Google Scholar] [CrossRef]
- Holst, J.J.; Orskov, C.; Nielsen, O.V.; Schwartz, T.W. Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut. FEBS Lett. 1987, 211, 169–174. [Google Scholar] [CrossRef] [PubMed]
- Holz, G.G.; Kühtreiber, W.M., 4th; Habener, J.F. Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7–37). Nature 1993, 361, 362–365. [Google Scholar] [CrossRef] [PubMed]
- Fehmann, H.C.; Habener, J.F. Functional receptors for the insulinotropic hormone glucagon-like peptide-I(7–37) on a somatostatin secreting cell line. FEBS Lett. 1991, 279, 335–340. [Google Scholar] [CrossRef]
- Creutzfeldt, W.O.; Kleine, N.; Willms, B.; Orskov, C.; Holst, J.J.; Nauck, M.A. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I (7–36) amide in type I diabetic patients. Diabetes Care 1996, 19, 580–586. [Google Scholar] [CrossRef]
- Dupre, J.; Behme, M.T.; Hramiak, I.M.; McFarlane, P.; Williamson, M.P.; Zabel, P.; McDonald, T.J. Glucagon-like peptide I reduces postprandial glycemic excursions in IDDM. Diabetes 1995, 44, 626–630. [Google Scholar] [CrossRef] [PubMed]
- Nauck, M.A.; Heimesaat, M.M.; Orskov, C.; Holst, J.J.; Ebert, R.; Creutzfeldt, W. Preserved incretin activity of glucagon-like peptide 1 [7–36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J. Clin. Investig. 1993, 91, 301–307. [Google Scholar] [CrossRef]
- Nauck, M.A.; Homberger, E.; Siegel, E.G.; Allen, R.C.; Eaton, R.P.; Ebert, R.; Creutzfeldt, W. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J. Clin. Endocrinol. Metab. 1986, 63, 492–498. [Google Scholar] [CrossRef]
- Knop, F.K.; Vilsbøll, T.; Højberg, P.V.; Larsen, S.; Madsbad, S.; Vølund, A.; Holst, J.J.; Krarup, T. Reduced incretin effect in type 2 diabetes: Cause or consequence of the diabetic state? Diabetes 2007, 56, 1951–1959. [Google Scholar] [CrossRef]
- Nauck, M.; Stöckmann, F.; Ebert, R.; Creutzfeldt, W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 1986, 29, 46–52. [Google Scholar] [CrossRef]
- Calanna, S.; Piro, S.; Di Pino, A.; Maria Zagami, R.; Urbano, F.; Purrello, F.; Maria Rabuazzo, A. Beta and alpha cell function in metabolically healthy but obese subjects: Relationship with entero-insular axis. Obesity 2013, 21, 320–325. [Google Scholar] [CrossRef]
- Stinson, S.E.; Fernández de Retana Alzola, I.; Brünner Hovendal, E.D.; Lund, M.A.V.; Fonvig, C.E.; Holm, L.A.; Jonsson, A.E.; Frithioff-Bøjsøe, C.; Christiansen, M.; Pedersen, O.; et al. Altered Glucagon and GLP-1 Responses to Oral Glucose in Children and Adolescents with Obesity and Insulin Resistance. J. Clin. Endocrinol. Metab. 2024, 109, 1590–1600. [Google Scholar] [CrossRef] [PubMed]
- Aulinger, B.A.; Bedorf, A.; Kutscherauer, G.; de Heer, J.; Holst, J.J.; Göke, B.; Schirra, J. Defining the role of GLP-1 in the enteroinsulinar axis in type 2 diabetes using DPP-4 inhibition and GLP-1 receptor blockade. Diabetes 2014, 63, 1079–1092. [Google Scholar] [CrossRef] [PubMed]
- Galderisi, A.; Tricò, D.; Lat, J.; Samuels, S.; Weiss, R.; Van Name, M.; Pierpont, B.; Santoro, N.; Caprio, S. Incretin effect determines glucose trajectory and insulin sensitivity in youths with obesity. JCI Insight 2023, 8, e165709. [Google Scholar] [CrossRef] [PubMed]
- Michaliszyn, S.F.; Mari, A.; Lee, S.; Bacha, F.; Tfayli, H.; Farchoukh, L.; Ferrannini, E.; Arslanian, S. β-cell function, incretin effect, and incretin hormones in obese youth along the span of glucose tolerance from normal to prediabetes to type 2 diabetes. Diabetes 2014, 63, 3846–3855. [Google Scholar] [CrossRef]
- Tomasik, P.J.; Sztefko, K.; Starzyk, J.; Rogatko, I.; Szafran, Z. Entero-insular axis in children with anorexia nervosa. Psychoneuroendocrinology 2005, 30, 364–372. [Google Scholar] [CrossRef]
- Seymour, N.; Volpert, A.; Andresen, D. Regulation of hepatic insulin receptors by pancreatic polypetide in fasting feeding. J. Surg. Res. 1996, 65, 1–4. [Google Scholar] [CrossRef]
- Sato, T.; Laviano, A.; Meguid, M.M.; Chen, C.; Rossi-Fanelli, F.; Hatakeyama, K. Involvement of plasma leptin, insulin and free tryptophan in cytokine-induced anorexia. Clin. Nutr. 2003, 22, 139–146. [Google Scholar] [CrossRef]
- McHugh, P.; Moran, T. The stomach, cholecystokinin and satiety. Fed. Proc. 1986, 45, 1384–1390. [Google Scholar]
- Flint, A.; Raben, A.; Ersboll, A.K.; Holst, J.J.; Astrup, A. The effect of physiological levels of glucagon-like peptide-1 on appetite gastric emptying energy substrate metabolism in obesity. Int. J. Obes. Relat. Metab. Disord. 2001, 25, 781–792. [Google Scholar] [CrossRef]
- Katole, N.T.; Salankar, H.V.; Khade, A.M.; Kale, J.S.; Bankar, N.J.; Gosavi, P.; Dudhe, B.; Mankar, N.; Noman, O. The Antiobesity Effect and Safety of GLP-1 Receptor Agonist in Overweight/Obese Adolescents Without Diabetes Mellitus: A Systematic Review and Meta-Analysis. Cureus 2024, 16, e66280. [Google Scholar] [CrossRef]
- Ryan, P.M.; Seltzer, S.; Hayward, N.E.; Rodriguez, D.A.; Sless, R.T.; Hawkes, C.P. Safety and Efficacy of Glucagon-Like Peptide-1 Receptor Agonists in Children and Adolescents with Obesity: A Meta-Analysis. J. Pediatr. 2021, 236, 137–147.e13. [Google Scholar] [CrossRef]
- Blüher, M.; Aras, M.; Aronne, L.J.; Batterham, R.L.; Giorgino, F.; Ji, L.; Pietiläinen, K.H.; Schnell, O.; Tonchevska, E.; Wilding, J.P. New insights into the treatment of obesity. Diabetes Obes. Metab. 2023, 25, 2058–2072. [Google Scholar] [CrossRef]
- Kelly, A.S.; Auerbach, P.; Barrientos-Perez, M.; Gies, I.; Hale, P.M.; Marcus, C.; Mastrandrea, L.D.; Prabhu, N.; Arslanian, S.; NN8022-4180 Trial Investigators. A Randomized, Controlled Trial of Liraglutide for Adolescents with Obesity. N. Engl. J. Med. 2020, 382, 2117–2128. [Google Scholar] [CrossRef] [PubMed]
- Anderson, S.L.; Beutel, T.R.; Trujillo, J.M. Oral semaglutide in type 2 diabetes. J. Diabetes Its Complicat. 2020, 34, 107520. [Google Scholar] [CrossRef] [PubMed]
- Knudsen, L.B.; Lau, J. The discovery and development of liraglutide and semaglutide. Front. Endocrinol. 2019, 10, 155. [Google Scholar] [CrossRef] [PubMed]
- Weghuber, D.; Barrett, T.; Barrientos-Pérez, M.; Gies, I.; Hesse, D.; Jeppesen, O.K.; Kelly, A.S.; Mastrandrea, L.D.; Sørrig, R.; Arslanian, S.; et al. Once-Weekly Semaglutide in Adolescents with Obesity. N. Engl. J. Med. 2022, 387, 2245–2257. [Google Scholar] [CrossRef]
- Knop, F.K.; Brønden, A.; Vilsbøll, T. Exenatide: Pharmacokinetics, clinical use, and future directions. Expert Opin. Pharmacother. 2017, 18, 555–571. [Google Scholar] [CrossRef]
- Kelly, A.S.; Metzig, A.M.; Rudser, K.D.; Fitch, A.K.; Fox, C.K.; Nathan, B.M.; Deering, M.M.; Schwartz, B.L.; Abuzzahab, M.J.; Gandrud, L.M.; et al. Exenatide as a weight-loss therapy in extreme pediatric obesity: A randomized, controlled pilot study. Obesity 2012, 20, 364–370. [Google Scholar] [CrossRef]
- Kelly, A.S.; Rudser, K.D.; Nathan, B.M.; Fox, C.K.; Metzig, A.M.; Coombes, B.J.; Fitch, A.K.; Bomberg, E.M.; Abuzzahab, M.J. The effect of glucagon-like peptide-1 receptor agonist therapy on body mass index in adolescents with severe obesity: A randomized, placebo-controlled, clinical trial. JAMA Pediatr. 2013, 167, 355–360. [Google Scholar] [CrossRef]
- Alfaris, N.; Waldrop, S.; Johnson, V.; Boaventura, B.; Kendrick, K.; Stanford, F.C. GLP-1 single, dual, and triple receptor agonists for treating type 2 diabetes and obesity: A narrative review. EClinicalMedicine 2024, 75, 102782. [Google Scholar] [CrossRef]
- Novo Nordisk: FDA Approves Once-Weekly Wegovy Injection for the Treatment of Obesity in Teens Aged 12 Years and Older. 2022. Available online: https://www.novonordisk-us.com/media/news-archive/news-details.html?id= (accessed on 20 March 2025).
- Danne, T.; Biester, T.; Kapitzke, K.; Jacobsen, S.H.; Jacobsen, L.V.; Petri, K.C.C.; Hale, P.M.; Kordonouri, O. Liraglutide in an Adolescent Population with Obesity: A Randomized, Double-Blind, Placebo-Controlled 5-Week Trial to Assess Safety, Tolerability, and Pharmacokinetics of Liraglutide in Adolescents Aged 12-17 Years. J. Pediatr. 2017, 181, 146–153. [Google Scholar] [CrossRef] [PubMed]
- Fox, C.K.; Barrientos-Pérez, M.; Bomberg, E.M.; Dcruz, J.; Gies, I.; Harder-Lauridsen, N.M.; Jalaludin, M.Y.; Sahu, K.; Weimers, P.; Zueger, T.; et al. Liraglutide for Children 6 to <12 Years of Age with Obesity—A Randomized Trial. N. Engl. J. Med. 2025, 392, 555–565. [Google Scholar]
- Mastrandrea, L.D.; Witten, L.; Carlsson Petri, K.C.; Hale, P.M.; Hedman, H.K.; Riesenberg, R.A. Liraglutide effects in a paediatric (7–11 y) population with obesity: A randomized, double-blind, placebo-controlled, short-term trial to assess safety, tolerability, pharmacokinetics, and pharmacodynamics. Pediatr. Obes. 2019, 14, e12495. [Google Scholar] [CrossRef]
- Weghuber, D.; Forslund, A.; Ahlström, H.; Alderborn, A.; Bergström, K.; Brunner, S.; Cadamuro, J.; Ciba, I.; Dahlbom, M.; Heu, V.; et al. A 6-month randomized, double-blind, placebo-controlled trial of weekly exenatide in adolescents with obesity. Pediatr. Obes. 2020, 15, e12624. [Google Scholar] [CrossRef]
- Ball, G.D.C.; Merdad, R.; Birken, C.S.; Cohen, T.R.; Goodman, B.; Hadjiyannakis, S.; Hamilton, J.; Henderson, M.; Lammey, J.; Morrison, K.M.; et al. Managing obesity in children: A clinical practice guideline. CMAJ 2025, 197, E372–E389. [Google Scholar] [CrossRef]
- Klein, D.J.; Battelino, T.; Chatterjee, D.J.; Jacobsen, L.V.; Hale, P.M.; Arslanian, S.; NN2211-1800 Study Group. Liraglutide’s safety, tolerability, pharmacokinetics, and pharmacodynamics in pediatric type 2 diabetes: A randomized, double-blind, placebo-controlled trial. Diabetes Technol. Ther. 2014, 16, 679–687. [Google Scholar] [CrossRef]
- Nathan, B.M.; Rudser, K.D.; Abuzzahab, M.J.; Fox, C.K.; Coombes, B.J.; Bomberg, E.M.; Kelly, A.S. Predictors of weight-loss response with glucagon-like peptide-1 receptor agonist treatment among adolescents with severe obesity. Clin. Obes. 2016, 6, 73–78. [Google Scholar] [CrossRef]
- Christoforidis, A.; Maniadaki, I.; Stanhope, R. Growth hormone/insulin-like growth factor-1 axis during puberty. Pediatr. Endocrinol. Rev. 2005, 3, 5–10. [Google Scholar]
- Chao, J.; Coleman, R.A.; Keating, D.J.; Martin, A.M. Gut Microbiome Regulation of Gut Hormone Secretion. Endocrinology 2025, 166, bqaf004. [Google Scholar] [CrossRef]
- Wang, L.; Xu, H.; Tan, B.; Yi, Q.; Liu, H.; Deng, H.; Chen, Y.; Wang, R.; Tian, J.; Zhu, J. Gut microbiota and its derived SCFAs regulate the HPGA to reverse obesity-induced precocious puberty in female rats. Front. Endocrinol. 2022, 13, 1051797. [Google Scholar] [CrossRef]
- Jaghutriz, B.A.; Heni, M.; Lutz, S.Z.; Fritsche, L.; Machicao, F.; Staiger, H.; Peter, A.; Häring, H.U.; Fritsche, A.; Wagner, R. Gene x Gene Interactions Highlight the Role of Incretin Resistance for Insulin Secretion. Front. Endocrinol. 2019, 10, 72. [Google Scholar] [CrossRef] [PubMed]
Drugs | Study Author and Year | Study Design | Sample Size, (n) | Ages and BMI Eligible for Study | Study Duration | Target Dose | Study Primary Objective | Study Secondary Anthropometric Objectives |
---|---|---|---|---|---|---|---|---|
Liraglutide | Danne T. et al., 2017 [95] NCT01789086 | Phase 1 randomized, placebo-controlled, double -blind, parallel-group | Total = 21 Liraglutide = 14 Placebo = 7 | 12–17 years BMI ≥ 30 kg/m2 and ≤45 kg/m2 BMI ≥ 95th percentile for age and sex | 6 weeks and 5–14-day follow-up period | Week 1: 0.6 mg/day, Week 2: 1.2 mg/day, Week 3: 1.8 mg/day, Week 4: 2.4 mg/day, Weeks 5–6: 3.0 mg/day | Number of treatment emergent adverse events |
|
Fox C.K. et al., 2025 [96] NCT04775082 SCALE KIDS | Phase 3 randomized, placebo-controlled, double -blind, parallel-group | Total = 82 Liraglutide = 56 Placebo = 26 | 6–12 years BMI ≥ 95th percentile for age and sex | 56 weeks and 26-week follow-up period | 3.0 mg/day Week 1: 0.6 mg/day for children with weight ≥ 45 kg and 0.3 mg/day for those with weight < 45 kg, and increased the dose in 0.6 mg increments weekly | Relative change in BMI (%) |
| |
Kelly A.S. et al., 2020 [86] NCT02918279 SCALE TEENS | Phase 3 randomized, placebo-controlled, double-blind, parallel-group | Total = 251 Liraglutide = 125 Placebo = 126 | 12–17 years BMI ≥ 30 kg/m2 BMI ≥ 95th percentile for age and sex | 56 weeks and 26-week follow-up period | Week 1: 0.6 mg/day, Week 2: 1.2 mg/day, Week 3: 1.8 mg/day, Week 4: 2.4 mg/day, Weeks 5–56: 3.0 mg/day | Change in BMI z-score |
| |
Mastrandrea L.D. et al., 2019 [97] NCT02696148 | Phase 1 randomized, placebo-controlled, double-blind, parallel-group | Total = 24 Liraglutide = 16 Placebo = 8 | 7–11 years BMI ≥ 30 kg/m2 and ≤45 kg/m2 BMI ≥ 95th percentile for age and sex | At least 7 weeks, and up to 6 optional treatment weeks, up to a maximum of 13 weeks. | Week 1: 0.3 mg/day Week 2: 0.6 mg/day, Week 3: 0.9 mg/day Week 4: 1.2 mg/day Week 5: 1.8 mg/day Week 6: 2.4 mg/day Weeks 7–13: 3.0 mg/day | Number of treatment-emergent adverse events |
| |
Exenatide | Weghuber D. et al., 2020 [98] NCT02794402 | Phase 2 randomized placebo-controlled, double-blind, parallel-group | Total = 44 Exenatide = 22 Placebo = 22 | 10–18 years BMI z-score > 2.0 or age-adapted BMI > 30 kg/m2 | 24 weeks and 2-week follow-up period | 2 mg/week | Change in BMI z-score |
|
Kelly A.S. et al., 2012 [91] NCT00886626 | Phase 2 randomized, crossover, controlled, open-label | Total = 12 | 8–19 years BMI ≥ 99th percentile for age and sex BMI ≥ 1.2 times the 95th percentile or BMI ≥ 35 kg/m2 | 6 months: 3-month control phase and 3-month drug phase | Month1: 5 mcg BID Months 2–3: 10 mcg BID | Change in BMI (Kg/m2) |
| |
Kelly A.S. et al., 2013 [92] NCT01237197 | Phase 2 randomized placebo-controlled, double-blind, parallel-group | Total = 26 Exenatide = 13 Placebo = 13 | 12–19 years BMI ≥ 1.2 times the 95th percentile or BMI ≥ 35 kg/m2 | 3-month randomization period and 3-month open-label extension period (all participants received exenatide) | Randomization period: Month 1: 5 mcg BID Months 2–3: 10 mcg BID Open-label extension period Month 1: 5 mcg BID Months 2–3: 10 mcg BID | Change in BMI (Kg/m2, %) | ||
Semaglutide | Weghuber D.et al., 2022 [89] NCT04102189 STEP TEENS | Phase 3 randomized, placebo-controlled, double-blind, parallel-group | Total = 201 Semaglutide = 134 Placebo = 67 | 12–17 years BMI ≥ 95th percentile for age and sex or BMI ≥ 85th percentile with ≥ 1 weight-related coexisting condition (hypertension, dyslipidemia, obstructive sleep apnea, or type 2 diabetes) | 68 weeks and 7-week follow-up period | Week 1–4: 0.25 mg/week Week 5–8: 0.5 mg/week Week 9–12: 1.0 mg/week Week 13–16: 1.7 mg/week Week 17–68: 2.4 mg/week | Relative change in BMI (%) |
|
Drugs | Study Author and Year | Efficacy Parameters | |||
---|---|---|---|---|---|
Weight Loss Effect | BMI Outcome | BMI z-Score | Others | ||
Liraglutide | Danne T. 2017 [95] | Body weight change (kg): Liraglutide: −2.55 Placebo: −1.85 | NA | BMI z-score change: Liraglutide: −0.12 Placebo: −0.10 | NA |
Fox C.K. 2025 [96] | Body weight absolute change (kg): Liraglutide:1.1 Placebo: 7.1 Body weight relative change (%) Liraglutide: 1.6 Placebo: 10.0 | BMI relative change (%): Liraglutide: −5.8 Placebo: 1.6 BMI as percentage of the 95th percentile (%) Liraglutide: −14.0 Placebo: −0.4 | BMI z-score change: Liraglutide: −0.7 Placebo: −0.3 | BMI reduction threshold (≥5%; ≥10%): Liraglutide: 46.2%; 34.6% Placebo: 8.7%; 4.3% Waist circumference (cm): Liraglutide: −2.0 Placebo: 1.3 | |
Kelly A.S. 2020 [86] | Body weight absolute change (kg): Liraglutide: −2.26 ± 0.94 Placebo: 2.25 ± 0.98 Body weight relative change (%) Liraglutide: −2.65 ± 0.93 Placebo: 2.37 ± 0.95 | BMI absolute change: Liraglutide: −1.39 ± 0.31 Placebo: 0.19 ± 0.33 BMI relative change (%): Liraglutide: −4.29 ± 0.88 Placebo: 0.35 ± 0.91 BMI as percentage of the 95th percentile (%) Liraglutide: −5.47 ± 1.2 Placebo: 0.77 ± 1.27 | BMI z-score absolute change: Liraglutide: −0.23 ± 0.05 Placebo: −0.00 ± 0.05 BMI z-score relative change (%): Liraglutide: −8.32 ± 1.68 Placebo: −0.68 ± 1.74 | BMI reduction threshold (≥5%; ≥10%): Liraglutide: 43.3%;26.1% Placebo: 18.7%;8.1% Waist circumference (cm): Liraglutide: −4.35 ± 0.85 Placebo: −1.42 ± 0.88 | |
Mastrandrea L.D. 2019 [97] | Body weight absolute change (kg): Liraglutide: −0.52 Placebo: 0.98 | NA | BMI z-score absolute change: Liraglutide: −0.3 Placebo: −0.01 | NA | |
Exenatide | Weghuber D. 2020 [98] | Body weight absolute change (kg): Exenatide: −0.5 Placebo: 2.5 | BMI absolute change (kg/m2): Exenatide: −0.3 Placebo: 0.5 BMI as percentage of the 95th percentile (%) Exenatide: −0.2 Placebo: 0.0 | BMI z-score absolute change: Exenatide: −0.1 Placebo: 0.0 | Waist circumference (cm): Exenatide: −1.9 Placebo: 1.0 |
Kelly A. S. 2012 [91] | Body weight absolute change (kg): Exenatide: −0.99 Control: 2.97 Body weight relative change (%) Exenatide: −1.2 Control: 2.68 | BMI absolute change (Kg/m2): Exenatide: −0.9 Control: 0.84 BMI relative change (%): Exenatide: −2.57% Control: 1.72 | NA | NA | |
Kelly A. S. 2013 [92] | Body weight absolute change (kg): Exenatide: −2.9 Placebo: 0.32 | BMI absolute change (Kg/m2): Exenatide: −1.18 Placebo: −0.04 BMI relative change (%): Exenatide: −2.9 Placebo: −0.15 | NA | Waist circumference (cm): Exenatide: −2.04 Placebo: −1.01 | |
Semaglutide | Weghuber D. 2022 [89] | Body weight absolute change (kg): Semaglutide: −17.0 Placebo: 2.3 Body weight relative change (%) Semaglutide: −16.3 Placebo: 2.6 | BMI absolute change (Kg/m2): Semaglutide: −6.5 Placebo: 0.1 BMI relative change (%): Semaglutide: −17.9% Placebo: 0.6% BMI as percentage of the 95th percentile (%) Semaglutide: −26.7% Placebo: −4.4% | BMI z-score absolute change: Semaglutide: −1.2 Placebo: −0.1 |
Semaglutide: 78.2% Placebo: 20.7%
Semaglutide: 75.6%; 64.7%; 56.3%; 39.5% Placebo: 15.5%; 8.6%; 5.2%; 3.4%
Semaglutide: 71.8% Placebo: 21.0%
Semaglutide: −13.9 Placebo: −0.1 |
Drugs | Study Author and Year | Safety Parameters: GLP-1 Agonist vs. Control (Percent of Participants Experiencing at Least One Adverse Event Episode) | ||||
---|---|---|---|---|---|---|
Any Treatment-Emergent Adverse Events (TEAEs) | Gastrointestinal Adverse Events | Adverse Events that Led to Treatment Discontinuation | Treatment-Emergent Serious Adverse Events | Others Adverse Events | ||
Liraglutide | Danne T., 2017 [95] | Total: 100% vs. 57.1% Total TEAEs possibly/probably related to investigational product: 14.3/92.9% vs. 0.0% | Total 85.7% vs. 28.6% Total GI AEs possibly or probably related to investigational product: 78.6% vs. 0.0% of which: Nausea 50.0% vs. 0.0% Vomiting 34.4% vs. 0.0% Diarrhea 22.4% vs. 0.0% Abdominal pain 8.0% vs. 0.0% | 0.0% vs. 0.0% | 0.0% vs. 0.0% | Hypoglycemic episodes: Confirmed: 14.3% vs. 0.0% ADA: 57.1% vs. 14.3% Nervous system disorders: 50.0% vs. 14.3% |
Fox C. K., 2025 [96] | 89.3% vs. 88.5% | Total 80.4% vs. 53.8% | 10.7% vs. 0.0% | 12.5% vs. 7.7% | Psychiatric disorders: 10.7% vs. 11.5% | |
Kelly A.S., 2020 [86] | 88.8% vs. 84.9% | Total 64.8% vs. 36.5% Nausea 42.4% vs. 14.3% Vomiting 34.4% vs. 4.0% Diarrhea 22.4% vs. 14.3% Abdominal pain 8.0% vs. 8.7% | 10.4% vs. 0.0% | 2.4% vs. 4.0% | Pancreatitis: 0.8% vs. 0.0% Hypoglycemia: 20.8% vs. 14.3% Psychiatric disorders/depression/suicidal ideation/completed suicide: 10.4/4.0/0.8/0.8% vs. 14.3/2.4/0.8/0.0% | |
[97] | Total: 56.3% vs. 62.5% Total TEAEs possibly/probably related to investigational product: 31.3/18.8% vs. 12.5/12.5% | Total 37.5% vs. 12.5% Nausea 12.5% vs. 0.0% Vomiting 25.0% vs. 0.0% Diarrhea 6.3% vs. 0.0% Abdominal pain 6.3% vs. 0.0% | 0.0% vs. 0.0% | 0.0% vs. 0.0% | Hypoglycemic episodes: ADA: 25.0% vs. 12.5% Nervous system disorders: 18.8% vs. 50.0% | |
Exenatide | Weghuber D. 2020 [98] | Total TEAEs possibly/probably related to investigational product: 81.8/68.2% vs. 13.6/13.6% | Total 81.8% vs. 45.5% | 4.5% vs. 0.0% | 0.0% vs. 0.0% | Hypoglycemic episodes: ADA: 0.0% vs. 0.0% Nervous system disorders: 72.7% vs. 59.1% Psychiatric disorders: 4.6% vs. 9.1% |
Kelly A. S., 2012 [91] | Total: 36.36% vs. 0.0% | Nausea 36.36% vs. 0.0% Vomiting 27.27% vs. 0.0% Abdominal pain 27.27% vs. 0.0% | 0.0% vs. 0.0% | Pancreatitis: 0.0% vs. 0.0% Hypoglycemia: 0.0% vs. 0.0% | ||
[92] | NA | Nausea 62% vs. 31% Vomiting 31%vs 8% Diarrhea 8% vs. 31% Abdominal pain 15.0% vs. 23.0% | NA | 0.0%vs 0.0% | Pancreatitis: 0.0% vs. 0.0% Hypoglycemia: 0.0% vs. 0.0% Nervous system disorders: 23.08% vs. 46.15% | |
Semaglutide | [89] | 79% vs. 82% | Total 61.7% vs. 41.8% Nausea 42.1% vs. 17.9% Vomiting 36.0% vs. 10.4% Diarrhea 21.8% vs. 19.4% Abdominal pain 15.04% vs. 5.97% | 5% vs. 4% | 11.28% vs. 8.96% | Pancreatitis: 0.0% vs. 0.0% Hypoglycemia: 0.0% vs. 0.0% Psychiatric disorders: 0.75% vs. 0.0% |
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Dira, L.-M.; Marin, L.-M.; Popa, S.-G.; Singer, C.-E.; Cosoveanu, C.-S.; Donoiu, I.; Golli, A.-L. New Perspectives in Modulating the Entero-Insular Axis in Pediatric Obesity. Int. J. Mol. Sci. 2025, 26, 6143. https://doi.org/10.3390/ijms26136143
Dira L-M, Marin L-M, Popa S-G, Singer C-E, Cosoveanu C-S, Donoiu I, Golli A-L. New Perspectives in Modulating the Entero-Insular Axis in Pediatric Obesity. International Journal of Molecular Sciences. 2025; 26(13):6143. https://doi.org/10.3390/ijms26136143
Chicago/Turabian StyleDira, Loredana-Maria, Loredana-Maria Marin, Simona-Georgiana Popa, Cristina-Elena Singer, Carmen-Simona Cosoveanu, Ionut Donoiu, and Andreea-Loredana Golli. 2025. "New Perspectives in Modulating the Entero-Insular Axis in Pediatric Obesity" International Journal of Molecular Sciences 26, no. 13: 6143. https://doi.org/10.3390/ijms26136143
APA StyleDira, L.-M., Marin, L.-M., Popa, S.-G., Singer, C.-E., Cosoveanu, C.-S., Donoiu, I., & Golli, A.-L. (2025). New Perspectives in Modulating the Entero-Insular Axis in Pediatric Obesity. International Journal of Molecular Sciences, 26(13), 6143. https://doi.org/10.3390/ijms26136143