Fasting Plasma GLP-1 Is Associated With Overweight/Obesity and Cardiometabolic Risk Factors in Children and Adolescents

Sara E Stinson, Anna E Jonsson, Morten A V Lund, Christine Frithioff-Bøjsøe, Louise Aas Holm, Oluf Pedersen, Lars Ängquist, Thorkild I A Sørensen, Jens J Holst, Michael Christiansen, Jens-Christian Holm, Bolette Hartmann, Torben Hansen, Sara E Stinson, Anna E Jonsson, Morten A V Lund, Christine Frithioff-Bøjsøe, Louise Aas Holm, Oluf Pedersen, Lars Ängquist, Thorkild I A Sørensen, Jens J Holst, Michael Christiansen, Jens-Christian Holm, Bolette Hartmann, Torben Hansen

Abstract

Context: The importance of fasting glucagon-like peptide-1 (GLP-1) in altered metabolic outcomes has been questioned.

Objective: This work aimed to assess whether fasting GLP-1 differs in children and adolescents with overweight/obesity compared to a population-based reference, and whether concentrations predict cardiometabolic risk (CMR) factors.

Methods: Analyses were based on The Danish Childhood Obesity Data- and Biobank, a cross-sectional study including children and adolescents, aged 6 to 19 years, from an obesity clinic group (n = 1978) and from a population-based group (n = 2334). Fasting concentrations of plasma total GLP-1 and quantitative CMR factors were assessed. The effects of GLP-1 as a predictor of CMR risk outcomes were examined by multiple linear and logistic regression modeling.

Results: The obesity clinic group had higher fasting GLP-1 concentrations (median 3.3 pmol/L; interquartile range, 2.3-4.3 pmol/L) than the population-based group (2.8 pmol/L; interquartile range, 2.1-3.8 pmol/L; P < 2.2E-16). Body mass index SD score (SDS), waist circumference, and total body fat percentage were significant predictors of fasting GLP-1 concentrations in boys and girls. Fasting GLP-1 concentrations were positively associated with homeostasis model assessment of insulin resistance, fasting values of insulin, high-sensitivity C-reactive protein, C-peptide, triglycerides, alanine transaminase (ALT), glycated hemoglobin A1c, and SDS of diastolic and systolic blood pressure. A 1-SD increase in fasting GLP-1 was associated with an increased risk of insulin resistance (odds ratio [OR] 1.59), dyslipidemia (OR 1.16), increased ALT (OR 1.14), hyperglycemia (OR 1.12) and hypertension (OR 1.12).

Conclusion: Overweight/obesity in children and adolescents is associated with increased fasting plasma total GLP-1 concentrations, which was predictive of higher CMR factors.

Trial registration: ClinicalTrials.gov NCT00928473.

Keywords: GLP-1; adolescents; cardiometabolic risk factors; children; obesity.

© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

Figures

Figure 1.
Figure 1.
Estimated regression β effects (95% CI) for associations of fasting plasma total glucagon-like peptide-1 (GLP-1) as a predictor of cardiometabolic risk (CMR) factors. The obesity clinic and population-based groups were pooled to estimate the effect sizes for CMR factors. The formula for linear regression in R: glm(CMR factor ~ fasting plasma total GLP-1 (SD units) + age + sex + BMI SDS). BMI SDS and BF% were not adjusted for BMI SDS. Bonferroni-Holm correction for multiple testing corresponds to P < .003. ALT, plasma alanine transaminase; BF%, body fat percentage; BMI SDS, body mass index SD score; serum C-peptide; CMR, cardiometabolic risk; DBP SDS, diastolic blood pressure; plasma glucose; HbA1c, whole blood glycated hemoglobin A1c; HDL-C, plasma high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; hs-CRP, serum high-sensitivity C-reactive protein; serum insulin; LDL-C, plasma low-density lipoprotein cholesterol; SBP SDS, systolic blood pressure; TG, plasma triglycerides; WC, waist circumference.
Figure 2.
Figure 2.
Estimated odds ratios (OR; 95% CI) for associations of fasting plasma total Glucagon-like peptide-1 (GLP-1) as a predictor of cardiometabolic risk (CMR) features. The obesity clinic and population-based groups were pooled to estimate the effect sizes for CMR features. Formula for interaction logistic regression in R: glm(CMR feature (0/1) ~ fasting plasma total GLP-1 (SD units) + age + sex + body mass index SDS). Bonferroni-Holm correction for multiple testing corresponds to P < .01. ALT, alanine transaminase.

References

    1. Hira T, Pinyo J, Hara H. What is GLP-1 really doing in obesity? Trends Endocrinol Metab. 2020;31(2):71-80.
    1. Holst JJ, Albrechtsen NJW, Rosenkilde MM, Deacon CF. Physiology of the incretin hormones, GIP and GLP-1—regulation of release and posttranslational modifications. Compr Physiol. 2019;9(4):1339-1381.
    1. Yabe D, Seino Y, Seino Y. Incretin concept revised: the origin of the insulinotropic function of glucagon-like peptide-1—the gut, the islets or both? J Diabetes Investig. 2018;9(1):21-24.
    1. Jorsal T, Rhee NA, Pedersen J, et al. . Enteroendocrine K and L cells in healthy and type 2 diabetic individuals. Diabetologia. 2018;61(2):284-294.
    1. Lewis JE, Miedzybrodzka EL, Foreman RE, et al. . Selective stimulation of colonic L cells improves metabolic outcomes in mice. Diabetologia. 2020;63(7):1396-1407.
    1. Hansen L, Hartmann B, Bisgaard T, Mineo H, Jørgensen PN, Holst JJ. Somatostatin restrains the secretion of glucagon-like peptide-1 and -2 from isolated perfused porcine ileum. Am J Physiol Endocrinol Metab. 2000;278(6):E1010-E1018.
    1. Toft-Nielson M, Madsbad S, Holst JJ. The effect of glucagon-like peptide I (GLP-I) on glucose elimination in healthy subjects depends on the pancreatic glucoregulatory hormones. Diabetes. 1996;45(5):552-556.
    1. Song Y, Koehler JA, Baggio LL, Powers AC, Sandoval DA, Drucker DJ. Gut-proglucagon-derived peptides are essential for regulating glucose homeostasis in mice. Cell Metab. 2019;30(5):976-986.e3.
    1. Lim GE, Huang GJ, Flora N, LeRoith D, Rhodes CJ, Brubaker PL. Insulin regulates glucagon-like peptide-1 secretion from the enteroendocrine L cell. Endocrinology. 2009;150(2):580-591.
    1. Jensen AB, Sørensen TIA, Pedersen O, Jess T, Brunak S, Allin KH. Increase in clinically recorded type 2 diabetes after colectomy. eLife. 2018;7:e37420.
    1. Nauck MA, Siemsglüss J, Orskov C, Holst JJ. Release of glucagon-like peptide 1 (GLP-1 [7-36 amide]), gastric inhibitory polypeptide (GIP) and insulin in response to oral glucose after upper and lower intestinal resections. Z Gastroenterol. 1996;34(3):159-166.
    1. Færch K, Torekov SS, Vistisen D, et al. . GLP-1 response to oral glucose is reduced in prediabetes, screen-detected type 2 diabetes, and obesity and influenced by sex: the ADDITION-PRO study. Diabetes. 2015;64(7):2513-2525.
    1. Zhang F, Tang X, Cao H, et al. . Impaired secretion of total glucagon-like peptide-1 in people with impaired fasting glucose combined impaired glucose tolerance. Int J Med Sci. 2012;9(7):574-581.
    1. Dybjer E, Engström G, Helmer C, Nägga K, Rorsman P, Nilsson PM. Incretin hormones, insulin, glucagon and advanced glycation end products in relation to cognitive function in older people with and without diabetes, a population-based study. Diabet Med. 2020;37(7):1157-1166.
    1. Toft-Nielsen MB, Damholt MB, Madsbad S, et al. . Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001;86(8):3717-3723.
    1. Guo SS, Wu W, Chumlea WC, Roche AF. Predicting overweight and obesity in adulthood from body mass index values in childhood and adolescence. Am J Clin Nutr. 2002;76(3):653-658.
    1. Field AE, Cook NR, Gillman MW. Weight status in childhood as a predictor of becoming overweight or hypertensive in early adulthood. Obes Res. 2005;13(1):163-169.
    1. Aarestrup J, Bjerregaard LG, Gamborg M, et al. . Tracking of body mass index from 7 to 69 years of age. Int J Obes (Lond). 2016;40(9):1376-1383.
    1. Engeland A, Bjørge T, Tverdal A, Søgaard AJ. Obesity in adolescence and adulthood and the risk of adult mortality. Epidemiology. 2004;15(1):79-85.
    1. Franks PW, Hanson RL, Knowler WC, Sievers ML, Bennett PH, Looker HC. Childhood obesity, other cardiovascular risk factors, and premature death. N Engl J Med. 2010;362(6):485-493.
    1. Baker JL, Olsen LW, Sørensen TIA. Childhood body-mass index and the risk of coronary heart disease in adulthood. N Engl J Med. 2007;357(23):2329-2337.
    1. Zimmermann E, Bjerregaard LG, Gamborg M, Vaag AA, Sørensen TIA, Baker JL. Childhood body mass index and development of type 2 diabetes throughout adult life—a large-scale Danish cohort study. Obesity (Silver Spring). 2017;25(5):965-971.
    1. Bjerregaard LG, Jensen BW, Ängquist L, Osler M, Sørensen TIA, Baker JL. Change in overweight from childhood to early adulthood and risk of type 2 diabetes. N Engl J Med. 2018;378(14):1302-1312.
    1. Reinehr T, de Sousa G, Roth CL. Fasting glucagon-like peptide-1 and its relation to insulin in obese children before and after weight loss. J Pediatr Gastroenterol Nutr. 2007;44(5):608-612.
    1. Lomenick JP, White JR, Smart EJ, Clasey JL, Anderson JW. Glucagon-like peptide 1 and pancreatic polypeptide responses to feeding in normal weight and overweight children. J Pediatr Endocrinol Metab. 2009;22(6):493-500.
    1. Manell H, Staaf J, Manukyan L, et al. . Altered plasma levels of glucagon, GLP-1 and glicentin during OGTT in adolescents with obesity and type 2 diabetes. J Clin Endocrinol Metab. 2016;101(3):1181-1189.
    1. Holm JC, Gamborg M, Bille DS, Gr Nb K HN, Ward LC, Faerk J. Chronic care treatment of obese children and adolescents. Int J Pediatr Obes. 2011;6(3-4):188-196.
    1. Lausten-Thomsen U, Christiansen M, Fonvig CE, et al. . Reference values for serum total adiponectin in healthy non-obese children and adolescents. Clin Chim Acta. 2015;450:11-14.
    1. Kloppenborg JT, Fonvig CE, Nielsen TRH, et al. . Impaired fasting glucose and the metabolic profile in Danish children and adolescents with normal weight, overweight, or obesity. Pediatr Diabetes. 2018;19(3):356-365.
    1. Nysom K, Mølgaard C, Hutchings B, Michaelsen KF. Body mass index of 0 to 45-y-old Danes: reference values and comparison with published European reference values. Int J Obes Relat Metab Disord. 2001;25(2):177-184.
    1. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114(2 Suppl 4th Report):555-576.
    1. Nielsen TRH, Lausten-Thomsen U, Fonvig CE, et al. . Dyslipidemia and reference values for fasting plasma lipid concentrations in Danish/North-European White children and adolescents. BMC Pediatr. 2017;17(1):116.
    1. Frithioff-Bøjsøe C, Lund MAV, Kloppenborg JT, et al. . Glucose metabolism in children and adolescents: population-based reference values and comparisons to children and adolescents enrolled in obesity treatment. Pediatr Diabetes. 2019;20(5):538-548.
    1. Lund MAV, Thostrup AH, Frithioff-Bøjsøe C, et al. . Low-grade inflammation independently associates with cardiometabolic risk in children with overweight/obesity. Nutr Metab Cardiovasc Dis. 2020;30(9):1544-1553.
    1. Johansen MJ, Gade J, Stender S, et al. . The effect of overweight and obesity on liver biochemical markers in children and adolescents. J Clin Endocrinol Metab. 2019;105(2):dgz010.
    1. Bak MJ, Wewer Albrechtsen NJ, Pedersen J, et al. . Specificity and sensitivity of commercially available assays for glucagon-like peptide-1 (GLP-1): implications for GLP-1 measurements in clinical studies. Diabetes Obes Metab. 2014;16(11):1155-1164.
    1. Nielsen TRH, Fonvig CE, Dahl M, et al. . Childhood obesity treatment; effects on BMI SDS, body composition, and fasting plasma lipid concentrations. PloS One. 2018;13(2):e0190576.
    1. Lausten-Thomsen U, Nielsen TRH, Thagaard IN, Larsen T, Holm JC. Neonatal anthropometrics and body composition in obese children investigated by dual energy x-ray absorptiometry. Eur J Pediatr. 2014;173(5):623-627.
    1. Wohlfahrt-Veje C, Tinggaard J, Winther K, et al. . Body fat throughout childhood in 2647 healthy Danish children: agreement of BMI, waist circumference, skinfolds with dual x-ray absorptiometry. Eur J Clin Nutr. 2014;68(6):664-670.
    1. Kavey RE, Daniels SR, Lauer RM, Atkins DL, Hayman LL, Taubert K; American Heart Association . American Heart Association guidelines for primary prevention of atherosclerotic cardiovascular disease beginning in childhood. Circulation. 2003;107(11):1562-1566.
    1. American Diabetes Association. 2. Classification and diagnosis of diabetes: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S13-S28.
    1. Flynn JT, Kaelber DC, Baker-Smith CM, et al. . Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics. 2017;140(3):e20171904.
    1. RC Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing. 2021.
    1. Rigby RA, Stasinopoulos DM. Generalized additive models for location, scale and shape (with discussion). J R Stat Soc Ser C ApplStat. 2005;54(3):507-554.
    1. Rigby RA, Stasinopoulos DM. Using the Box-Cox t distribution in GAMLSS to model skewness and kurtosis. Stat Modelling. 2016;6(3):209-229.
    1. Stinson SE, Jonsson AE, Lund MAV, et al. . Data from: Fasting plasma GLP-1 associates with overweight/obesity and cardiometabolic risk factors in children and adolescents. Figshare. Deposited February 3, 2021. 10.6084/m9.figshare.13553579.v3
    1. Sørensen TI, Virtue S, Vidal-Puig A. Obesity as a clinical and public health problem: is there a need for a new definition based on lipotoxicity effects? Biochim Biophys Acta. 2010;1801(3):400-404.
    1. Czech MP. Insulin action and resistance in obesity and type 2 diabetes. Nat Med. 2017;23(7):804-814.
    1. Virtue S, Vidal-Puig A. Adipose tissue expandability, lipotoxicity and the metabolic syndrome—an allostatic perspective. Biochim Biophys Acta. 2010;1801(3):338-349.
    1. Richards P, Pais R, Habib AM, et al. . High fat diet impairs the function of glucagon-like peptide-1 producing L-cells. Peptides. 2016;77:21-27.
    1. Timper K, Dalmas E, Dror E, et al. . Glucose-dependent insulinotropic peptide stimulates glucagon-like peptide 1 production by pancreatic islets via interleukin 6, produced by α cells. Gastroenterology. 2016;151(1):165-179.
    1. Ellingsgaard H, Hauselmann I, Schuler B, et al. . Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat Med. 2011;17(11):1481-1489.
    1. Ellingsgaard H, Seelig E, Timper K, et al. . GLP-1 secretion is regulated by IL-6 signalling: a randomised, placebo-controlled study. Diabetologia. 2020;63(2):362-373.
    1. Christiansen CB, Lind SJ, Svendsen B, et al. . Acute administration of interleukin-6 does not increase secretion of glucagon-like peptide-1 in mice. Physiol Rep. 2018;6(13):e13788.
    1. Lang Lehrskov L, Lyngbaek MP, Soederlund L, et al. . Interleukin-6 delays gastric emptying in humans with direct effects on glycemic control. Cell Metab. 2018;27(6):1201-1211.e3.
    1. Zimmermann E, Anty R, Tordjman J, et al. . C-reactive protein levels in relation to various features of non-alcoholic fatty liver disease among obese patients. J Hepatol. 2011;55(3):660-665.
    1. Atabaki-Pasdar N, Ohlsson M, Viñuela A, et al. . Predicting and elucidating the etiology of fatty liver disease: a machine learning modeling and validation study in the IMI DIRECT cohorts. PloS Med. 2020;17(6):e1003149.
    1. Greiner TU, Bäckhed F. Microbial regulation of GLP-1 and L-cell biology. Mol Metab. 2016;5(9):753-758.
    1. Paone P, Cani PD. Mucus barrier, mucins and gut microbiota: the expected slimy partners? Gut. 2020;69(12):2232-2243.
    1. Chambers ES, Viardot A, Psichas A, et al. . Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut. 2015;64(11):1744-1754.
    1. Adrian TE, Gariballa S, Parekh KA, et al. . Rectal taurocholate increases L cell and insulin secretion, and decreases blood glucose and food intake in obese type 2 diabetic volunteers. Diabetologia. 2012;55(9):2343-2347.
    1. Boyle JG, Livingstone R, Petrie JR. Cardiovascular benefits of GLP-1 agonists in type 2 diabetes: a comparative review. Clin Sci (Lond). 2018;132(15):1699-1709.
    1. Seino Y, Yabe D. Glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1: incretin actions beyond the pancreas. J Diabetes Investig. 2013;4(2):108-130.
    1. Page LC, Freemark M. Role of GLP-1 receptor agonists in pediatric obesity: benefits, risks, and approaches to patient selection. Curr Obes Rep. 2020;9(4):391-401.
    1. Holst JJ, Deacon CF. Glucagon-like peptide-1 mediates the therapeutic actions of DPP-IV inhibitors. Diabetologia. 2005;48(4):612-615.

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