Hyperglucagonemia in Pediatric Adiposity Associates With Cardiometabolic Risk Factors but Not Hyperglycemia

Abstract

Context: In adults, hyperglucagonemia is associated with type 2 diabetes, impaired glucose tolerance, and obesity. The role of glucagon in pediatric overweight/obesity remains unclear.

Objective: We examined whether fasting concentrations of glucagon are elevated in youth with overweight/obesity and whether this associates with cardiometabolic risk profiles.

Methods: Analyses were based on the cross-sectional HOLBAEK study, including children and adolescents 6 to 19 years of age, with overweight/obesity from an obesity clinic group (n = 2154) and with normal weight from a population-based group (n = 1858). Fasting concentrations of plasma glucagon and cardiometabolic risk outcomes were assessed, and multiple linear and logistic regressions models were performed.

Results: The obesity clinic group had higher glucagon concentrations than the population-based group (P < 0.001). Glucagon positively associated with body mass index (BMI) standard deviation score (SDS), waist, body fat %, liver fat %, alanine transaminase (ALT), high-sensitivity C-reactive protein, homeostasis model assessment of insulin resistance, insulin, C-peptide, LDL-C, triglycerides, SDS of diastolic and systolic blood pressure, and was inversely associated with fasting glucose. The inverse relationship between glucagon and glucose was attenuated in individuals with high BMI SDS and high fasting insulin. Glucagon was associated with a higher prevalence of insulin resistance, increased ALT, dyslipidemia, and hypertension, but not with hyperglycemia. Glucagon was positively associated with fasting total glucagon-like peptide-1.

Conclusion: Compared with normal weight peers, children and adolescents with overweight/obesity had elevated concentrations of fasting glucagon, which corresponded to worsened cardiometabolic risk outcomes, except for hyperglycemia. This suggests hyperglucagonemia in youth may precede impairments in glucose regulation.

Trial registration: ClinicalTrials.gov NCT00928473.

Keywords: adolescent; cardiometabolic risk; child; glucagon; hyperglycemia; obesity.

© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.

Figures

Figure 1.

Estimated regression β-effects (95% CI) for associations of fasting plasma glucagon as an indicator of cardiometabolic risk factors in a pooled model, adjusted for age, sex, and BMI SDS. Cardiometabolic risk factors: BMI SDS, waist, and body fat % were not adjusted for BMI SDS. Cardiometabolic risk factors were nonnormally distributed (right-skewed) and log-transformed, except for BMI SDS, DBP SDS, and SBP SDS. Abbreviations: ALT, alanine aminotransferase; DBP, diastolic blood pressure; HbA1c, glycated hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; SDS, standard deviation score.

Figure 2.

Estimated regression β-effects (95% CI) for associations of fasting plasma glucagon as an indicator of fasting plasma glucose, stratified by BMI SDS quartiles, in an interaction model (fasting glucagon × fasting insulin [High vs Low]), adjusted for age and sex. Fasting plasma glucose was nonnormally distributed and log-transformed. Median BMI SDS for Quartile 1 = -0.37, Quartile 2 = 0.72, Quartile 3 = 2.53, Quartile 4 = 3.33. High insulin (red) and Low insulin (blue) groups were defined by median fasting insulin concentration in each quartile. Abbreviation: SDS, standard deviation score.

Figure 3.

Estimated OR (95% CI) for associations of fasting plasma glucagon as an indicator of cardiometabolic risk features in a pooled model, adjusted for age, sex, and BMI SDS. Abbreviations: ALT, alanine aminotransferase; OR, odds ratio; SDS, standard deviation score.