Hannes Manell1,2, Hjalti Kristinsson1, Joel Kullberg3, Sarojini Jayantha Kumari Ubhayasekera4, Katharina Mörwald5, Johan Staaf1,2, Janne Cadamuro6, Fanni Zsoldos6,7, Sven Göpel8, Ernest Sargsyan1, Håkan Ahlström3, Jonas Bergquist4, Daniel Weghuber6,7, Anders Forslund2, Peter Bergsten1,2. 1. Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden. 2. Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden. 3. Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, Sweden. 4. Department of Chemistry-BMC, Analytical Chemistry & Neurochemistry, Uppsala University, Uppsala, Sweden. 5. Obesity Research Unit, Paracelsus Medical University, Salzburg, Austria. 6. Department of Laboratory Medicine, Paracelsus Medical University, Salzburg, Austria. 7. Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria. 8. Cardiovascular and Metabolic Diseases (CVMD), Innovative Medicines and Early Development Biotech Unit (iMed), AstraZeneca AB, Mölndal, Sweden.
Abstract
OBJECTIVE: To delineate potential mechanisms for fasting hyperglucagonemia in childhood obesity by studying the associations between fasting plasma glucagon concentrations and plasma lipid parameters and fat compartments. METHODS: Cross-sectional study of children and adolescents with obesity (n = 147) and lean controls (n = 43). Differences in free fatty acids (FFAs), triglycerides, insulin, and fat compartments (quantified by magnetic resonance imaging) across quartiles of fasting plasma glucagon concentration were analyzed. Differences in oral glucose tolerance test (OGTT) glucagon response was tested in high vs low FFAs, triglycerides, and insulin. Human islets of Langerhans were cultured at 5.5 mmol/L glucose and in the absence or presence of a FFA mixture with total FFA concentration of 0.5 mmol/L and glucagon secretion quantified. RESULTS: In children with obesity, the quartile with the highest fasting glucagon had higher insulin (201 ± 174 vs 83 ± 39 pmol/L, P < .01), FFAs (383 ± 52 vs 338 ± 109 μmol/L, P = .02), triglycerides (1.5 ± 0.9 vs 1.0 ± 0.7 mmol/L, P < .01), visceral adipose tissue volume (1.9 ± 0.8 vs 1.2 ± 0.3 dm3 , P < .001), and a higher prevalence of impaired glucose tolerance (IGT; 41% vs 8%, P = .01) than the lowest quartile. During OGTT, children with obesity and high insulin had a worse suppression of glucagon during the first 10 minutes after glucose intake. Glucagon secretion was 2.6-fold higher in islets treated with FFAs than in those not treated with FFAs. CONCLUSIONS: Hyperglucagonemia in childhood obesity is associated with hyperinsulinemia, high plasma FFAs, high plasma triglycerides, visceral adiposity, and IGT. The glucagonotropic effect of FFAs on isolated human islets provides a potential mechanism linking high fasting plasma FFAs and glucagon levels.
OBJECTIVE: To delineate potential mechanisms for fasting hyperglucagonemia in childhood obesity by studying the associations between fasting plasma glucagon concentrations and plasma lipid parameters and fat compartments. METHODS: Cross-sectional study of children and adolescents with obesity (n = 147) and lean controls (n = 43). Differences in free fatty acids (FFAs), triglycerides, insulin, and fat compartments (quantified by magnetic resonance imaging) across quartiles of fasting plasma glucagon concentration were analyzed. Differences in oral glucose tolerance test (OGTT) glucagon response was tested in high vs low FFAs, triglycerides, and insulin. Human islets of Langerhans were cultured at 5.5 mmol/L glucose and in the absence or presence of a FFA mixture with total FFA concentration of 0.5 mmol/L and glucagon secretion quantified. RESULTS: In children with obesity, the quartile with the highest fasting glucagon had higher insulin (201 ± 174 vs 83 ± 39 pmol/L, P < .01), FFAs (383 ± 52 vs 338 ± 109 μmol/L, P = .02), triglycerides (1.5 ± 0.9 vs 1.0 ± 0.7 mmol/L, P < .01), visceral adipose tissue volume (1.9 ± 0.8 vs 1.2 ± 0.3 dm3 , P < .001), and a higher prevalence of impaired glucose tolerance (IGT; 41% vs 8%, P = .01) than the lowest quartile. During OGTT, children with obesity and high insulin had a worse suppression of glucagon during the first 10 minutes after glucose intake. Glucagon secretion was 2.6-fold higher in islets treated with FFAs than in those not treated with FFAs. CONCLUSIONS:Hyperglucagonemia in childhood obesity is associated with hyperinsulinemia, high plasma FFAs, high plasma triglycerides, visceral adiposity, and IGT. The glucagonotropic effect of FFAs on isolated human islets provides a potential mechanism linking high fasting plasma FFAs and glucagon levels.
Authors: Sara E Stinson; Anna E Jonsson; Ierai Fernández de Retana Alzola; Morten A V Lund; Christine Frithioff-Bøjsøe; Louise Aas Holm; Cilius E Fonvig; Oluf Pedersen; Lars Ängquist; Thorkild I A Sørensen; Jens J Holst; Michael Christiansen; Jens-Christian Holm; Bolette Hartmann; Torben Hansen Journal: J Clin Endocrinol Metab Date: 2022-05-17 Impact factor: 6.134
Authors: Katharina Maruszczak; Konrad Radzikowski; Sebastian Schütz; Harald Mangge; Peter Bergsten; Anders Forslund; Hannes Manell; Thomas Pixner; Håkan Ahlström; Joel Kullberg; Katharina Mörwald; Daniel Weghuber Journal: Front Endocrinol (Lausanne) Date: 2022-09-05 Impact factor: 6.055