Fasting indices of glucose-insulin-metabolism across life span and prediction of glycemic deterioration in children with obesity from new diagnostic cut-offs

Maximiliane Chiara Hammel; Robert Stein; Jürgen Kratzsch; Mandy Vogel; Alexander J Eckert; Rima Destya Triatin; Marco Colombo; Christof Meigen; Ronny Baber; Juraj Stanik; Ulrike Spielau; Anette Stoltze; Kerstin Wirkner; Anke Tönjes; Harold Snieder; Reinhard W Holl; Michael Stumvoll; Matthias Blüher; Wieland Kiess; Antje Körner

doi:10.1016/j.lanepe.2023.100652

Fasting indices of glucose-insulin-metabolism across life span and prediction of glycemic deterioration in children with obesity from new diagnostic cut-offs

Lancet Reg Health Eur. 2023 May 23:30:100652. doi: 10.1016/j.lanepe.2023.100652. eCollection 2023 Jul.

Authors

Maximiliane Chiara Hammel¹, Robert Stein^{1

2}, Jürgen Kratzsch³, Mandy Vogel⁴, Alexander J Eckert^{5

6}, Rima Destya Triatin⁷, Marco Colombo¹, Christof Meigen⁴, Ronny Baber^{3

4}, Juraj Stanik^{1

8}, Ulrike Spielau¹, Anette Stoltze¹, Kerstin Wirkner^{4

9}, Anke Tönjes¹⁰, Harold Snieder⁷, Reinhard W Holl^{5

6}, Michael Stumvoll¹⁰, Matthias Blüher^{2

10}, Wieland Kiess^{1

4}, Antje Körner^{1

2

4}

Affiliations

¹ Medical Faculty, University Hospital for Children and Adolescents, Center for Pediatric Research, University of Leipzig, Leipzig, Germany.
² Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Germany.
³ Medical Faculty, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnosis, University of Leipzig, Leipzig, Germany.
⁴ LIFE Child Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.
⁵ University of Ulm, Institute of Epidemiology and Medical Biometry, ZIBMT, Ulm, Germany.
⁶ German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany.
⁷ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁸ Medical Faculty, Department of Pediatrics, and DIABGENE Laboratory, Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Comenius University, Bratislava, Slovakia.
⁹ Institute for Medical Informatics, Statistics and Epidemiology, Medical Faculty, University of Leipzig, Leipzig, Germany.
¹⁰ Department of Endocrinology, Nephrology und Rheumatic Diseases, Medical Faculty, University of Leipzig, Leipzig, Germany.

Abstract

Background: Fasting indices of glucose-insulin-metabolism are an easy and affordable tool to assess insulin resistance. We aimed to establish reference ranges for fasting insulin indices that reflect age-dependent variation over the entire life span and subsequently test their clinical application regarding the prediction of glycemic deterioration in children.

Methods: We calculated age- and puberty-dependent reference values for HOMA-IR, HOMA2-IR, HOMA-β, McAuley index, fasting insulin, and fasting glucose from 6994 observations of 5512 non-obese healthy subjects aged 5-80 years. Applying those references, we determined the prevalence of insulin resistance among 2538 subjects with obesity. Furthermore, we investigated the intraindividual stability and the predictive values for future dysglycemia of these fasting indices in 516 children and adolescents with obesity up to 19 years of follow-up. We validated the results in three independent cohorts.

Findings: There was a strong age-dependent variation of all indices throughout the life span, including prolonged recovery of pubertal insulin resistance and a subsequent continuous increase throughout adulthood. Already from age 5 years onwards, >40% of children with obesity presented with elevated parameters of insulin resistance. Applying newly developed reference ranges, insulin resistance among children with obesity doubled the risk for future glycemic deterioration (HOMA-IR HR 1.88 (95% CI 1.1-3.21)), fasting insulin HR 1.89 (95% CI 1.11-3.23). In contrast, fasting glucose alone was not predictive for emerging dysglycemia in children with obesity (HR 1.03 (95% CI 0.62-1.71)). The new insulin-based thresholds were superior to fasting glucose and HbA1c in detecting children eventually manifesting with dysglycemia in prospective analyses.

Interpretation: The variation of fasting glucose-insulin-metabolism across the life span necessitates age-specific reference ranges. The improved prediction of future glycemic deterioration by indices based on fasting insulin beyond simple glucose measures alone could help to stratify risk characteristics of children with obesity in order to guide patient-tailored prevention and intervention approaches.

Funding: German Research Foundation (DFG)-through SFB 1052, project number 209933838, subproject C5; Federal Ministry of Education and Research, Germany; European Union-European Regional Development Fund; Free State of Saxony. The German Diabetes Association, the CarbHealth consortium (01EA1908B). EU-IMI2-Consortium SOPHIA (grant agreement No 875534), German Center for Diabetes Research (DZD), grant number 82DZD14E03.

Keywords: Childhood obesity; HOMA-IR; Insulin resistance; Insulin sensitivity; McAuley index; Obesity; Prediabetes; Reference values; Type 2 diabetes.