The relationship of changes in insulin demand and insulin adequacy over the life course
Authors: Zhang Yingchai , Tam Claudia H. T. , Lau Eric S. H. , Ng Noel Y. H. , Yang Aimin , Fan Baoqi , Wu Hongjiang , Lim Cadmon K. P. , Chow Elaine Y. K. , Luk Andrea O. Y. , Kong Alice P. S. , Tam Wing Hung , Chan Juliana C. N. , Ma Ronald C. W. 
Published: November 2024

Abstract

Aims/hypothesis
Insulin requirements in the human body undergo continuous changes in response to growth and development. We assessed the life course relationships between insulin demand and insulin adequacy.

Methods
Three independent Chinese cohorts (204 children, aged [mean ± SD] 7.0 ± 0.5 years; 214 adolescents, aged 15.0 ± 1.8 years; 605 adults, aged 41.5 ± 9.3 years), recruited between 1998 and 2013, underwent OGTT tests. Indices of insulin sensitivity and insulin secretion were calculated based on paired glucose/insulin values during fasting, early phase and late phase of OGTT. Insulin demand and insulin adequacy were calculated by standardised major axis (SMA) regression from the paired insulin sensitivity and secretion indices. We derived the natural logarithm of ratio between the exponential functions of insulin adequacy and insulin demand (RAD) index for further evaluating the relationship between insulin demand and adequacy. The risk of abnormal glucose tolerance (AGT) was evaluated by logistic regression analyses. Area under the receiver-operating characteristic curve (AUC-ROC) analyses, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indices were used to demonstrate the discriminative value of the RAD method model.

Results
Adolescents had the lowest insulin sensitivity and the highest insulin secretion in all phases (fasting, early and late phase) of the OGTT, as compared with children and adults in each phase (all p<0.001). Adolescents had the highest insulin demand in all phases and lowest insulin adequacy in the fasting phase (p<0.001). In general, adults had the lowest insulin adequacy in both the early phase (p>0.05) and late phase (p<0.001) of the OGTT. Adolescents had negative RAD values irrespective of overweight and obesity, while, in general, children and adults had positive RAD values (p<0.001 between age groups in each of the fasting, early and late phases of the OGTT). Participants with RAD values below the 25th percentile had a higher risk of AGT compared with those above the 25th percentile (fasting-phase OR 1.86 [95% CI 1.18, 2.91]; early-phase OR 1.99 [95% CI 1.24, 3.19]; late-phase OR 2.49 [95% CI 1.57, 3.97]). The late-phase RAD index had the best performance in evaluating the risk of AGT compared with the fasting- and early-phase RAD indices (late-phase AUC-ROC = 0.635 [95% CI 0.583, 0.687]; late-phase NRI = 0.350 [95% CI 0.190, 0.510]; late-phase IDI = 0.033 [95% CI 0.015, 0.050]).

Conclusions/interpretation
The relationship between insulin demand and insulin adequacy changed throughout the life course. Adolescents had an imbalanced relationship between insulin demand and insulin adequacy, while, in general, children and adults had a balanced relationship. RAD is a novel index that was used to efficiently describe this relationship and evaluate the risk of AGT.

Graphical Abstract