ESPE Yearbook of Paediatric Endocrinology

TODAY Study Group. Diabetologia. 2025 Mar;68(3):676-687. doi: 10.1007/s00125-024-06327-w

Brief Summary: This paper presents a secondary analysis of the U.S. TODAY randomized clinical trial, evaluating insulin clearance (IC) in 640 youth with T2D, highlighting differences by sex, race/ethnicity, and response to treatments (metformin alone, metformin plus lifestyle intervention, or metformin plus rosiglitazone). IC was lower in females compared to males, and notably lower IC among non-Hispanic Black youth compared with Hispanic and non-Hispanic White youth. Lower IC correlated with higher obesity, insulin resistance, and lower adiponectin concentrations over 5 years. Treatment with metformin plus rosiglitazone increased IC, an effect largely attributable to improvements in adiponectin and insulin sensitivity, whereas lifestyle intervention showed minimal impact.

Comment: Insulin clearance (IC) is the rate at which insulin is removed from circulation, primarily mediated by the liver (via first-pass extraction). In obesity, IC is typically reduced through a direct effect of insulin sensitivity on clearance, contributing to hyperinsulinemia. In T2D, IC is further reduced, associated with both hepatic steatosis and worsening glycemic control. The saturable nature of hepatic insulin extraction means that at high rates of insulin secretion (as seen in insulin-resistant states), the liver’s capacity to clear insulin plateaus, leading to increased systemic insulin levels. Lower IC has been consistently associated with obesity, insulin resistance, increased visceral fat, and hepatic steatosis. Furthermore, significant differences in IC have been observed by sex and ancestry, with lower IC among females and individuals of non-Hispanic Black background.

This secondary analysis reports that IC is notably lower among non-Hispanic Black youth, aligning with findings in adults and the known increased metabolic risk in this population. The improvement in IC with rosiglitazone suggests the metabolic benefits of enhancing adipose tissue function and insulin sensitivity through pharmacological intervention, while lifestyle intervention alone was insufficient. These findings confirm that T2D in youth is an aggressive metabolic disorder requiring tailored and aggressive treatment strategies, especially for those from high-risk demographic groups.

Key Message: Insulin clearance is low in female and non-Hispanic Black youth with T2D and is closely linked to obesity, insulin resistance, and dysmetabolism. Reduced IC contributes to hyperinsulinemia, which further exacerbates insulin resistance and β-cell stress, perpetuating metabolic disturbances. While IC does not directly predict glycemic outcomes, interventions improving insulin sensitivity, particularly with pharmacotherapy, effectively enhance IC and metabolic health.

References: 1. Bizzotto R, Tricò D, Natali A, et al. New Insights on the Interactions Between Insulin Clearance and the Main Glucose Homeostasis Mechanisms. Diabetes Care. 2021;44(9):2115-2123. doi: 10.2337/dc21-0545.2. Jung SH, Jung CH, Reaven GM, Kim SH. Adapting to Insulin Resistance in Obesity: Role of Insulin Secretion and Clearance. Diabetologia. 2018;61(3):681-687. doi: 10.1007/s00125-017-4511-0.3. Najjar SM, Caprio S, Gastaldelli A. Insulin Clearance in Health and Disease. Annual Review of Physiology. 2023;85:363-381. doi: 10.1146/annurev-physiol-031622-043133.