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Randomized Controlled Trial
. 2025 Mar;68(3):676-687.
doi: 10.1007/s00125-024-06327-w. Epub 2024 Dec 20.

Insulin clearance at randomisation and in response to treatment in youth with type 2 diabetes: a secondary analysis of the TODAY randomised clinical trial

Kristen J Nadeau  1 , Silva A Arslanian  2 , Fida Bacha  3 , Sonia Caprio  4 , Lily C Chao  5 , Ryan Farrell  6 , Kara S Hughan  2 , Maria Rayas  7 , Melinda Tung  8 , Kaitlyn Cross  8 , Laure El Ghormli  9 ; TODAY Study Group
Affiliations
Randomized Controlled Trial

Insulin clearance at randomisation and in response to treatment in youth with type 2 diabetes: a secondary analysis of the TODAY randomised clinical trial

Kristen J Nadeau et al. Diabetologia. 2025 Mar.

Abstract

Aims/hypothesis: Insulin resistance and compensatory hyperinsulinaemia are core features leading to beta cell failure in youth-onset type 2 diabetes. Insulin clearance (IC) is also a key regulator of insulin concentrations, but few data exist on IC in youth-onset type 2 diabetes. In a secondary analysis of our Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) randomised clinical trial, we investigated potential sex-, race-, ethnicity- and treatment-related differences in IC in youth-onset type 2 diabetes and aimed to identify metabolic phenotypes associated with IC at baseline and in response to metformin, metformin plus a lifestyle intervention, and metformin plus rosiglitazone.

Methods: A total of 640 youth aged 10-18 years with type 2 diabetes underwent fasting blood tests, anthropometric measurements, dual-energy x-ray absorptiometry to estimate subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) mass, and OGTTs longitudinally over 5 years. IC was calculated from the fasting C-peptide:insulin ratio (fasting IC) and 2 h OGTT C-peptide incremental AUC (iAUC):insulin iAUC ratio (2 h IC). Linear mixed models were used to assess covariate effects on the mean of IC over repeated time points.

Results: Baseline fasting IC (×10-2 nmol/pmol) was significantly lower in female participants than male participants (median [IQR] 0.72 [0.57-0.93] vs 0.79 [0.63-1.00], respectively; p=0.04) and in non-Hispanic Black participants than Hispanic and non-Hispanic White participants (median [IQR] 0.64 [0.51-0.81] vs 0.78 [0.64-1.00] vs 0.84 [0.68-1.01], respectively; p<0.0001). Similar results were observed for 2 h IC. Lower IC most strongly correlated with higher weight over time (% change [95% CI] in IC per 5 kg increase: fasting IC -1.52 [-2.05, -0.99]; 2 h IC -3.46 [-4.05, -2.86]). Lower IC also correlated with other markers of adiposity (higher BMI and SAT mass), and markers of insulin sensitivity (higher waist:height ratio, VAT mass, VAT:SAT mass ratio, triacylglycerol concentrations, triacylglycerol:HDL-cholesterol ratio, aspartate aminotransferase [AST] and alanine aminotransferase [ALT] concentrations, and systolic and diastolic BP, and lower HDL-cholesterol and total and high molecular weight adiponectin concentrations) over time. Beta cell function as determined from OGTTs, not insulin sensitivity or IC, was predictive of persistently elevated blood glucose levels. IC was higher with metformin+rosiglitazone than metformin alone (p=0.03 for fasting IC; p=0.02 for 2 h IC) and metformin+lifestyle (2 h IC, p=0.005), but not after adjusting for adiponectin (p value not significant for all).

Conclusions/interpretation: In youth with type 2 diabetes, low IC is correlated with female sex, non-Hispanic Black race and ethnicity, and markers of adiposity and insulin resistance, but not with beta cell function. Along with insulin sensitivity and adiponectin, IC increased in response to rosiglitazone treatment. These findings suggest that, in youth-onset type 2 diabetes, low IC is a compensatory response to changes in insulin sensitivity and/or adiponectin concentrations and is not a mediator of beta cell function.

Trial registration: ClinicalTrials.gov NCT00081328 DATA AVAILABILITY: Data from the TODAY study (V4; https://doi.org/10.58020/2w6w-pv88 ) reported here are available on request from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repository (NIDDK-CR) Resources for Research ( https://repository.niddk.nih.gov/ ).

Keywords: Insulin clearance; Obesity; Race and ethnicity; Type 2 diabetes; Youth.

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Conflict of interest statement

Acknowledgements: The TODAY Study Group thanks the following companies for donations in support of the study’s efforts: Becton Dickinson, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, LifeScan, Pfizer and Sanofi Aventis. We also gratefully acknowledge the participation and guidance of the American Indian partners associated with the clinical centre located at the University of Oklahoma Health Sciences Center, including members of the Absentee Shawnee Tribe, Cherokee Nation, Chickasaw Nation, Choctaw Nation of Oklahoma and Oklahoma City Area Indian Health Service. The opinions expressed in this paper are those of the authors and do not necessarily reflect the views of the respective Tribes and the Indian Health Service. Data availability: Data from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study (V4; https://doi.org/ https://doi.org/10.58020/2w6w-pv88 ) reported here are available on request from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repository (NIDDK-CR) Resources for Research ( https://repository.niddk.nih.gov/ ). Funding: This work was completed with funding from the NIDDK and National Institutes of Health (NIH) Office of the Director through grants U01-DK61212, U01-DK61230, U01-DK61239, U01-DK61242 and U01-DK61254; the National Center for Research Resources General Clinical Research Center Program through grants M01-RR00036 (Washington University School of Medicine), M01-RR00043-45 (Children’s Hospital Los Angeles), M01-RR00069 (University of Colorado Denver), M01-RR00084 (Children’s Hospital of Pittsburgh), M01-RR01066 (Massachusetts General Hospital), M01-RR00125 (Yale University) and M01-RR14467 (University of Oklahoma Health Sciences Center); and the NCRR Clinical and Translational Science Awards through grants UL1-RR024134 (Children’s Hospital of Philadelphia), UL1-RR024139 (Yale University), UL1-RR024153 (Children’s Hospital of Pittsburgh), UL1-RR024989 (Case Western Reserve University), UL1-RR024992 (Washington University in St Louis), UL1-RR025758 (Massachusetts General Hospital) and UL1-RR025780 (University of Colorado Denver). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Authors’ relationships and activities: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: KJN conceptualised the study, acquired and interpreted data, and led the writing of the manuscript. SAA, FB, SC, LCC, RF, KSH and MR acquired data. LE performed the analyses. MT and KC performed parts of the analyses. LE, MT, KC, SAA, FB, SC, LCC, RF, KSH and MR contributed to researching and interpretation of key content and edited the manuscript. All authors approved the final version to be published. LE is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

References

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