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

Authors: NADEAU, KRISTEN - University Of Colorado; ARSLANIAN, SILVA - University Of Pittsburgh School Of Medicine; BACHA, FIDA - Children'S Nutrition Research Center (CNRC); CAPRIO, SONIA - Yale University; CHAO, LILY - Children'S Hospital Los Angeles; FARRELL, RYAN - University Hospitals; HUGHAN, KARA - University Of Pittsburgh School Of Medicine; RAYAS, MARIA - University Of Texas Health Science Center; TUNG, MELINDA - George Washington University; CROSS, KAITLYN - George Washington University; EL GHORMLI, LAURE - George Washington University

Submitted to: Diabetologia
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/26/2024
Publication Date: 12/20/2024
Citation: Nadeau, K.J., Arslanian, S.A., Bacha, F., Caprio, S., Chao, L.C., Farrell, R., Hughan, K.S., Rayas, M., Tung, M., Cross, K., El Ghormli, L. 2025. Insulin clearance at randomisation and in response to treatment in youth with type 2 diabetes: a secondary analysis of the TODAY randomised clinical trial. Diabetologia. 68:676-687. https://doi.org/10.1007/s00125-024-06327-w.
DOI: https://doi.org/10.1007/s00125-024-06327-w

Interpretive Summary: Insulin clearance (IC) helps maintain appropriate insulin levels in the blood, balancing insulin release and removal. This study aimed to understand how insulin clearance varies in young people with type 2 diabetes, considering factors like sex, race, ethnicity, and treatment types. Investigators at the Children’s Nutrition Research Center in Houston, TX, and their colleagues analyzed data from 640 youths aged 10-18 with type 2 diabetes. They measured various health indicators, including insulin levels, body fat, and blood tests, over five years. They found that IC was lower in females and non-Hispanic Black participants compared to males and other ethnic groups. Lower IC was linked to higher body weight and other markers of body fat and insulin resistance. The functioning of the beta cells (cells that produce insulin) and not IC was crucial for controlling blood sugar levels. The study also showed important treatment effects. IC improved more with a combination of metformin and rosiglitazone than with metformin alone or metformin plus lifestyle changes. In summary, in young people with type 2 diabetes, low IC is related to sex, race, body fat and insulin resistance but does not directly affect beta cell function. Treatments like rosiglitazone can improve IC. The findings emphasize the need for personalized treatment approaches considering sex, ethnicity, and individual metabolic profiles. This could lead to more effective and tailored interventions for youth with type 2 diabetes.

Technical Abstract: Insulin resistance and compensatory hyperinsulinemia 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) randomized 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. 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. 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). 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.