Background and Aims: Impaired insulin sensitivity in type 1 diabetes (T1D) is an under-appreciated cardiovascular risk factor yet is challenging to measure. Euglycemic hyperinsulinemic clamps are the “gold standard” for quantifying insulin sensitivity. Adding stable isotope-labeled glucose allows for differentiation of hepatic and muscle insulin sensitivity (assessed by endogenous glucose production [EGP] and glucose infusion rate [GIR] respectively). Non-invasive estimation of both EGP and GIR using biomarkers has not been previously assessed in T1D.
Methods: Two-step clamps were conducted in 40 adults with T1D in the INTIMET trial (INsulin resistance in Type 1 diabetes managed with METformin, ACTRN12619001440112). Subjects were characterized with 33 clinical and research biomarkers. Exhaustive search (XLStat, Lumivero, Denver, CO) was used to derive equations correlating with baseline clamp-quantified EGP and GIR.
Results: Exhaustive search analyses derived a formula predicting unfavorable GIR (dichotomous variable: below median of 60.4 µmol/kgFFM/min) using: total daily insulin dose (TDI), fasting triglycerides (TG), insulin-like growth factor-1 and aspartate aminotransferase (AST) levels, with an AUROC of 0.97, p<0.0001, R2 (Nagelkerke)=0.78, 92.5% accuracy. A model predicting unfavorable EGP level (above median of 6.2 µmol/kgFFM/min) contained four variables: TDI, TG, alkaline phosphatase and uric acid levels, with an AUROC of 0.86, p=0.001, R2 (Nagelkerke) of 0.47, 80% accuracy. Our free online calculator (available at https://bit.ly/EGP-GIR-calculator) enables estimation of GIR and EGP by these binary categories.
Conclusions: Tissue specific estimation of insulin sensitivity is feasible in T1D using clinical and research biomarkers. Incorporating estimates of hepatic and muscle insulin sensitivity in clinical trials may predict response to lifestyle and drug interventions. Validation studies are merited.
A.S. Januszewski: None. J.R. Snaith: None. G.M. Kowalski: None. C. Bruce: None. J. Holmes-Walker: None. A. Jenkins: Research Support; Abbott, Viatris Inc. Advisory Panel; Abbott. Research Support; Medtronic. Board Member; Insulin for Life. Research Support; Leona M. and Harry B. Helmsley Charitable Trust, Juvenile Diabetes Research Foundation (JDRF), Jaeb Center for Health Research, National Institutes of Health, National Health and Medical Research Council Australia. J. Greenfield: Other Relationship; Novo Nordisk.
