Tissue-specific and whole-body insulin sensitivity by integrated imaging and hyperinsulinemic euglycemic clamp: A repeatability study in people with T2DM and overweight/obesity.

Abstract

Background: Assessment of glucose uptake by PET imaging under hyperinsulinemic euglycemic clamp (HEC) is an insightful tool for quantification of insulin resistance, a hallmark of diabetes and an area of interest in drug development. To enable the use of the method in metabolic trials, the repeatability of dynamic whole-body PET/MRI assessments of the tissue-specific glucose uptake and the total body glucose utilisation were investigated. The study included participants with type 2 diabetes mellitus (T2DM) and overweight/obesity, for two repeated examinations in standardised conditions. All participants signed informed consent, and the study plan was approved by the Swedish Ethical Review Authority (#2020-04140). After an overnight fast, HEC was established and a series of [¹⁸F]FDG-PET/MRI scans were performed. Total body glucose utilisation (M-value) was calculated for the duration of the scan and the tissue-specific metabolic rates of glucose uptake (MRGlu) were calculated using Patlak model. The repeatability was assessed by calculating the intraclass correlation coefficient (ICC).

Results: Repeatability was assessed in per protocol set of 12 participants (PPS, defined by a consistent HEC) and in full analysis set (FAS n = 16). The measured M-values and tissue MRGlu demonstrated varying levels of insulin resistance. M-value ICC was 0.95 (95% CI 0.86-0.99) for PPS, indicating excellent repeatability. Tissue-specific MRGlu repeatability was excellent for skeletal muscle (ICC 0.94), and good to at least fair for SAT, VAT, myocardium, and brain. The FAS had lower, but at least fair repeatability, emphasising the importance of standardisation in metabolic assessments.

Conclusion: Dynamic [¹⁸F]FDG-PET/MRI provides quantitative information on tissue-specific insulin sensitivity during hyperinsulinemic euglycemic clamp with a reliability comparable to total body glucose utilisation assessment. The method has potential to add value in monitoring and evaluating T2DM treatment effects on glucose uptake and insulin resistance in interventional trials.