F.P. Haans1 , V.B. Schrauwen-Hinderling2,3 , K. Brouwers1, T. van de Weijer1,4, J.E. Wildberger1, P. Iozzo5, K.H.M. Roumans*4, M. Buitinga*4,1
1Department of Radiology and Nuclear Medicine, Maastricht University Medical Center+, Maastricht, Netherlands,
2 Institute for Clinical Diabetology, German
Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany,
3German Center for Diabetes Research, München-Neuherberg, Germany,
4Department of Nutrition and Movement Sciences, Maastricht University, Maastricht, Netherlands,
5National Research Council (CNR), Pisa, Italy.
*shared last author
Background and aims: Oral glucose tolerance test (OGTT)-derived indices such as the Muscle Insulin Sensitivity Index (MISI) and Hepatic Insulin Resistance Index
(HIRI) are proposed as clinically accessible tissue-specific surrogates of insulin resistance and predictors of Type 2 Diabetes. Although both indices have been
linked to clamp-derived measures, it remains unclear which physiological processes these indices reflect across different aspects of glucose metabolism. We
therefore assessed their relationship with tissue-specific glucose uptake, as one aspect of glucose metabolism, under physiological conditions using FDG-PET
following an OGTT.
Materials and methods: Twenty-five overweight participants (BMI 29.4±1.9 kg/m2; age 65±7 year; 8 females and 17 males) were enrolled. Insulin resistance
phenotyping was performed on MISI and HIRI indices derived from a five-point OGTT, enabling stratification into non-insulin resistant (NIR, n=9), muscle insulin
resistant (MIR, n=5), liver insulin resistant (LIR, n=4), and combined (MIR/LIR, n=7) groups. 18F-FDG positron emission tomography (PET) during OGTT was used
to quantify postprandial skeletal muscle and hepatic glucose uptake.
Results: The prediabetic group demonstrated a 20% lower Oral Glucose Insulin Sensitivity index (OGIS) (p<0.0001), while age, sex, and BMI were comparable
between groups. Skeletal muscle glucose uptake measured by 18F-FDG-PET after an OGTT correlated with MISI (r²=0.44; p=0.0004) and was reduced in MIR and
MIR/LIR phenotypes, consistent with impaired peripheral glucose disposal. In contrast, hepatic glucose uptake did not correlate with HIRI (r²=0.02; p=0.53).
Conclusion: Here we show that MISI reflects physiological skeletal muscle glucose uptake following glucose ingestion, supporting its relevance as a marker of
peripheral insulin resistance and postprandial glucose disposal in prediabetes. In contrast, HIRI was not associated with hepatic glucose uptake. This is in line with
prior studies demonstrating an association between HIRI and clamp-derived measures of endogenous glucose production, and the current study shows that the
physiological correlates of HIRI do not extend to hepatic glucose uptake under postprandial conditions. Together, these findings are in line with OGTT-derived
MISI and HIRI indices capturing distinct components of insulin action, with MISI reflecting glucose uptake in muscle, while HIRI appears to relate to other aspects
of insulin sensitivity.