Jeroen HPM van der Velde¹, Suzan Wopereis², Johanneke E Oosterman², Tim J van den Broek², Frits R Rosendaal¹, Hildo J Lamb³, Femke Rutters⁴, Renée de Mutsert¹

¹Department of Clinical Epidemiology, LUMC, Leiden

²Research group Microbiology & Systems Biology, TNO, Leiden

³Department of Radiology, LUMC, Leiden

⁴Department of Epidemiology and Data Science, Amsterdam University Medical Centers, Location VU Medical Center, Amsterdam

jeroen.vandervelde@lumc.nl

Background: Different insulin resistance (IR) subtypes have been suggested varying in IR of liver and muscle and pancreatic beta-cell function. These subtypes may differentially affect T2D risk. Hence, we investigated differences in visceral fat, liver fat and T2D risk between IR subtypes in a middle-aged population with overweight.

Methods: In 5509 participants of the Netherlands Epidemiology of Obesity study without T2D, visceral and liver fat content were measured at baseline using MRI and participants were followed for T2D occurrence via their general practitioner. From a mixed-meal challenge we computed hepatic IR index, muscle IR index, and disposition index and grouped participants into 8 IR subtypes (table). For each subtype, we calculated differences in visceral and liver fat using linear regression as well as hazard ratios (HR) of T2D using Cox regression with 95% confidence intervals [95% CI], using insulin sensitive subtype as reference. Analyses were adjusted for age, sex, education, physical activity, diet quality, and total body fat.

Results: In our population (53% women) with mean(SD) age of 54(6) years and BMI of 30(5) kg/m², subtype ’low DI+hepatic IR+muscle IR’ had most visceral fat (33.9 cm²; [95% CI: 28.0, 39.8]) and liver fat (2.8-fold higher [2.4; 3.1]) compared to insulin sensitive subtype. During median follow-up of 6.6 years, 283 participants developed T2D. Compared to insulin sensitive subtype, T2D risk was increased in all subtypes with low DI (table), most notably in those with ‘low DI+hepatic IR+muscle IR’ (HR=20.2 [9.3-43.6]).

Conclusion: T2D risk differed strongly between IR subtypes with hepatic IR+pancreatic insufficiency posing the highest risk.