C-11-Raclopride-displacement and altered functional connectivity after intranasal application of insulin in humans. A PET/MRI study.

Objectives: Animal studies provided evidence that effects from insulin on food intake are at least in part mediated by central dopaminergic activity. Specifically, insulin inhibits excitatory synaptic transmission in the ventral tegmental area and reduces dopamine release in the nucleus accumbens. fMRI studies showed that insulin decreases striatal activation. No study so far has investigated the effect of central insulin action on central dopaminergic activity in humans. Hence, we investigated whether centrally/intranasally administered insulin influences dopaminergic activity in striatal regions and resting-state functional connectivity.

Methods: 10 healthy normal weight men (age 27±3 years, BMI 23.6±2.3 kg/m²) underwent two dynamic C-11-raclopride-PET/MRI (376±79 MBq) including resting-state fMRI after intranasal application of insulin or placebo (randomized order). Binding potential (BPnd) was estimated in regions of interest (ROIs) using the multilinear reference tissue model MRTM2 (t[asterisk]=10 min, cerebellum as reference region). ROIs were defined according to the label atlas from Neuromorphometrics, Inc.: ventral striatum, dorsal striatum, caudate and putamen. BPnd (insulin vs. placebo) in striatal subregions were compared using one-sided paired t-tests. Functional connectivity (FC) was calculated voxelwise using the ventral striatum as seed.

Results: After intranasal insulin administration, BPndincreased significantly in all striatal subregions (p<0.05), most significantly in the ventral striatum (p=0.02). Insulin induced changes of FC between the ventral striatum and VTA correlated significantly with the increase of BPnd in the ventral striatum (p=0.02).

Conclusions: This is the first study in humans showing that central insulin action modulates dopaminergic activity and functional connectivity in the striatum. C-11-raclopride-PET/MRI may help to understand the role of central insulin action in obesity.