Central insulin resistance is common to both Type 2 Diabetes and Obesity. Magnetic resonance imaging (MRI) studies that investigated the effects of intranasally administered insulin, have highlighted the involvement of insulin in homeostatic, hedonic and to a lesser extent cognitive regulation of appetite control. This thesis documents a study that set out to explore the effects of intranasal insulin on brain function, using a pharmacological MRI protocol that probed the effects of insulin on resting state connectivity, resting state cerebral perfusion and the cerebral reward response to a food administration paradigm. This study was conducted in a group of healthy, male individuals, with normal and overweight participants. A drug delivery device optimised for efficient nasal delivery of insulin, was employed. A customised, long-label pseudo continuous arterial spin labelling sequence was employed. It was shown that intranasal insulin leads to decreases in cerebral blood flow in the left insula, putamen, hippocampus and para-hippocampal gyrus. These decreases were limited to the overweight group. Furthermore, both hippocampal and putamen blood flow responses in the overweight group were associated with their dietary intake of saturated fat and sugar. Functional, blood oxygen level dependent (BOLD) images acquired during a paradigm in which participants received glucose and artificial sugar solutions, highlighted group differences in response to intranasal insulin in prefrontal, cognitive regions of brain. The normal weight individuals showed greater engagement of the anterior cingulate cortex, ventromedial prefrontal cortex and nucleus accumbens compared to overweight individuals when presented with conditioned stimuli for sweet tasting rewards. Resting state connectivity data was acquired with a novel, multi-echo pulse sequence, developed to minimise artefactual sources of temporal variance. A seed5 based connectivity analysis showed that connectivity between the left posterior hippocampus and the left fusiform gyrus was increased in response to intranasal insulin in normal weight individuals. Furthermore, normal weight group connectivity between the left posterior hippocampus and prefrontal regions was increased compared to overweight individuals following insulin administration. The results from this pharmacological MRI study indicate differential insulin responsiveness in normal weight and overweight individuals. These differences in responsiveness show changes in brain function as a result of increased weight in otherwise healthy individuals. This work adds to a large body of knowledge on central insulin signalling and has provided further supporting evidence of the involvement of insulin in the cognitive modulation of appetite control.
|Date of Award||2019|
|Supervisor||Fernando Zelaya (Supervisor) & Stephanie Amiel (Supervisor)|