Student: Jed Wingrove
1st supervisor: Steve Williams, King’s College London
2nd supervisor: Stephanie Amiel, King’s College London
High fat, high calorie diets in modern lifestyles drive the current exacerbation of insulin resistance (IR), type 2 diabetes and obesity. Accumulation of fat in the blood brain barrier (BBB) in IR interferes with penetration of insulin to the central nervous system and may underpin reduced central actions of insulin in IR. IN-Ins administration by-passes the BBB, allowing investigation of insulin’s central effects on glucose regulation and appetite control in healthy and obese populations (Heni, 2012); as well as the chance to evaluate the impact of IR and IN-Ins on affective processing, executive function and memory, with possible therapeutic implications in appetite control and cognitive function in, for example, IR syndromes (Ott, 2012).
We will utilise two novel MRI techniques that have transformed non-invasive functional imaging. The first one is Arterial Spin Labelling MRI (ASL, Dai et al 2008), which non-invasively labels arterial blood and provides high-resolution maps (2x2x3mm) of the rate of regional Cerebral Blood Flow (rCBF). Due to the mechanism of neurovascular coupling, the intimate link between rCBF and brain activity provides a new way of imaging brain function. Because ASL is free of ionising radiation or exogenous contrasts, it is ideal for repeated measures studies like this one in which the cerebral response of IN-INS administration will be compared with placebo (Schilling 2013).
The second technique, resting state Blood-Oxygen-Level-Dependent Contrast MRI (rs-BOLD fMRI, Lee 2012), will complement the ASL measurements by allowing us to probe changes in functional connectivity elicited by IN-InS compared with placebo. The brain has traditionally been assumed not to be sensitive to insulin. However, it is now known that insulin receptors are ubiquitously expressed in the central nervous system (CNS) and are especially prevalent in the prefrontal cortex and hippocampus (regions involved in higher cognitive function), the hypothalamus (involved in regulating food intake), the limbic system (involved in mood) and the olfactory bulb (Zhao, 2001). Since insulin can be rapidly delivered to the CSF compartment through IN-Ins (~30mins) without changes in systemic blood glucose and serum insulin levels, its effects on cognition, energy homeostasis and to a lesser extent mood, are being elucidated. In healthy men, IN-InS has shown anorexigenic effects (Hallschmid, 2004), in this study we will evaluate this effect on the brain before and after food administration. State-of-the-art Statistical Parametric and Multi-Variate analytical techniques will be developed and applied during the course of the work to analyse these data.
In addition to the imaging based investigations described above, we will have the opportunity to evaluate several, recently published and hitherto unknown effects of insulin on affective, executive processing and memory (Ott, 2012).
Enhancing central nervous insulin signalling via IN-In administration has been demonstrated to improve memory in healthy subjects and patients, including Alzheimer’s disease (Freiherr, 2013). Declarative memory, which is hippocampus-dependent, is preferentially affected but improvements in working memory have also been observed. Gender differences in the cognitive response to IN-Ins may also exist with women demonstrating greater sensitivity compared to men (Benedict, 2008).