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PET IMAGING AND SEROTONIN LIGANDS IN EATING DISORDERS

Principal Investigator: KAYE, WALTER H

Several lines of indirect evidence suggest that brain serotonin alterations occur in women with anorexia nervosa (AN) and bulimia nervosa (BN) when they are ill and after recovery. In theory, a trait-related increase of 5-HT neurotransmission may contribute to vulnerabilities (restricted feeding, obsessions with order and perfectionism, harm avoidance and negative affect) that contribute to developing AN and BN. In turn, malnutrition may reduce 5-HT neuronal activity, which in turn reduces dysphoric affective states, particularly in AN. New technologies offer the potential of direct characterization of dynamic relations between 5-HT receptor function and human behavior. In the short term (years 1 to 4), funded studies will investigate five groups of women 18 to 45 years old: 1) ill AN and BN women; 2) recovered AN and BN women (greater than 1 year normal menses, no binging and purging, and healthy and stable weight); and 3) healthy control women. In Aim 1, 150 PET imaging and 18-F-altanserin will assess 5-HT-2A postsynaptic receptor binding. Preliminary data support the possibility that recovered AN and BN women will have a reduction of orbitofrontal 5-HT-2A receptor finding associated with evidence of increased extracellular 5-HT. In Aim 2 150 PET imaging and 11-C-WAY100635 studies will assess 5-HT-1A receptor binding. Knockout gene studies in mice support the hypothesis that a malfunction of pre-synaptic raphe autoreceptors could contribute to increased 5-HT activity and behavioral symptoms. Aim 3 will test whether core AN or BN symptoms or impulse control are related to 5-HT neuronal activity. To fully characterize the 14 or more receptors and other components of the 5-HT neuronal pathways may require multiple ligands. In the long term (years 3 to 5) the candidate seeks to use this K05 to develop a multicenter collaborative study to 1) use PET imaging and radioligands to comprehensively characterize 5-HT and related systems in AN and BN and 2) develop rodent models relating 5-HT to behavior. Understanding whether biologic vulnerabilities, such as a 5-HT disturbance, occurs in AN and BN may contribute to developing a new treatment interventions for these often chronic and deadly disorders as well as shed light on the relation of 5-HT neurotransmission and behavior.

PET IMAGING OF MUSCLE METABOLISM IN INSULIN RESISTANCE

Principal Investigator: WILLIAMS, KATHERINE V.

Insulin resistance is a key component in the pathogenesis of type 2 diabetes mellitus (DM), and is present early in the disease process. Weight loss improves the insulin resistance of skeletal muscle, and weight loss is a cornerstone of type 2 DM therapy. Moreover, recent evidence suggests that weight loss may play a role in the prevention of type 2 DM. An enhanced understanding of the pathogenesis of insulin resistance in this disorder; and the potential for weight loss to reduce insulin resistance, could advance efforts in the prevention and treatment of this disorder. This award will provide an opportunity for the candidate, Katherine Williams M.D., M.P.H., to learn specific skills necessary to develop into an independent clinical investigator with the overall goal of linking interventional studies with state-of-the-art physiological assessments of substrate metabolism. Glucose transport into skeletal muscle is regarded as the rate-limiting step in insulin resistance., but it has been methodologically difficult to assess the transport step during clinical investigations of glucose metabolism, Dr, Kelley's laboratory has used PET imaging of [F-18]- labeled fluorodeoxyglucose (FDG) uptake into muscle, during insulin- stimulated conditions, to quantify the severity of skeletal muscle insulin resistance and to measure rate constants for glucose transport and phosphorylation. Based on the physiologic modeling of dynamic patterns of tissue activity of FDG, impairments in the rate constants for glucose transport have been found in obese subjects, and defects in both glucose transport and phosphorylation have been found in obese subjects with type 2 DM. Using this technique, Dr. Williams will test the hypothesis that defects of glucose transport and glucose phosphorylation are present in the obese offspring of parents with type 2 DM. Using her prior training in conducting weight loss interventions, she will further test the hypothesis that weight-loss improves glucose transport and phosphorylation in 3 groups of obese subjects: 1) subjects with no family history and type 2 DM and normal glucose tolerance, 2) subjects with a parental history of type 2 DM and normal glucose tolerance, and 3) subjects with type 2 DM.




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