John P. Ryan - US grants

DESCRIPTION (provided by applicant): Type 2 Diabetes (T2D) is a significant public health burden in the United States, affecting more than 20 million people over the age of 20. Diabetes has pathogenic effects on numerous organ systems, causing complications related to kidney function, vision, and the cardiovascular system. One precursor to T2D is insulin resistance. One organ that is particularly sensitive to insulin is the brain, where insulin is actively transported across the blood brain barrier. To date, however, few human studies have investigated how brain structure and function are altered in individuals with insulin resistance. The brain controls numerous physiological systems in the body, and one such system is the autonomic nervous system. Individuals with insulin resistance and T2D have alterations in their autonomic nervous system activity that can increase their risk for death due to cardiovascular disease. The goal of the present proposal is to investigate how activity in one particular brain region, the ventral striatum, covaries with fasting insulin levels and autonomic function. This research fits well within the strategic aims of the National Institute of Diabetes and Digestive and Kidney Diseases, especially within the Integrative Biology of Obesity Program, which supports "basic and clinical research investigating the neural and endocrine mechanisms contributing to obesity and the pathophysiological consequences of obesity, particularly type 2 diabetes." This application will enable the Applicant to receive formal training in the physiology and pathology of the endocrine system that underlies T2D, as well as extend his training in functional neuroimaging to include advanced techniques to understand the interactions between brain regions and how they covary with physiological conditions. Combined with the measurement of autonomic activity, this research will further our understanding of the mechanisms by which insulin resistance alters autonomic activity and increases risk for pathogenic outcomes. PUBLIC HEALTH RELEVANCE: Insulin resistance is a precursor to Type 2 Diabetes, a public health epidemic in the United States afflicting more than 20 million people. Type 2 Diabetes increases risk for cardiovascular disease, possibly through alterations in the autonomic nervous system. The proposed study will examine how resting brain activity covaries with insulin resistance and autonomic activity to help understand the pathways by which insulin and autonomic function are related.

DESCRIPTION (provided by applicant): Type 2 diabetes is a public health epidemic in the United States, afflicting more than 20 million Americans. It is a complex disease with pathologic effects on numerous organ systems including central and autonomic nervous systems. Insulin resistance is a precursor to type 2 diabetes and is marked by a reduced sensitivity to insulin. A key network of the brain that is sensitive to insulin is the mesolimbic system. This network also plays a role in the control of autonomic function. Understanding how mesolimbic activity is altered in insulin resistance will help us understand pathways by which insulin resistance leads to autonomic dysregulation. The present study will recruit 11 individuals with insulin resistance and 11 individuals with normal insulin sensitivity. Participants will be screened by providing a fasting blood sample from which HOMA-IR values will be calculated. Qualifying participants will complete four clinical visits: (1) An initial screening visit, (2) A 2-hour oral glucose tolerance est, (3) An fMRI scan while in a fasting state, (4) An fMRI scan after consuming a mixed-meal preload. The fMRI scan will include a taste-reward task designed to evoke activity in the mesolimbic system. The goal of the present proposal is to identify functional alterations the mesolimbic system that occur in insulin resistance and may explain dysregulation in autonomic activity. Heart rate variability, a marker of autonomic regulation of the heart, will be recorded i the scanner and compared across days in conjunction with changes in resting brain activity. The applicant will receive training in the pathophysiology of diabetes, gain expertise in functional neuroimaging, and further study the central control of autonomic functioning. Training will include coursework, meetings with mentors and consultants, attendance of national conferences and local colloquia. The applicant will also gain experience in recruiting participants, collecting data, and writing scientific papers. This research will inform and influence the diabetes literatur by integrating the role of the central nervous system in the pathology of the autonomic nervous system that often accompanies type 2 diabetes. By using a within-subject design, the feasibility of the study is greatly increased such that a smaller participant sample can yield more reliable data. A more comprehensive understanding of the mechanisms that link insulin resistance to autonomic dysregulation, promises to guide the development of preventative strategies for slowing the progression from insulin resistance to type 2 diabetes.

? DESCRIPTION (provided by applicant): Insulin is a hormone released by the pancreas in response to increases in glucose levels that result from food intake. In addition to stimulating glucose uptake in the periphery, insulin signals the central nervous system to induce satiety and inhibit feeding behavior. Previous studies have compared brain responses to palatable food receipt across obese and lean individuals, or through the ingestion of a mixed meal. However, obesity is a complex metabolic state, and a mixed meal preload induces changes in a variety of hormones. Furthermore, it is unknown how insulin resistance may alter the ability of circulating insulin to affect brain activity. The current study builds upon a K01 project that is comparing brain responses to palatable food across insulin resistant and healthy individuals, during fasting and after a mixed meal preload. Initial findings show that following a meal, insulin resistant individuals show a hyper-reactivity of the striatum - a network involved in reward - relative to healthy controls. To begin to identify the mechanistic basis of these findings, the current study will recruit healthy participants who will undergo two functional magnetic resonance imaging scans. One scan will be performed in the fasted state, and the alternate scan will be conducted during an isoglycemic hyperinsulinemic clamp. This project will allow us to identify the specific effects of circulating insulin on brain reactivity to palatable food. We will also use state of theart functional imaging techniques to identify how insulin affects the functional connectivity between brain regions, particularly those in the striatum. The study team includes Dr. Howard Aizenstein, an expert in functional and structural neuroimaging, Dr. Frederico Toledo, a clinical endocrinologist with years of experience in implementing and interpreting clamp studies, and Dr. John Ryan (PI), a neuroscientist who specializes in the effects of diabetes on the brain. This work will bridge the findings of the K01 project and lay the groundwork for future studies in insulin resistant individuals to identify how insulin resistance in the brain may alter the abilityof peripheral hormones to provide appropriate feedback signals.