Rasgon, Natalie L. , MD, PhD
Effects of Liraglutide on Hippocampal Structure and Function in Aging Adults with Prediabetes
General Research Subject: Insulin Resistance Pre Diabetes
Focus: Clinical Therapeutics/New Technology, Clinical Therapeutics/New Technology\Treatment of Insulin Resistance
Type of Grant: ADA-Novo Nordisk Award in Neurohormonal Control of Metabolism
Project Start Date: July 1, 2012
Project End Date: June 30, 2015
Type 2 diabetes (DM2) and cardiovascular disease (CVD) increase the risk for neurodegeneration, such as Alzheimer's disease (AD). In addition to increasing age, insulin resistance (IR) may be the unifying pathologic link between these disorders. Our preliminary data shows a distinct deleterious effect of IR on brain structure and function, but the potential effects of treatment-associated improvements in IR are unknown. We propose an investigation of the specific neurohormonal and neuroprotective effects of liraglutide, a glucagon-like peptide-1 analogue that may improve insulin action in the brain. Our study goal is to evaluate the effects of double-blind randomized liraglutide-vs-placebo on the hippocampal volume and its functional connectivity using structural and functional MRI, and performance on hippocampal-mediated cognitive tasks in 80 subjects who are older (ages 50-70 years), overweight/obese, and with prediabetes -- individuals who are at increased risk for IR, DM2, CVD, and pathological brain aging.
We will further enrich the study sample by recruiting half to be with family history of AD and half without family history of AD, and explore potential interactions between modifiable (IR/prediabetes) and non-modifiable (genetic) risk factors for AD in secondary analyses. We hypothesize that all subjects will be at risk for pathological brain aging, specifically hippocampal neurodegeneration, by virtue of having prediabetes, and that liraglutide will have positive effects on this brain region and its functional connectivity and cognitive performance, as a result of its central IR-improving effects. This proposal stems from the unique expertise of our research team in neurohormonal regulation of brain function.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
The focus of this research project is the evaluation of the effects of liraglutide on the hippocampus and its functional connectivity, and performance on hippocampal-mediated cognitive tasks in subjects who are older (50 to 70 years of age), overweight/obese, and with prediabetes. Liraglutide is a GLP-1 analogue that improves insulin resistance in patients with both type 2 diabetes and non-diabetic individuals with prediabetes, and may have specific neurohormonal effects on cognitive function and brain structure and function. This project will improve our understanding of the potential utility of GLP-1 compounds in non-diabetic individuals at greatly increased risk of DM2 and CVD, and therefore, of cognitive decline and dementia.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
As the baby boomer population ages, issues of early diagnosis and prevention of cognitive impairment is ever more pressing. The growth of insulin resistance is in direct association with the overall worsening rates of obesity and increasingly poor diet and exercise habits. This further highlights the importance of the improvement of insulin resistance in protection from cognitive decline. Our project aims to improve understanding of the neurohormonal mechanisms of insulin resistance and its treatment on the brain and cognitive function, toward the goal of improving cognitive health and lengthen the duration of fruitful professional life.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Although I do not personally suffer from diabetes, I have many family members who do, including both of my parents and my husband. My interest in the effects of metabolic dysfunction and its treatment on the brain has evolved as a result of numerous studies that I have conducted on hormonal influences in psychiatry over the past 20 years. This specific award will provide me with the opportunity to study the effects of the treatment of insulin resistance on cognitive function and brain structure and function using state-of-the-art metabolic and neuroimaging techniques.
In what direction do you see the future of diabetes research going?
I think that the future of diabetes research should be focused not only on treatment, but also on the prevention of diabetes, for a better understanding of the multi-system development of the illness.
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