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McNay, Ewan, PhD

Research Foundation of SUNY, Albany, New York

Project Title:

Recurrent Hypoglycemia and Cognition

Grant Number:

7-12-BS-126

Type of Grant:

Basic Science

General Research Subject:

Both Type 1 and Type 2 Diabetes

Project Start Date:

Jul 1, 2012

Project End Date:

Jun 30, 2015

Focus:

Complications, Complications\Hypoglycemia, Complications\Neuropathy, Integrated Physiology, Integrated Physiology\Regulation of Glucose Kinetics

Research Description



The overall aim is to prevent negative cognitive and neural consequences of repeated, moderate hypoglycemia, a common side-effect of insulin therapy in both type 1 and type 2 diabetes mellitus (T1 and T2DM). This recurrent hypoglycemia (RH) is the most feared consequence of such treatment, presenting both a major obstacle to intensive insulin therapy and a potentially damaging limitation to such therapy. When completed, this work will guide both prevention and treatment of T1 and T2DM. In order to prevent and treat RH, understanding of the molecular mechanisms by which RH affects cognitive and neural processes is required; preliminary data presented here show that in fact the effects of RH appear to be widely variable across brain structures and functions and previous data in rat experiments have shown effects at behavioral, metabolic, protein and electrophysiological levels that have proven difficult to identify in human studies, in part because of difficulty in controlling for treatment history, cardiovascular damage and other confounding variables. This project will examine, using an established rat model, the impact of RH on cognitive tasks chosen to reflect symptoms reported by patients, and which are mediated by discrete brain regions including the hippocampus, amygdala and prefrontal cortex. Measures will include cognitive performance, local metabolism, and peripheral hormones as well as a range of brain markers, taken in both diabetic and non-diabetic animals. Finally, a potential therapy (administration of medium-chain fatty acids) will be evaluated, that was recently shown to protect against acute hypoglycemia in humans.

Research Profile



What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This project has relevance to both type 1 and type 2 diabetes: it looks as the cognitive and neural impact of recurrent hypoglycemia (RH), which is the most feared consequence of insulin therapy and a major cause of hypoglycemia unawareness. We previously performed the first animal studies of RH and hippocampal function, showing marked impact at many levels from behavioral through metabolic, synaptic and molecular. The overall aim is to prevent negative cognitive and neural consequences of repeated, moderate hypoglycemia, a common side-effect of insulin therapy in both type 1 and type 2 diabetes mellitus (T1 and T2DM). This recurrent hypoglycemia (RH) is the most feared consequence of such treatment, presenting both a major obstacle to intensive insulin therapy and a potentially damaging limitation to such therapy. When completed, this work will guide both prevention and treatment of T1 and T2DM. In order to prevent and treat RH, understanding of the molecular mechanisms by which RH affects cognitive and neural processes is required; preliminary data presented here show that in fact the effects of RH appear to be widely variable across brain structures and functions and previous data in rat experiments have shown effects at behavioral, metabolic, protein and electrophysiological levels that have proven difficult to identify in human studies, in part because of difficulty in controlling for treatment history, cardiovascular damage and other confounding variables. This project will examine, using an established rat model, the impact of RH on cognitive tasks chosen to reflect symptoms reported by patients, and which are mediated by discrete brain regions including the hippocampus, amygdala, and prefrontal cortex. Measures will include cognitive performance, local metabolism, and peripheral hormones as well as a range of brain markers, taken in both diabetic and non-diabetic animals. Finally, a potential therapy (administration of medium-chain fatty acids) will be evaluated, that was recently shown to protect against acute hypoglycemia in humans.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
This project will (i) help you understand the cause(s) and effect(s) of repeated hypoglycemia - thereby improving both clinical guidance on optimal therapy and patient understanding and compliance, and then (ii) guide development of therapeutic interventions that can prevent any negative effects from such repeat hypoglycemic events.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I've spent the past 18 years building expertise in the role that metabolism plays in brain and cognitive function, with the past 12 focussing on the role of metablic disorders (specifically, diabetes and Alzheimer's disease). This is the way that I am best able to help patients and reduce suffering, along with improving scientific understanding of our brains. This award will allow my research to continue for the next three years, which would not otherwise have occurred; it will support both myself and the team of researchers in my lab.

In what direction do you see the future of diabetes research going?
This is too complex a question to answer in one paragraph. However, with regard to research on diabetes and the brain it is still uncommon for clinicians to consider any region of the brain above the hypothalamus; that needs to change, and is beginning to do so. Moreover, there is increasing understanding that insulin, in particular, is not just a peripheral hormone but a key player in neural processes: this will be a key area for ongoing research, and we know still very little about brain insulin synthesis and processing.