The rising prevalence of type 2 diabetes mellitus (T2DM) amongst both younger and older individuals has led to increases in the lifetime exposure to T2DM. A growing body of evidence suggests that chronic hyperglycemia and T2DM leads to many adverse effects on brain function, particularly neurovascular disorders and cognitive impairment. However, the underlying mechanisms behind these associations remain unclear. The purpose of this application is to evaluate the role of the polyol pathway as a potential mediator of the CNS effects of hyperglycemia. The polyol pathway (glucose ? sorbitol ? fructose) is an alternate glucose pathway that is present throughout the human body, including the brain. In addition to fructose generation, polyol pathway activity has also been associated with increased oxidative stress and has been linked to the complications of diabetes including diabetic retinopathy, neuropathy and cardiovascular disease. However, the role of this pathway in the brain remains unclear. This K23 application will investigate the potential role of the polyol pathway in mediating the central nervous system effects of hyperglycemia by using nuclear magnetic resonance spectroscopy (MRS) which allows for the non-invasive measurements of brain metabolites as well as metabolic study methodology to alter peripheral glucose levels. The results from the physiology-based human studies in both healthy individuals as well as individuals with poorly controlled T2DM in this application will provide insights regarding whether the polyol pathway contributes to the endogenous production of fructose from glucose in the human brain as well as whether excessive activity through the pathway is associated with measures of increased oxidative stress in the brain. This research application will capitalize on the rich academic environment at Yale School of Medicine where a team of multidisciplinary independent investigators have joined together to utilize cutting edge imaging methodologies to investigate central questions in metabolism. Dr. Hwang, the Candidate for this K23 application, will gain important experience in the conduct and analysis of studies using MRS as well as metabolic techniques such as glucose clamp methodology. The findings from this study will lay the foundation for future studies targeting the polyol pathway to combat the central nervous system effects of diabetes and will help Dr. Hwang establish a long-term career as an independent investigator with an expertise in using state-of-the-art imaging modalities to understand the central nervous system effects of diabetes.

Public Health Relevance

The number of individuals with type 2 diabetes (T2DM) continues to rise around the world, and a growing body of evidence suggests that chronic T2DM leads to many adverse effects on brain function; however, the underlying mechanisms behind these associations remain unclear. Thus, the goal of this study is to use magnetic resonance spectroscopy, a non-invasive technique to measure metabolites in the human brain, to understand a potential mechanism by which high blood sugars can directly affect the brain. The results from this study may generate novel strategies for future treatments for T2DM as well as its central nervous system consequences

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mentored Patient-Oriented Research Career Development Award (K23)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK-B)
Program Officer
Spain, Lisa M
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Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
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Belfort-DeAguiar, Renata; Seo, Dongju; Lacadie, Cheryl et al. (2018) Humans with obesity have disordered brain responses to food images during physiological hyperglycemia. Am J Physiol Endocrinol Metab 314:E522-E529
Hwang, Janice Jin; Parikh, Lisa; Lacadie, Cheryl et al. (2018) Hypoglycemia unawareness in type 1 diabetes suppresses brain responses to hypoglycemia. J Clin Invest 128:1485-1495
Hwang, Janice J; Jiang, Lihong; Hamza, Muhammad et al. (2017) The human brain produces fructose from glucose. JCI Insight 2:e90508
Hwang, Janice J; Jiang, Lihong; Hamza, Muhammad et al. (2017) Blunted rise in brain glucose levels during hyperglycemia in adults with obesity and T2DM. JCI Insight 2: