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Title:Hypoglycemia-induced changes in glucose metabolism in the hypothalamus
Author(s):Mun, Jonathan
Director of Research:Beverly, Joseph L.
Doctoral Committee Chair(s):Johnson, Rodney W.
Doctoral Committee Member(s):Beverly, Joseph L.; Rhodes, Justin S.; Nakamura, Manabu T.
Department / Program:Nutritional Sciences
Discipline:Nutritional Sciences
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):hypoglycemia
glucose
metabolism
hypothalamus
ventromedial hypothalamus (VMH)
brain
glycogen
Abstract:Hypoglycemia is the most common acute complication associated with insulin-dependent diabetes mellitus (Type 1 and advanced Type 2), which affects 300,000-500,000 individuals of all ages in the United States, with 30,000 new cases each year (1). It is characterized by low blood glucose concentration (less than 70 mg/dL or 4 mM) that can be attributed to a mismatch of insulin, food intake, sleep, and physical activity and can result in serious morbidity or death (2). The glucose counterregulatory response is the primary defense against hypoglycemia and involves (A) secretion of epinephrine and glucagon to elevate blood glucose concentration and (B) sympathetic activation to prompt the individual to take action against hypoglycemia through symptoms that include hunger, shaking, rapid heart rate, and sweating (2). Recurrent episodes of hypoglycemia result in failure of the counterregulatory response, which increases the frequency and severity of subsequent hypoglycemia. The underlying physiology by which this occurs is not well understood (3), but changes occurring in the ventromedial hypothalamus (VMH), a brain region that is responsible for initiating the counterregulatory response to hypoglycemia (4) is the most promising target. In the following studies, we utilized metabolomic (Chapter 2), transcriptomic (Chapter 3), and isotope tracer approaches (Chapter 4) to identify changes in glucose metabolism in the VMH. We did not see significant changes in glucose metabolite concentrations, but we observed altered glycogen metabolism through changes in expression of genes involved in glycogen synthesis and mobilization. Impact of altered brain glycogen metabolism in the development of HAAF is underway, but research to gain a robust understanding brain glycogen kinetics will be necessary before investigating the impact of recurrent hypoglycemia on its turnover. Many genes were identified to be associated with the hypoglycemia treatments and among them, were advanced glycosylation end product-specific receptor and Vgf nerve growth factor, which are promising candidate genes for future research due to their functions and associations with diabetes. We also identified changes in arachidonate 15-lipoxygenase (Alox15) gene expression, which is an enzyme that oxidizes polyunsaturated fatty acids, phospholipids, and other complex substrates. Alox15 expression was highly correlated with the hypoglycemia treatments and was complemented by changes in cholesterol and phospholipid metabolites in response to recurrent hypoglycemia. We demonstrate in these studies a role of altered VMH glucose metabolism in response to hypoglycemia and propose a novel role of altered VMH lipid metabolism in the development of impaired glucose counterregulation.
Issue Date:2014-05-30
URI:http://hdl.handle.net/2142/49849
Rights Information:Copyright 2014 Jonathan Guo-Han Mun
Date Available in IDEALS:2014-05-30
2016-09-22
Date Deposited:2014-05


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