Date of Award
Doctor of Philosophy
Theses & dissertations (Interdisciplinary)
Kevin L. Schalinske
Mark R. Ackermann
Steven L. Nissen
Folate, homocysteine, and methyl group metabolism mutually function to provide methyl groups for numerous biosynthetic- and modification-type reactions necessary for optimal health. Methyl groups from these pathways are utilized in the production of important compounds such as nucleic acids, protein, and phospholipids. Thus it is vital to understand the factors that both disrupt and maintain their delicate balance to prevent disease. Disruption of these metabolic pathways is associated with several pathologies including carcinogenesis, birth defects, and vascular disease. Moreover, the disruption of these metabolic pathways may be a link between chronic disease and complications of that disease. Both nutritional and hormonal factors have been shown to modulate these interrelated metabolic pathways, commonly altering enzymes involved.;Diabetes mellitus is estimated to affect approximately 21 million Americans, constituting nearly seven percent of the population. Roughly one-third of this group is unaware that they even have diabetes, which is a major cause of morbidity and mortality in this country. Both type 1 and type 2 diabetes, characterized by elevated blood glucose concentrations, lack of or insensitivity to insulin, and elevated counter-regulatory hormones to insulin ( i.e. glucagon and glucocorticoids), have been shown to disrupt, homocysteine and methyl group metabolism.;Homocysteine pools, the non-protein forming amino acid synthesized and catabolized by these pathways, were also disrupted in diabetics. Hypohomocysteinemia is commonly reported in diabetics without renal complications; however as renal function deteriorates in chronic diabetes, hyperhomocysteinemia results. Furthermore, hyperhomocysteinemia is considered an independent risk factor for vascular disease. It is estimated that heart disease and stroke account for 65 percent of deaths in diabetics. Glycine N-methyltransferase (GNMT), the enzyme responsible for controlling methyl group supply and utilization, is also disrupted in diabetes, leading to depletion of essential methyl groups. Activity of this enzyme is allosterically regulated by the folate coenzyme, 5-methyltetrahydofolate.;Vitamin D status has been implicated in diabetic pathogenesis. In particular, vitamin D deficiency has been shown to increase the risk of developing type 1 diabetes and supplementation may reduce this risk. Further, vitamin D deficiency has been associated with impaired insulin secretion and glucose intolerance, but ameliorated by repletion. As a result, this research was aimed at determining if supplemental folate, supplemental vitamin D, and insulin repletion could prevent perturbations in homocysteine and methyl group metabolism induced by a type 1 diabetic state.;Insulin administration restored enzyme activity, protein abundance, and homocysteine concentrations in diabetic rats. Indicating perturbations in folate, homocysteine and methyl group metabolism do result from a diabetic state and are not the result of streptozotocin toxicity. GNMT, perturbed by a diabetic state, was attenuated in diets containing adequate or supplemental folate, likely due to posttranslational modification. Although these results would suggest that adequate folate status has a positive effect under diabetic conditions, supplemental folate did not confer any added benefit at the level tested. Further, betaine homocysteine S-methyltransferase (BHMT), the folate-independent remethylation enzyme, and GNMT mRNA were induced in diabetic animals indicating modification in a diabetic state is possibly at the level of transcription. Vitamin D supplementation restored homocysteine pools disrupted in a diabetic state potentially as a result of increased homocysteine production. This research indicates folate, vitamin D, and insulin may be involved in modulating homocysteine and methyl group metabolism in a diabetic state. Ultimately it will be critical in future work to more clearly determine and evaluate the factors that both regulate and alleviate diabetes-perturbed homocysteine and methyl group metabolism for optimal health and prevention of complications associated with diabetes.
Digital Repository @ Iowa State University, http://lib.dr.iastate.edu/
Kristin M. Nieman
Nieman, Kristin M., "Nutritional and hormonal modulation of diabetes-perturbed folate, homocysteine, and methyl group metabolism" (2008). Retrospective Theses and Dissertations. 15707.