Aurora, CO, United States
Aurora, CO, United States

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Yracheta J.M.,University of Washington | Lanaspa M.A.,Aurora University | Lanaspa M.A.,Colorado Research Partners LLC | Le M.T.,Aurora University | And 6 more authors.
Mayo Clinic Proceedings | Year: 2015

Since the early 20th century, a marked increase in obesity, diabetes, and chronic kidney disease has occurred in the American Indian population, especially the Pima Indians of the Southwest. Here, we review the current epidemic and attempt to identify remediable causes. A search was performed using PubMed and the search terms American Indian and obesity, American Indian and diabetes, American Indian and chronic kidney disease, and American Indian and sugar or fructose, Native American, Alaska Native, First Nations, Aboriginal, Amerind, and Amerindian for American Indian for articles linking American Indians with diabetes, obesity, chronic kidney disease, and sugar; additional references were identified in these publications traced to 1900 and articles were reviewed if they were directly discussing these topics. Multiple factors are involved in the increased risk for diabetes and kidney disease in the American Indian population, including poverty, overnutrition, poor health care, high intake of sugar, and genetic mechanisms. Genetic factors may be especially important in the Pima, as historical records suggest that this group was predisposed to obesity before exposure to Western culture and diet. Exposure to sugar-sweetened beverages may also be involved in the increased risk for chronic kidney disease. In these small populations in severe health crisis, we recommend further studies to investigate the role of excess added sugar, especially sugar-sweetened beverages, as a potentially remediable risk factor. © 2015 Mayo Foundation for Medical Education and Research.


Yracheta J.M.,University of Washington | Alfonso J.,Aurora University | Lanaspa M.A.,Aurora University | Lanaspa M.A.,Colorado Research Partners LLC | And 7 more authors.
Postgraduate Medicine | Year: 2015

The Hispanic American, the largest minority population in the United States, is at increased risk for obesity, diabetes and end-stage renal disease. Here we review genetic and environmental factors that might account for their increased risk for these conditions. Whereas many environmental and genetic factors have important roles in driving the increased risk for obesity and kidney disease in this population, a case is made that excessive intake of sugary beverages is a contributory cause. Studies focusing on decreasing intake of sugary beverages among the Hispanic American could potentially reduce renal and cardiovascular complications in this population. © 2015 Informa UK Ltd.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 183.69K | Year: 2015

DESCRIPTION provided by applicant Intake of added sweeteners high fructose corn syrup and sucrose independently predicts the development of obesity metabolic syndrome and diabetes Despite recommendations by WHO and the AHA to reduce sugar intake to to percent of total energy intake the mean intake of added sugars remains percent of the diet and percent of the population ingest more than of their diet as added sugars While public health interventions may help reduce sugar intake the addicting properties of sugar coupled with its ubiquitous presence in processed foods makes this a laudable challenge Our group has focused on the biology by which sugar induces obesity and metabolic syndrome We have identified fructokinase C as the key enzyme driving sugar associated metabolic disorders It is the ideal therapeutic target as fructokinase is specific for fructose metabolism and because people and mice lacking fructokinase are asymptomatic with normal lifespans Moreover mice lacking fructokinase are protected from developing obesity or insulin resistance in response to fructose and while they appear to still like sugar they ingest less sugar than normal mice suggesting that blocking fructokinase may help individuals reduce their sugar intake as opposed to the reverse To date there is no drug available to block sugar induced metabolic disorders or to block sugar craving so developing a fructokinase inhibitor would be novel and significant As such Colorado Research Partners LLC CRP has initiated a drug development program We have screened botanicals using a high throughput enzymatic assay and identified andgt purified compounds that inhibit KHK C with IC s ranging from to M We have also been able to show that some of these compounds are effective inhibitors in both cell culture and in vivo in the rat and mouse We have further performed computer modeling Schr dinger software of these compounds with the crystal structure of fructokinase C to evaluate binding energies and have identified different scaffolds that can be synthetically modified using a smart drug design approach Using structure based drug design SBDD and pharmacophore modeling virtual screening we have identified over derivatives with superior binding energies compared to the original prototypes We have also assembled a team of chemists and biologists that will allow us to chemically prepare and test new chemical entities NCEs for inhibitory activity to fructokinase in cell free systems in cell culture and in animal models We now propose for this Phase I to generate NCEs based on these scaffolds that are active in the sub micromolar andlt nM range Our goal milestone is to develop at least distinct compounds that are active in cell culture and in vivo proof of mechanism in a rodent model and that is specific for fructokinase compared to other sugar kinases potency Our goal at the end of phase I is to have several lead compounds that are ready for more detailed studies including pharmacokinetics efficacy in long term models of sugar induced obesity and metabolic syndrome and for intensive toxicology studies We believe that the development of the first in a class of drug molecules to block sugar based metabolism will represent a major breakthrough in the battle against obesity and diabetes PUBLIC HEALTH RELEVANCE Sugar makes up percent of the average diet and is strongly associated with the development of obesity and diabetes yet no specific drug exists to block the metabolic effects of sugar We have identified fructokinase as the key enzyme driving sugar metabolic effects and have identified several promising chemical scaffolds with inhibitory activity The goal of this Phase I study is to develop new lead chemical entities with activity i the nanomolar range that are specific and have in vivo efficacy and which can be further developed as lead compounds for future development as the first drugs to block sugar induced metabolic disorders


Saab K.R.,Aurora University | Kendrick J.,Aurora University | Yracheta J.M.,University of Washington | Lanaspa M.A.,Aurora University | And 4 more authors.
Journal of the American Society of Nephrology | Year: 2015

African Americans are at increased risk for cardiovascular and metabolic diseases, including obesity, high BP, diabetes, CKD, myocardial infarction, and stroke. Here we summarize the current risks and provide an overview of the underlying risk factors that may account for these associations. By reviewing the relationship between cardiovascular and renal diseases and the African-American population during the early 20th century, the historic and recent associations of African heritage with cardiovascular disease, and modern population genetics, it is possible to assemble strong hypotheses for the primary underlying mechanisms driving the increased frequency of disease in African Americans. Our studies suggest that underlying genetic mechanisms may be responsible for the increased frequency of high BP and kidney disease in African Americans, with particular emphasis on the role of APOL1 polymorphisms in causing kidney disease. In contrast, the Western diet, particularly the relatively high intake of fructose-containing sugars and sweetened beverages, appears to be the dominant force driving the increased risk of diabetes, obesity, and downstream complications. Given that intake of added sugars is a remediable risk factor, we recommend clinical trials to examine the reduction of sweetened beverages as a primary means for reducing cardiovascular risk in African Americans. Copyright © 2015 by the American Society of Nephrology.

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