Browsing by Subject "Metabolic Diseases"
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Item Can we stop the tsunami of common, chronic disease in the post-pandemic era?(2021-04-16) Califf, Robert M.Item Epigenetics in medicine: the rise and fall and rise of Lamarckian thought(2014-11-14) Terada, Lance S.Item Ethnic Differences in Fatty Acid Oxidation(2014-02-04) Benjamin, Brian; Wada, Yasuyo; Vega, Gloria; Szuszkiewicz-Garcia, Magdalene; Grundy, ScottINTRODUCTION: Triglyceride levels of African Americans are significantly lower than those of Caucasians. This discrepancy complicates the recognition and diagnosis of metabolic disease in African Americans and represents a paradox in the metabolic health of African Americans. Many reasons for this difference have been explored including increased lipoprotein lipase activity, decreased hepatic lipase activity, and increased suppression of adipocyte lipolysis. Another possible explanation for this triglyceride discrepancy that has been sparsely explored is a difference in fatty acid oxidation between the two groups. The hypothesis of the present study is that the discrepancy in triglycerides can be explained, at least in part, by more efficient beta oxidation of fatty acids in the African American population. METHODS: A pilot study was initiated to examine whether a difference in beta oxidation of fatty acids between the two groups exists by examining the ratio of downstream metabolites of beta oxidation (beta hydroxybutyrate; BHB) to upstream metabolites (nonesterified fatty acids; NEFA). Healthy lean African American and Caucasian males were given a fat bolus (200 mg/kg Schepp's dairy heavy cream) hourly over a ten hour time period (fat tolerance test). BHB, NEFA, and plasma triglycerides were measured throughout the test. The data were plotted against time and area under the curve (AUC) was calculated for each plot using the trapezoid rule. The ratio of BHB to NEFA total AUC was calculated and compared between groups. One volunteer from the Caucasian group was excluded from analysis as an outlier based on fasting BHB levels (Grubb's test p<0.01). Groups were compared using 2 sample t-tests. RESULTS: Preliminary results (n=9 African Americans, n=8 Caucasians) demonstrate a trend, as predicted, for the ratio of BHB AUC to NEFA AUC to be higher in African Americans compared to Caucasians (p<0.05). Additionally, the BHB AUC is significantly higher in African Americans (p<0.05), further supporting the study hypothesis. CONCLUSIONS: Initial results suggest that healthy lean African American men may be more efficient oxidizers of fatty acids when compared to healthy lean Caucasian men. This difference could be a contributing factor to the triglyceride difference observed in African Americans and Caucasians. The study is still ongoing and further recruitment and analysis remains to be done.Item The lipoidoses(1957-12-19) Siperstein, Marvin D.Item Loss of TBK1 Kinase Function Improves Disease Outcome in Pancreatic Cancer and Metabolic Syndrome(2018-07-30) Cruz, Victoria Haley; Castrillon, Diego H.; Brekken, Rolf A.; MacDonald, Raymond J.; Scherer, PhilippAberrant expression and activity of TANK binding kinase 1 (TBK1) has been observed in numerous diseases. Here I've identified novel functions for TBK1 in pancreatic ductal adenocarcinoma (PDA) and in metabolic syndrome that promote disease progression. Activating mutations in KRAS are present in 90% of human PDA cases; yet direct pharmacological inhibition of K-RAS remains a challenge, indicating a need for effective therapies. Higher levels of TBK1 mRNA, a critical downstream mediator of oncogenic K-RAS in lung cancer, correlate with poorer outcome in PDA patients. Given these observations, I hypothesized that TBK1 is also an effector of K-RAS in PDA. KRAS mutant PDA cell lines are selectively sensitive to small molecule inhibition of TBK1. In K-RAS-driven genetic mouse models of PDA, Tbk1 supports spontaneous pancreatic tumor growth as evidenced by smaller tumors and fewer metastases in Tbk1 mutant PDA mice relative to normal PDA mice. Additionally, Tbk1 mutant tumors are more epithelial; an observation consistent with the reduced migratory phenotype of Tbk1 mutant tumor cell lines and lack of detectable metastases in Tbk1 mutant PDA animals. Mechanistic studies indicate that TBK1 is central to Axl-driven EMT and is activated with RAS in response to Axl stimulation in PDA cell lines. The latter part of this thesis is focused on the contribution of TBK1 to mice with metabolic disorder. TBK1 is implicated in the regulation of metabolism through studies with amlexanox, an inhibitor of IκB kinase (IKK)-related kinases. Amlexanox induced weight loss, reduced fatty liver and insulin resistance in high fat diet (HFD) fed mice and has now progressed into clinical testing for the treatment and prevention of obesity and type 2 diabetes. However, since amlexanox is a dual IKKε/TBK1 inhibitor, the specific contribution of TBK1 is unclear. To distinguish metabolic functions unique to TBK1, I examined the metabolic profile of global Tbk1 mutant mice challenged with HFD and investigated potential mechanisms for the improved metabolic phenotype. I report that systemic loss of TBK1 kinase function has a protective effect on metabolic readouts in HFD-fed mice, which is mediated by loss of an inhibitory interaction between TBK1 and the insulin receptor.Item The origins, genetics and diseases of Mexican-Americans(1990-07-05) Dietschy, John M.Item [Southwestern News](2004-09-30) Maier, Scott