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Title: Alterations in branched-chain amino acid kinetics in nonobese but insulin-resistant Asian men

Author
item TAN, HONG - SINGAPORE GENERAL HOSPITAL
item HSU, JEAN - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item KHOO, CHIN - NATIONAL UNIVERSITY OF SINGAPORE
item TAI, E - NATIONAL UNIVERSITY OF SINGAPORE
item YU, SIDNEY - SINGAPORE GENERAL HOSPITAL
item CHACKO, SHAJI - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item LAI, OI - SINGAPORE GENERAL HOSPITAL
item JAHOOR, FAROOK - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)

Submitted to: The American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/25/2018
Publication Date: 10/24/2018
Citation: Tan, H.C., Hsu, J.W., Khoo, C.M., Tai, E.S., Yu, S., Chacko, S., Lai, O.F., Jahoor, F. 2018. Alterations in branched-chain amino acid kinetics in nonobese but insulin-resistant Asian men. American Journal of Clinical Nutrition. 108(6):1220-1228. https://doi.org/10.1093/ajcn/nqy208.
DOI: https://doi.org/10.1093/ajcn/nqy208

Interpretive Summary: After we eat a meal the carbohydrates are converted to glucose (sugar) which enters our blood causing the sugar level to rise. In people with a normal body weight the sugar level in their blood soon comes down to a normal level because of the action of a hormone called insulin which is needed to remove sugar from the blood. As people put on extra weight and become fatter the ability of insulin to remove sugar from their blood starts to decrease and more insulin is needed to maintain a normal blood sugar level. Such people have a condition called insulin resistance. As people with insulin resistance become more overweight their blood sugar rises even higher and soon they develop a disease called type 2 diabetes mellitus (T2DM). Because of the high sugar in their blood people with T2DM soon develop heart, eye and kidney disease. This is a costly problem for most countries in the world as governments have to spend more money to prevent people from becoming overweight and developing insulin resistance and T2DM. However, it is not only overweight people who become insulin resistant and develop T2DM. For example, Asian people with normal or just slightly higher body weight can become insulin resistant and develop T2DM. In such people other methods are needed to predict who will become insulin resistant and develop T2DM. In this regard, we and others have found that three compounds called branched-chain amino acids (BCAA), leucine, isoleucine and valine are higher in the blood of people with insulin resistance. This includes Asian people who are not overweight. This is important because it is possible to use high blood levels of BCAA to predict which normal weight person will develop insulin resistance and T2DM. Based on their work some scientists also believe that the high BCAA may be the cause of insulin resistance in these people. If this is true, it is important to know why BCAA are higher in people with insulin resistance. Because the amount of BCAA in the blood depends on the amount that is produced in the body minus the amount that is broken down and converted to other products, we measured how much BCAA is produced and how much of it is broken down in two sets of normal weight Asian men who either had insulin resistance or did not have insulin resistance. We found that compared to people who did not have insulin resistance, those with insulin resistance were producing more BCAA, and although they were also breaking down more BCAA, the proportion that they were breaking down was much lesser. Therefore, the higher BCAA in their blood in all likelihood is due to the fact that they were producing more BCAA.

Technical Abstract: Branched-chain amino acids (BCAAs) are elevated in the insulin-resistant (IR) state. The reasons for this increase remain unclear, but it may be related to abnormalities in BCAA metabolism and free fatty acid (FFA) metabolism. In this study, we quantified BCAA and FFA kinetics of IR and insulin-sensitive (IS) non-obese Asian men with the use of stable-isotope tracers. We hypothesized that in addition to greater substrate flux, the BCAA oxidative pathway is also impaired to account for the higher plasma BCAA concentration in the IR state. We recruited 12 IR and 14 IS non-obese and healthy Asian men. Oral-glucose-tolerance tests (OGTTs) were performed to quantify insulin sensitivity, and subjects underwent 2 stable-isotope infusion studies. [U-13C6]Leucine was infused to measure leucine flux and oxidation as indexes of BCAA metabolism, whereas [U-13C16] palmitate was infused to measure palmitate flux and oxidation to represent FFA metabolism, the 2H2O dilution method was used to estimate body composition. IR subjects had greater adiposity and significantly higher fasting and post-OGTT glucose and insulin concentrations compared with the IS group. However, none of the subjects were diabetic. Despite similar dietary protein intake, IR subjects had a significantly higher plasma BCAA concentration and greater leucine flux. Leucine oxidation was also greater in the IR group, but the relation between leucine oxidation and flux was significantly weaker in the IR group than in the IS group (r = 0.530 compared with 0.695, P < 0.0388 for differences between slope). FFA oxidation was, however, unaffected despite higher FFA flux in the IR group. The higher plasma BCAA concentration in healthy nonobese individuals with IR is associated with a weaker relation between BCAA oxidation and BCAA flux and this occurs in the presence of accelerated FFA flux and oxidation.