THU136 Insulin Resistance, Insulin Secretion, And Body Fat In Youth: Associations With Branched-chain Amino-acids (BCAA), Branched-chain Keto-acids (BCKAs), Glutamate/Glutamine (Glx), And Kynurenine (KYN)
Authors: Blew Kathryn , Wang Qiao , Hong Hwanhee , Ilkayeva Olga , Muehlbauer Michael , Crawford Matthew , Grant Russell P , Hsia Daniel S , Bain James R , Freemark Michael , Balikcioglu Pinar Gumus 
Published: October 2023

Disclosure: K. Blew: None. Q. Wang: None. H. Hong: None. O. Ilkayeva: None. M. Muehlbauer: None. M. Crawford: Employee; Self; Laboratory Corporations of America. Stock Owner; Self; Laboratory Corporations of America. R.P. Grant: Employee; Self; Laboratory Corporations of America. Stock Owner; Self; Laboratory Corporations of America. D.S. Hsia: None. J.R. Bain: None. M. Freemark: None. P. Gumus Balikcioglu: None.

Objective: We recently showed that insulin resistance (IR) and Type 2 diabetes (T2D) in youth with obesity are associated with disordered metabolism of BCAA and diversion of tryptophan (TRP) metabolism from the serotonin to the kynurenine (KYN) pathway. In this study we determined if BCAAs, BCKAs, Glx and KYN/TRP correlate with metrics of obesity, insulin sensitivity, and insulin secretion. Methods: We performed frequently sampled oral glucose tolerance tests (OGTT) in 16 youth with normal weight and 16 non-diabetic youth with overweight/obesity and mild-moderate IR ages 18-21 yo. After an overnight fast of 8-12 hours, subjects underwent a 3-hour (1.75 g/kg, max 75 g) frequently sampled OGTT. Glucose (G) and insulin (I) were measured at times -15, 0, 10, 15, 30, 45, 60, 90, 120, and 180 minutes. Plasma metabolomic profiles were obtained at time 0. HOMA-S, HOMA-B, HOMA-IR, Matsuda Index, AUC glucose, AUC insulin, insulinogenic index (IGI) and disposition index (DI) at 10, 15 and 30 min were calculated. % Body fat was measured by TANITA. Results: Groups were comparable in age (19±1.2 vs 19.6±1.1 years), sex, race, ethnicity and pubertal status. Overweight/obese participants had higher BMI (22±2.3 vs 33.7±8.1), BF% (19.6±7.2 vs 37±9.2), leptin, and CRP and were more insulin resistant as evidenced by higher HOMA-IR and HOMA-B and lower HOMA-S and Matsuda Index. Glucose at 120’, insulin at -15’,0’,15’ and 120’, and IGI at 15’ were higher among overweight/obese subjects. AUC glucose, AUC insulin and DI were comparable across groups, as were fasting BCAA, BCAA/BCKA ratio, TRP, KYN, Kynurenic acid, and the KYN/TRP ratio. BCKA levels trended lower (p=0.05) in the overweight/obese group. Glx levels were higher among overweight/obese subjects (p=0.03) and correlated positively with BMI, % body fat, and metrics of hepatic IR including HOMA IR and ALT. BCAA levels correlated positively with fasting KYN and negatively with DI at 15’ and HMW-adiponectin, a metric of insulin sensitivity, but did not correlate with BMI or % body fat. The ratio of BCAA to BCKA correlated positively with KYN, KYN/TRP ratio and BMI. In contrast, BCKAs correlated negatively with BMI and % body fat but did not correlate with metrics of insulin sensitivity. KIV, the α-keto-acid of valine, associated negatively with metrics of insulin secretion including DI and IGI at 15’ and AUC glucose. Conclusions: In this cohort of non-diabetic youth, the levels of Glx correlated strongly with body fat mass and metrics of hepatic insulin resistance. The levels of BCAA and the ratio of BCAA/BCKA associated positively with KYN and negatively with HMW-adiponectin, a metric of insulin sensitivity, but did not correlate with % body fat. In contrast, BCKAs correlated negatively with % body fat and insulin secretion but did not correlate with metrics of IR. These findings suggest complex effects of fat deposition and insulin sensitivity on BCAA and glutamate metabolism.

Presentation: Thursday, June 15, 2023