(P15-003-25) The Effect of Dietary Insulinogenic and Branched-Chain Amino Acids Depletion on Glucose Homeostasis in Mice

Objectives: The insulinogenic amino acids (IAA) including Leu, Ile, Val, Arg, Phe, Thr, and Ala and in particular branched-chain amino acids (BCAA), i.e., Leu, Ile, Val are linked to an increased risk of noncommunicable metabolic diseases, such as diabetes and obesity, impaired insulin sensitivity, and altered glucose uptake. This study aims to investigate the impact of IAA and BCAA depletion on glucose metabolism in mice.

Methods: Following 2 weeks of acclimation, six-week-old C57bl/6J male mice (n=72) were randomly assigned into one of three dietary treatment groups (n=24/group) for 4 weeks: 1) Control (CON) diet: no amino acid depletion; 2) IAA depleted diet (D-IAA), and 3) BCAA depleted diet (D-BCAA). A cohort of each group was subjected to either an intraperitoneal glucose tolerance test (IPGTT, 1 g/kg glucose) or an insulin tolerance test (IPITT; 0.75 U/kg insulin) at the end of weeks 1 and 3. At the end of week 4, following an overnight fast, all mice were refed for 4 hours and euthanized immediately. Liver samples were collected and analyzed for mRNA abundance of genes associated with glucose metabolism. All data were analyzed with GLM Univariate with Dunnett’s post-hoc (SPSS^®).

Results: Both D-BCAA and D-IAA fed mice had improved glucose tolerance and glucose clearance following IPGTT and IPITT, during weeks 1 and 3 of the experiment when compared to CON. The mRNA abundance of key rate-limiting enzymes regulating hepatic gluconeogenesis, i.e., phosphoenolpyruvate carboxykinase (PEPCK), pyruvate carboxylase (PC), and glucose-6-phosphate (G6P) was reduced in both D-BCAA and D-IAA compared to CON suggestive of suppressed gluconeogenesis following dietary BCAA and IAA depletion. While there was no difference across groups on the gene expression of hepatic glycogen phosphorylase (PYGL), the mRNA abundance of glycogen synthase 2 (GYS2) decreased or trended to be decreased in D-IAA and D-BCAA mice, respectively. This is suggestive of a reduced rate of hepatic glycogenesis.

Conclusions: In conclusion, the dietary depletion of IAA and BCAA improved glucose tolerance and glucose clearance likely through suppression of hepatic gluconeogenesis and glycogenesis.

Funding Sources: Hatch project accession no. 1012889 from the USDA National Institute of Food and Agriculture (NIFA).