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Title: Metabolomic profiling of amino acids and beta-cell function relative to insulin sensitivity in youth

Author
item MICHALISZYN, SARA - University Of Pittsburgh Medical Center
item SJAARDA, LINDSEY - University Of Pittsburgh Medical Center
item MIHALIK, STEPHANIE - University Of Pittsburgh
item LEE, SOJUNG - University Of Pittsburgh Medical Center
item BACHA, FIDA - Children'S Nutrition Research Center (CNRC)
item CHACE, DONALD - Pediatrix National Medical Group
item DE JESUS, VICTOR - Centers For Disease Control And Prevention (CDC) - United States
item VOCKLEY, JERRY - University Of Pittsburgh Medical Center
item ARSLANIAN, SILVA - University Of Pittsburgh Medical Center

Submitted to: Journal of Clinical Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/21/2012
Publication Date: 11/1/2012
Citation: Michaliszyn, S.F., Sjaarda, L.A., Mihalik, S.J., Lee, S., Bacha, F., Chace, D.H., De Jesus, V.R., Vockley, J., Arslanian, S.A. 2012. Metabolomic profiling of amino acids and beta-cell function relative to insulin sensitivity in youth. Journal of Clinical Endocrinology and Metabolism. 97(11):E2119-E2124.

Interpretive Summary: In longitudinal studies of adults, elevated amino acid (AA) concentrations predicted future type 2 diabetes mellitus (T2DM). This study evaluated whether byproducts of protein and fat called acylcarnitines and amino acids are elevated in young children with type 2 diabetes. These byproducts are high in the circulation of adults with type 2 diabetes as a result of impairment of the body's utilization of these substances. We found that these substances are not elevated in children with type 2 diabetes, indicating that the defects in utilization of protein and fat are not involved in the disease process in children but may occur over time with aging and increased adiposity. Such findings will be important to researchers.

Technical Abstract: In longitudinal studies of adults, elevated amino acid (AA) concentrations predicted future type 2 diabetes mellitus (T2DM). The aim of the present investigation was to examine whether increased plasma AA concentrations are associated with impaired beta-cell function relative to insulin sensitivity [i.e. disposition index (DI)], a predictor of T2DM development. Metabolomic analysis for fasting plasma AAs was performed by tandem mass spectrometry in 139 normal-weight and obese adolescents with and without dysglycemia. First-phase insulin secretion was evaluated by a hyperglycemic (approximately 225 mg/dl) clamp and insulin sensitivity by a hyperinsulinemic-euglycemic clamp. DI was calculated as the product of first-phase insulin and insulin sensitivity. DI was positively associated with branched-chain AAs (leucine/isoleucine and valine; r = 0.27 and 0.29, P = 0.001), neutrally transported AAs (phenylalanine and methionine; r = 0.30 and 0.35, P < 0.001), basic AAs (histidine and arginine; r = 0.28 and 0.23, P <= 0.007), serine (r = 0.35, P <0.001), glycine (r = 0.26, P = 0.002), and branched-chain AAs-derived intermediates C3, C4, and C5 acylcarnitine (range r = 0.18–0.19, P <= 0.04). In youth, increased plasma AA concentrations are not associated with a heightened metabolic risk profile for T2DM; rather, they are positively associated with beta-cell function relative to insulin sensitivity. These contrasting observations between adults and youth may be a reflection of developmental differences along the lifespan dependent on the combined impact of the aging process together with the impact of progressive obesity.