BMI, RQ, Diabetes, and Sex Affect the Relationships Between Amino Acids and Clamp Measures of Insulin Action in Humans

Abstract

Previous studies have used indirect measures of insulin sensitivity to link circulating amino acids with insulin resistance and identify potential biomarkers of diabetes risk. Using direct measures (i.e., hyperinsulinemic-euglycemic clamps), we examined the relationships between the metabolomic amino acid profile and insulin action (i.e., glucose disposal rate [GDR]). Relationships between GDR and serum amino acids were determined among insulin-sensitive, insulin-resistant, and type 2 diabetic (T2DM) individuals. In all subjects, glycine (Gly) had the strongest correlation with GDR (positive association), followed by leucine/isoleucine (Leu/Ile) (negative association). These relationships were dramatically influenced by BMI, the resting respiratory quotient (RQ), T2DM, and sex. Gly had a strong positive correlation with GDR regardless of BMI, RQ, or sex but became nonsignificant in T2DM. In contrast, Leu/Ile was negatively associated with GDR in nonobese and T2DM subjects. Increased resting fat metabolism (i.e., low RQ) and obesity were observed to independently promote and negate the association between Leu/Ile and insulin resistance, respectively. Additionally, the relationship between Leu/Ile and GDR was magnified in T2DM males. Future studies are needed to determine whether Gly has a mechanistic role in glucose homeostasis and whether dietary Gly enrichment may be an effective intervention in diseases characterized by insulin resistance.

Impact of combined resistance and aerobic exercise training on branched-chain amino acid turnover, glycine metabolism and insulin sensitivity in overweight humans

“…High levels of circulating glycine in lean individuals and increased glycine in the OW group with exercise training, along with altered levels of several urinary glycine adducts and other metabolites, suggest that exercise induces more efficient elimination of excess acyl groups derived from BCAA and aromatic AA metabolism by urinary excretion. These findings, coupled with other reports of strong negative associations between glycine and insulin-resistant states [5, 45], suggest that stimulation of glycine adduct formation may be responsible for part of the exercise-induced changes in whole-body insulin action. A better understanding of the contributions of liver, muscle, adipose tissue and the gut microbiota to these processes during nutrient excess and with exercise will further our understanding of the systemic changes that occur during the development of IR and may help to identify novel targets for therapy.…”

Metabolomics in Prediabetes and Diabetes: A Systematic Review and Meta-analysis

“…Of these, seven focused on prediabetes-related measures (18–24), mainly using 2-h post–oral glucose tolerance glucose, and/or HOMA-IR. Another nine studies (25–33) focused on both prediabetes and type 2 diabetes. The remaining 11 studies (34–44) evaluated type 2 diabetes as the main outcome.…”

A Glycine-Insulin Autocrine Feedback Loop Enhances Insulin Secretion From Human β-Cells and Is Impaired in Type 2 Diabetes

“…The glycine concentration of the cerebrospinal fluid is ;5 mmol/L (33), whereas glycine levels in the plasma are ;40-fold higher (150-400 mmol/L) (8,18). These plasma glycine levels are above the half-maximal effective concentration (EC 50 ) of the GlyR in b-cells (see above), and ligand-gated ion channels desensitize during prolonged exposure to high agonist concentrations.…”

“…A strong correlation exists between plasma glycine concentrations and insulin sensitivity (7,13), glucose disposal (8), and obesity (9,17). Circulating plasma glycine concentrations are inversely related to the risk of T2D (6)(7)(8). Furthermore, glycine supplementation raises plasma insulin (18,19).…”

“…Proper neurotransmitter signaling is critical for coordinating insulin secretion from all the islets in the pancreas, and dysfunction in this signaling may be involved with the pathogenesis of diabetes. A multitude of recent metabolic studies investigating biomarkers for type 2 diabetes (T2D) have identified glycine as a potential candidate (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). A strong correlation exists between plasma glycine concentrations and insulin sensitivity (7,13), glucose disposal (8), and obesity (9,17).…”