Serum and plasma amino acids as markers of prediabetes, insulin resistance, and incident diabetes

OBJECTIVE To conduct a systematic review of cross-sectional and prospective human studies evaluating metabolite markers identified using high-throughput metabolomics techniques on prediabetes and type 2 diabetes. RESEARCH DESIGN AND METHODS We searched MEDLINE and EMBASE databases through August 2015. We conducted a qualitative review of cross-sectional and prospective studies. Additionally, meta-analyses of metabolite markers, with data estimates from at least three prospective studies, and type 2 diabetes risk were conducted, and multivariable-adjusted relative risks of type 2 diabetes were calculated per study-specific SD difference in a given metabolite. RESULTS We identified 27 cross-sectional and 19 prospective publications reporting associations of metabolites and prediabetes and/or type 2 diabetes. Carbohydrate (glucose and fructose), lipid (phospholipids, sphingomyelins, and triglycerides), and amino acid (branched-chain amino acids, aromatic amino acids, glycine, and glutamine) metabolites were higher in individuals with type 2 diabetes compared with control subjects. Prospective studies provided evidence that blood concentrations of several metabolites, including hexoses, branched-chain amino acids, aromatic amino acids, phospholipids, and triglycerides, were associated with the incidence of prediabetes and type 2 diabetes. We meta-analyzed results from eight prospective studies that reported risk estimates for metabolites and type 2 diabetes, including 8,000 individuals of whom 1,940 had type 2 diabetes. We found 36% higher risk of type 2 diabetes per study-specific SD difference for isoleucine (pooled relative risk 1.36 [1.24–1.48]; I 2 = 9.5%), 36% for leucine (1.36 [1.17–1.58]; I 2 = 37.4%), 35% for valine (1.35 [1.19–1.53]; I 2 = 45.8%), 36% for tyrosine (1.36 [1.19–1.55]; I 2 = 51.6%), and 26% for phenylalanine (1.26 [1.10–1.44]; I 2 = 56%). Glycine and glutamine were inversely associated with type 2 diabetes risk (0.89 [0.81–0.96] and 0.85 [0.82–0.89], respectively; both I 2 = 0.0%). CONCLUSIONS In studies using high-throughput metabolomics, several blood amino acids appear to be consistently associated with the risk of developing type 2 diabetes.

The frequency of remission of type 2 diabetes achievable with lifestyle intervention is unclear. To examine the association of a long-term intensive weight-loss intervention with the frequency of remission from type 2 diabetes to prediabetes or normoglycemia. Ancillary observational analysis of a 4-year randomized controlled trial (baseline visit, August 2001-April 2004; last follow-up, April 2008) comparing an intensive lifestyle intervention (ILI) with a diabetes support and education control condition (DSE) among 4503 US adults with body mass index of 25 or higher and type 2 diabetes. Participants were randomly assigned to receive the ILI, which included weekly group and individual counseling in the first 6 months followed by 3 sessions per month for the second 6 months and twice-monthly contact and regular refresher group series and campaigns in years 2 to 4 (n=2241) or the DSE, which was an offer of 3 group sessions per year on diet, physical activity, and social support (n=2262). Partial or complete remission of diabetes, defined as transition from meeting diabetes criteria to a prediabetes or nondiabetic level of glycemia (fasting plasma glucose <126 mg/dL and hemoglobin A1c <6.5% with no antihyperglycemic medication). RESULTS Intensive lifestyle intervention participants lost significantly more weight than DSE participants at year 1 (net difference, -7.9%; 95% CI, -8.3% to -7.6%) and at year 4 (-3.9%; 95% CI, -4.4% to -3.5%) and had greater fitness increases at year 1 (net difference, 15.4%; 95% CI, 13.7%-17.0%) and at year 4 (6.4%; 95% CI, 4.7%-8.1%) (P < .001 for each). The ILI group was significantly more likely to experience any remission (partial or complete), with prevalences of 11.5% (95% CI, 10.1%-12.8%) during the first year and 7.3% (95% CI, 6.2%-8.4%) at year 4, compared with 2.0% for the DSE group at both time points (95% CIs, 1.4%-2.6% at year 1 and 1.5%-2.7% at year 4) (P < .001 for each). Among ILI participants, 9.2% (95% CI, 7.9%-10.4%), 6.4% (95% CI, 5.3%-7.4%), and 3.5% (95% CI, 2.7%-4.3%) had continuous, sustained remission for at least 2, at least 3, and 4 years, respectively, compared with less than 2% of DSE participants (1.7% [95% CI, 1.2%-2.3%] for at least 2 years; 1.3% [95% CI, 0.8%-1.7%] for at least 3 years; and 0.5% [95% CI, 0.2%-0.8%] for 4 years). In these exploratory analyses of overweight adults, an intensive lifestyle intervention was associated with a greater likelihood of partial remission of type 2 diabetes compared with diabetes support and education. However, the absolute remission rates were modest. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00017953.

OBJECTIVE Branched-chain and aromatic amino acids are associated with the risk for future type 2 diabetes; however, the underlying mechanisms remain elusive. We tested whether amino acids predict insulin resistance index in healthy young adults. RESEARCH DESIGN AND METHODS Circulating isoleucine, leucine, valine, phenylalanine, tyrosine, and six additional amino acids were quantified in 1,680 individuals from the population-based Cardiovascular Risk in Young Finns Study (baseline age 32 ± 5 years; 54% women). Insulin resistance was estimated by homeostasis model assessment (HOMA) at baseline and 6-year follow-up. Amino acid associations with HOMA of insulin resistance (HOMA-IR) and glucose were assessed using regression models adjusted for established risk factors. We further examined whether amino acid profiling could augment risk assessment of insulin resistance (defined as 6-year HOMA-IR >90th percentile) in early adulthood. RESULTS Isoleucine, leucine, valine, phenylalanine, and tyrosine were associated with HOMA-IR at baseline and for men at 6-year follow-up, while for women only leucine, valine, and phenylalanine predicted 6-year HOMA-IR (P < 0.05). None of the other amino acids were prospectively associated with HOMA-IR. The sum of branched-chain and aromatic amino acid concentrations was associated with 6-year insulin resistance for men (odds ratio 2.09 [95% CI 1.38–3.17]; P = 0.0005); however, including the amino acid score in prediction models did not improve risk discrimination. CONCLUSIONS Branched-chain and aromatic amino acids are markers of the development of insulin resistance in young, normoglycemic adults, with most pronounced associations for men. These findings suggest that the association of branched-chain and aromatic amino acids with the risk for future diabetes is at least partly mediated through insulin resistance.