Hyperglycemia and a common variant of GCKR are associated with the levels of eight amino acids in 9,369 Finnish men

Abstract

We investigated the association of glycemia and 43 genetic risk variants for hyperglycemia/type 2 diabetes with amino acid levels in the population-based Metabolic Syndrome in Men (METSIM) Study, including 9,369 nondiabetic or newly diagnosed type 2 diabetic Finnish men. Plasma levels of eight amino acids were measured with proton nuclear magnetic resonance spectroscopy. Increasing fasting and 2-h plasma glucose levels were associated with increasing levels of several amino acids and decreasing levels of histidine and glutamine. Alanine, leucine, isoleucine, tyrosine, and glutamine predicted incident type 2 diabetes in a 4.7-year follow-up of the METSIM Study, and their effects were largely mediated by insulin resistance (except for glutamine). We also found significant correlations between insulin sensitivity (Matsuda insulin sensitivity index) and mRNA expression of genes regulating amino acid degradation in 200 subcutaneous adipose tissue samples. Only 1 of 43 risk single nucleotide polymorphisms for type 2 diabetes or hyperglycemia, the glucose-increasing major C allele of rs780094 of GCKR, was significantly associated with decreased levels of alanine and isoleucine and elevated levels of glutamine. In conclusion, the levels of branched-chain, aromatic amino acids and alanine increased and the levels of glutamine and histidine decreased with increasing glycemia, reflecting, at least in part, insulin resistance. Only one single nucleotide polymorphism regulating hyperglycemia was significantly associated with amino acid levels.

FIG. 1.

Amino acid levels in categories of FPG (A) and 2hPG (B) levels across the entire range of glucose tolerance. Points represent unadjusted means of amino acid levels in each glucose category. P values were calculated using general linear model adjusted for age and BMI. *P < 0.05. **P < 10⁻¹⁰. ***P < 10⁻³⁰.

FIG. 2.

Correlations of mRNA levels of three key enzymes in BCAA degradation with insulin sensitivity (Matsuda ISI), early-phase insulin secretion (InsAUC_0–30/GluAUC_0–30), FPG and 2hPG. r’, partial Pearson correlation coefficient controlled for Matsuda ISI. *P < 0.05. **P < 1 × 10⁻⁴. ***P < 1 × 10⁻¹⁰. The solid line indicates the linear regression line for the unadjusted variable, and the dotted line indicates linear regression line for the variable adjusted for Matsuda ISI.

FIG. 3.

Associations between GCKR rs780094 and amino acid levels in nondiabetic men. Bars show unadjusted means ± SE. P values were adjusted for age and BMI with linear regression. CC, homozygotes for the glucose-increasing major allele; CT, heterozygotes; TT, homozygotes for the glucose-decreasing minor allele.