Introduction: Blood metabolic profiling is a promising approach for gaining novel insights into early metabolic changes preceding the onset of diabetes and for the detection of early markers for insulin resistance. Therefore, we aimed to identify blood metabolites associated with different aspects of glucose regulation in non-diabetic individuals. 

Methods: This study was conducted in a subset of non-diabetic middle-aged participants from the Leiden Longevity Study (N = 202). We analyzed 192 metabolites from two metabolomics platforms, including metabolites from several different chemical classes, like acylcarnitines, glyerophospholipids, sphingolipids, amino acids and fatty acids. Linear regression analyses were performed to assess associations between different measures of glucose metabolism (fasting glucose, fasting insulin, HOMA-IR, Matsuda Index, Insulinogenic Index and HbA1c) and fasting serum metabolites adjusted for age, sex and BMI. 

Results: We identified 22 metabolites associated with different fasting and postprandial measures of glucose metabolism. Ten metabolites, including for example hexadecanoic acid and tyrosine, were associated with higher fasting glucose and five metabolites, including for example glutamine and glycine metabolites, were associated with lower fasting glucose. Alanine, lactic acid, tryptophan, phenylalanine, tyrosine, uric acid, valine and alpha-ketoglutaric acid were positively associated with fasting insulin and the Matsuda Index. Of these eight metabolites, all but valine was associated with higher HOMA-IR. Moreover, we observed alanine and proline to be associated with a higher Insulinogenic Index. In addition, 1.5-anhydro-d-glucitol and threonine were associated with lower HbA1c. 

Conclusion: Of the metabolites associated with measures of glucose metabolism, alpha-ketoglutaric acid and threonine have not been related to diabetes previously, therefore, requiring further studies. Once replicated, our results may improve understanding of the mechanisms involved in disease etiology and thereby improving treatment possibilities.