NMR based clinical metabolomics study revealed disturbed glucose-alanine metabolism in Gestational Diabetes

<p><strong>Background and Aim:</strong> Altered gluconeogenesis from alanine (i.e. glucose-alanine cycle) that increases the levels of<br> serum alanine aminotransferase (ALT) are linked to the development of type II diabetes (T2DM)&nbsp;[1,2]. A recent study also revealed that&nbsp;elevated serum ALT levels in early pregnancy are associated with the risk of subsequent development of gestational<br> diabetes mellitus (GDM) and preeclampsia in late pregnancy [3]. So based on this, we hypothesized that the circulatory<br> alanine and alanine to glucose ratio (AGR) would be altered in GDM and may serve as an indicative biomarker to improve<br> the clinical diagnosis of GDM.&nbsp;<strong>Methods:</strong> The circulatory levels of alanine and glucose were estimated for 50 GDM patients and 49 age matched healthy&nbsp;female subjects using 800 MHz NMR spectroscopy. The NMR spectra were analyzed using NMR suite of commercial&nbsp;software (CHENOMX). The estimated circulatory levels of alanine and glucose were used to determine the circulatory<br> AGR levels as [Alanine in &micro;M]/[Glucose in mM] and the values are reported as Mean &plusmn; SEM (SEM is standard error in mean).<br> <strong>Results:</strong> The present study aims to compare the serum metabolic profiles of alanine (Ala) and alanine to glucose ratio (AGR)<br> between age and sex matched GDM patients (N=50; pre term =32, post term=18) and healthy normal control (NC) female<br> subjects (N=49). The comparison revealed that the circulatory levels of alanine and AGR are significantly decreased in GDM<br> patients (Ala=397.5 &plusmn; 28.12| AGR=94.65 &plusmn; 9.06) compared to NC subjects (Ala =515.1 &plusmn; 24.03 | AGR=166.3 &plusmn; 7.577) <strong>(Figure 1A and 1B)</strong>. The respective&nbsp;p-values for comparison of alanine and AGR found to be 0.002 (**) and &lt;0.0001, ****). The disturbed glucose-alanine&nbsp;metabolic cycle in GDM patients was further corroborated through performing metabolic Pearson r correlation analysis&nbsp;between alanine and glucose <strong>(Figure 1C&nbsp;and 1D)</strong>. For NC subjects, the circulatory metabolites alanine and glucose found to be strongly correlated&nbsp;(r=0.61, 95% CI=0.40 to 0.76; R square =0.37) with two-tailed p-value &lt;0.0001 (see Table depicted in <strong>Figure 1E)</strong>. Whereas for GDM subjects, the circulatory&nbsp;metabolites alanine and glucose found to be moderately correlated (r=0.45, 95% CI=0.19 to 0.64; R square =0.20, <strong>Fig. 1E</strong>) with two tailed p-value =0.002 suggesting that the glucose-alanine metabolic cycle is altered in GDM. Overall, the observed changes in&nbsp;circulatory metabolites and metabolic ratios clearly suggested that the gluconeogenesis from alanine is disturbed in GDM and&nbsp;this abnormal glucose-alanine metabolism is possibly associated with the development of disease and its progression.</p> <p><strong>References:</strong><br> [1] N. Sattar, O. Scherbakova, I. Ford, D.S. O&#39;Reilly, A. Stanley, E. Forrest, P.W. MacFarlane, C.J. Packard, S.M. Cobbe, J.<br> Shepherd, Elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk<br> factors, metabolic syndrome, and C-reactive protein in the west of Scotland coronary prevention study, Diabetes 53<br> (2004) 2855-2860.<br> [2] N.H. Cho, H.C. Jang, S.H. Choi, H.R. Kim, H.K. Lee, J.C. Chan, S. Lim, Abnormal liver function test predicts type 2<br> diabetes: a community-based prospective study, Diabetes care 30 (2007) 2566-2568.<br> [3] S.M. Lee, J.S. Park, Y.J. Han, W. Kim, S.H. Bang, B.J. Kim, C.W. Park, M.Y. Kim, Elevated alanine aminotransferase in<br> early pregnancy and subsequent development of gestational diabetes and preeclampsia, Journal of Korean Medical<br> Science 35 (2020)</p>