Triangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes

Abstract

The number of people affected by Type 2 diabetes mellitus (T2DM) is close to half a billion and is on a sharp rise, representing a major and growing public health burden. Given its mild initial symptoms, T2DM is often diagnosed several years after its onset, leaving half of diabetic individuals undiagnosed. While several classical clinical and genetic biomarkers have been identified, improving early diagnosis by exploring other kinds of omics data remains crucial. In this study, we have combined longitudinal data from two population-based cohorts CoLaus and DESIR (comprising in total 493 incident cases vs. 1360 controls) to identify new or confirm previously implicated metabolomic biomarkers predicting T2DM incidence more than 5 years ahead of clinical diagnosis. Our longitudinal data have shown robust evidence for valine, leucine, carnitine and glutamic acid being predictive of future conversion to T2DM. We confirmed the causality of such association for leucine by 2-sample Mendelian randomisation (MR) based on independent data. Our MR approach further identified new metabolites potentially playing a causal role on T2D, including betaine, lysine and mannose. Interestingly, for valine and leucine a strong reverse causal effect was detected, indicating that the genetic predisposition to T2DM may trigger early changes of these metabolites, which appear well-before any clinical symptoms. In addition, our study revealed a reverse causal effect of metabolites such as glutamic acid and alanine. Collectively, these findings indicate that molecular traits linked to the genetic basis of T2DM may be particularly promising early biomarkers.

Several Metabolite Families Display Inflexibility during Glucose Challenge in Patients with Type 2 Diabetes: An Untargeted Metabolomics Study

“…Increased fasting levels of the aromatic amino acid phenylalanine and threonine have also been associated with diabetes [ 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Recent evidence employing the Mendelian randomization method has confirmed a causal role of several amino acids’ disrupted metabolism in the development of insulin resistance [ 42 ]. Additionally, lower glutamine levels or glutamine-to-glutamate ratio are associated with a higher risk of diabetes [ 36 , 39 , 40 ] and a worse cardiometabolic profile [ 43 ].…”

The “Common Soil Hypothesis” Revisited—Risk Factors for Type 2 Diabetes and Cardiovascular Disease

“…Mechanisms related to how mannose increases the risk of T2D remain unknown. Recently, an MR study confirmed that mannose is causally associated with T2D [53].…”

Bioactive compounds in mothers milk affecting offspring outcomes: A narrative review

“…From a mechanistic perspective, the human milk metabolome has the potential to influence infant growth via several distinct mechanisms, including direct interactions between individual milk biochemicals and infant intestinal or immune cells, nutritional effects (e.g., providing higher or lower amounts of essential amino acids or vitamins), effects of absorbed metabolites on distant organs, effects on the developing infant microbiome and other pathways. The possibility of metabolome—microbiome interactions is supported by a recent study by Ribo et al, which found reduced levels of betaine (a one‐carbon metabolite previously linked to cardiovascular and diabetes risk 62,63 ) in milk from obese mothers 64 . Betaine supplementation of mouse dams resulted in increased betaine content in milk, and long‐term improvements in metabolic health of offspring including decreased adiposity and improved glucose tolerance, via a microbiome‐dependent mechanism.…”