Metabolomics & Lipids in T1D Progression
By: Mari Yamamoto and Hadeel Saab
Many researchers looked into whether metabolomics is able to detect the onset of autoimmunity and progression to T1D much earlier than seroconversion, or the time period during which a specific antibody develops and becomes detectable in the blood. Metabolomics is a field of research that studies the chemical pathways of metabolites within a biological system. The measurement of metabolites’ changing concentrations over time can reflect both genetic and environmental factors, as the metabolic phenotype is vulnerable to factors like nutrition, gut microbiota, age and lifestyle. Over time, researchers have been able to narrow down their research with more advanced techniques.
In 2008, researchers took advantage of the plethora of genetic data available from the DIPP (Type 1 Diabetes Prediction and Prevention) project, that included children who tested positive for T1D-associated autoimmunity and further progressed to clinical diabetes, as well as nonprogressors who remained healthy and autoantibody negative. In comparing serum metabolomes, they found initial evidence that metabolic dysregulation precedes overt autoimmunity in T1D. Specifically, among progressors to T1D, prior to seroconversion, there were reduced levels of phosphatidylcholine (a class of phospholipids), succinic acid and other lipids at birth and in follow-ups.
A later study in 2013 sought to determine whether the decreased levels of lipids in progressors are associated with beta cell autoimmunity or with clinical T1D. The researchers conducted an umbilical cord serum lipidome analysis in infants who later developed T1D; in infants who developed between one and four islet autoantibodies, and in control infants. Here’s what they found:
- In agreement with prior studies, T1D progressors had a specific lipidomic profile with reduced levels of major choline-containing phospholipids, specifically sphingomyelins and phosphatidylcholines.
- These changes are associated with T1D progression, but not the development of beta cell autoimmunity.
- Because choline levels can be modulated through diet or gut microbiota, they propose the possibility that environmental factors may affect choline metabolism during pregnancy, and thus important developmental processes choline is implicated in as well, such as genetic imprinting and genome stability.
Because of its importance in beta cell structure and signaling, another group of researchers further inspected sphingolipid metabolism’s involvement in T1D progression. Sulfatide, a sphingolipid, works as an “insulin chaperone” by preserving and regulating the secretion of insulin. Conducting a transcriptional analysis,The researchers analyzed blood and tissue samples from pancreas biopsies of individuals recently diagnosed with T1D looking for the presence of sulfatide . Their findings:
- Sphingolipid metabolism is involved in T1D pathology, as there was reduced expression of sulfatide in pancreatic islet cells.
- The reduced levels of sphingolipid can be explained by polymorphisms in the promoter regions of eight genes encoding sphingolipid metabolism enzymes.
- These gene polymorphisms were related to lower rates of T cell proliferation when presented with beta cell autoantigens, thus increasing the risk for developing T1D.
- In testing whether increasing pancreas sulfatide levels could prevent and reverse autoimmune diabetes in non-obese diabetic (NOD) mice with Fenofibrate, they found that the mice were protected from insulitis and diabetes.
A 2018 lipidomics study followed three different groups from birth until 3 years of age: Children who progressed to T1D; children who developed islet autoantibodies but not T1D, and healthy controls. Results showed specific lipid changes that preceded islet autoimmunity and T1D, most significant being a lower level of sphingomyelins in the T1D group. Each group had a distinct metabotype, with the T1D group having a persistently dysregulated lipid metabolism (supporting the earlier studies). Click here to read the full study and here for the data set from the experiment.
Swedish researchers just published a more recent study (October 2020) of 10 to 15 year olds with HLA genetic risk for T1D, building upon previous studies of lipids. They found that metabolic variation of specific phospholipids were related to autoimmunity, but not necessarily to the development of T1D. In the future, lipidomic profiling could be an important asset for predicting T1D, if autoantibodies can be matched with lipid variations in the future.
Recap: Lipidomics could have potential in identifying markers for progression to T1D and islet autoimmunity.