Ether lipids, sphingolipids and toxic 1‐deoxyceramides as hallmarks for lean and obese type 2 diabetic patients

Abstract

The worldwide increase in obesity and type 2 diabetes (T2D) represents a major health challenge. Chronically altered lipids induced by obesity further promote the development of T2D, and the accumulation of toxic lipid metabolites in serum and peripheral organs may contribute to the diabetic phenotype. Methods: To better understand the complex metabolic pattern of lean and obese T2D and non-T2D individuals, we analysed the lipid profile of human serum, skeletal muscle and visceral adipose tissue of two cohorts by systematic mass spectrometrybased lipid analysis. See editorial article: Sen P., Hyötyläinen T., and Orešič M. 2021. 1-Deoxyceramides-Key players in lipotoxicity and progression to type 2 diabetes? Acta Physiol (Oxf). e13635.2 of 20 | THOMAS HANNICH eT Al.

AdipoAtlas: A reference lipidome for human white adipose tissue

“…Previously believed to be mainly of hepatic origin, deoxyCers were shown to be directly synthesized by adipocytes during differentiation. 51 Thus, AdipoAtlas , as well as recently reported data, 51 allows us to propose human WAT as an important reservoir and a source of potentially toxic deoxyCer.…”

“…DeoxyCers were only recently identified in human adipose tissue, with higher levels in VAT relative to serum, particularly in obese individuals with T2DM. 51 Plasma levels of deoxyCer were positively associated with age, BMI, and waistto-hip ratio, 52,53 proposing them as a hallmark of metabolic complications. Interestingly, in plasma, SPB 18:1;O represents only a minor (0.1%-0.3%) fraction, 52 whereas AdipoAtlas revealed 10-times-higher values in human WAT (12.6%) (Figure 5A).…”

1-Deoxysphingolipids, Early Predictors of Type 2 Diabetes, Compromise the Functionality of Skeletal Myoblasts

“…One possible cellular mediator for the observed phenotype is the generation of 1-deoxyceramide, a downstream metabolite of 1-DSA that accumulates in cells upon 1-DSA treatment in vitro (70). In addition, 1deoxyceramide is highly enriched in vivo in visceral adipose tissue as well as in the serum of obese patients with T2DM (71). Ceramides are bioactive signalling molecules that counteract the activity of suppressors of autophagy, including Class I PI3K and AKT, via activation of PP2A (72).…”

Metabolism of HSAN1- and T2DM-associated 1-deoxy-sphingolipids inhibits the migration of fibroblasts

“…They are involved in essential cellular processes such as survival, proliferation, differentiation, metabolism, and apoptosis ( 2 , 3 , 4 ). SL metabolism is altered not only in a variety of monogenetic diseases ( 5 ) but also in several acquired conditions such as the metabolic syndrome, type 2 diabetes mellitus (T2DM), and cancer ( 6 , 7 , 8 , 9 , 10 , 11 , 12 ).…”

“…These complications are rather specific features in HSAN1 and not commonly seen in other inherited neuropathies. Interestingly, patients with T2DM ( 19 , 20 , 21 ) show a similar clinical and metabolic phenotype with peripheral neuropathy, impaired wound healing, and elevated 1-deoxySLs although these patients have no mutations in the genes encoding the SPT subunits ( 12 , 21 , 22 , 23 ).…”