Type 2 diabetes disrupts circadian orchestration of lipid metabolism and membrane fluidity in human pancreatic islets
Fig 2
Lipidomic analyses of human islets derived from T2D versus ND donors cultured and synchronized in vitro.
(A) Hierarchical clustering analysis (Distance Measure: Euclidian; Clustering algorithm: Ward) of top 30 islet lipids with most contrasting patterns between T2D and control ND counterpart. For each donor, islet lipids levels measured at 12 h and 24 h after forskolin synchronization were averaged (n = 5 for the islets from T2D donors and n = 4 for the islets from ND donors). (B) Volcano plots of differentially abundant islet lipids (fold change ≥ 1.5 and p < 0.05, Welch’s corrected) between T2D (n = 5) and ND donors (n = 4). Colored dots highlight significant up- or down-regulated individual lipid species. (C) Lipid class repartition (PC, PE, PI, PS, CL, HexCer, Cer, and SM) in human islets from ND and T2D donors (in mol%), synchronized in vitro and collected at 12 h and 24 h after in vitro synchronization. The data represent the average of the 2 time points (n = 5 for the islets from T2D donors and n = 4 for the islets from ND donors, mean ± SEM). (D) Comparison of the PC/PE ratio in islets from ND (n = 4) versus islets from T2D donors (n = 5). The data represent the average of the 2 time points (12 h and 24 h) ± SEM. (E, F) Representative examples of individual lipids (PI44:1 and HexCer34:1(-H2O)) down- (E) and up- (F) regulated in the islets from T2D donors compared to islets from ND donors. The data represent the log2 fold change. (G) DHCer42:0(-H2O) levels in T2D versus ND islets synchronized in vitro and collected after 12 h. (H, I) Abundance of significantly differentially regulated lipids between the control and the T2D groups at 12 h (H) and 24 h (I). Each bar represents the sum of the significantly differentially regulated individual lipids shown in Fig 3E and 3F, as percentage of the total lipids detected from the same class at the same time point. Data are represented as mean ± SEM. (J, K) Relative level changes (mol%) of DHCer, Cer, HexDHCer, and HexCer in islets from T2D (n = 5) and ND (n = 4) donors collected 12 h (J) and 24 h (K) after synchronization, mean ± SEM. (L, M) Representative examples of individual lipids (HexCer34:1(-H2O) and PI44:1) up- (L) and down- (M) regulated in T2D versus ND islets synchronized in vitro and collected after 24 h. The data represent the log2 fold change. (N, O) Relative PC (N) and PE (O) level changes (mol%) in islets from T2D and ND donors collected 24 h after synchronization. Lipids are clustered according to the nature of the fatty acid linkage (diacyl versus alkyl-acyl (ether) or monoacyl (lyso)). T2D donors (n = 5) and ND donors (n = 4), mean ± SEM. (P, Q) Relative PE level changes (in pmol/nmol of phosphate with lipid concentrations corrected for class II isotopic overlaps) in islets from T2D and ND donors collected 12 h (P) and 24 h (Q) after synchronization represented according to the degree of saturation. T2D donors (n = 5) and ND donors (n = 4), mean ± SEM. Statistical analyses for (C, D, H–K, and N–Q) are unpaired t test with Welch’s correction. *p < 0.05, **p < 0.01. See also S3 Data. Cer, ceramide; CL, cardiolipin; DHCer, dihydroceramide; HexCer, hexosylceramide; HexDHCer, hexosyldihydroceramide; ND, nondiabetic; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PI, phosphatidylinositol; PS, phosphatidylserine; SM, sphingomyelin; T2D, type 2 diabetes.