Lipidome characterisation and sex-specific differences in type 1 and type 2 diabetes mellitus

Abstract

Background: In this study, we evaluated the lipidome alterations caused by type 1 diabetes (T1D) and type 2 diabetes (T2D), by determining lipids significantly associated with diabetes overall and in both sexes, and lipids associated with the glycaemic state.

Methods: An untargeted lipidomic analysis was performed to measure the lipid profiles of 360 subjects (91 T1D, 91 T2D, 74 with prediabetes and 104 controls (CT)) without cardiovascular and/or chronic kidney disease. Ultra-high performance liquid chromatography-electrospray ionization mass spectrometry (UHPLC-ESI-MS) was conducted in two ion modes (positive and negative). We used multiple linear regression models to (1) assess the association between each lipid feature and each condition, (2) determine sex-specific differences related to diabetes, and (3) identify lipids associated with the glycaemic state by considering the prediabetes stage. The models were adjusted by sex, age, hypertension, dyslipidaemia, body mass index, glucose, smoking, systolic blood pressure, triglycerides, HDL cholesterol, LDL cholesterol, alternate Mediterranean diet score (aMED) and estimated glomerular filtration rate (eGFR); diabetes duration and glycated haemoglobin (HbA1c) were also included in the comparison between T1D and T2D.

Results: A total of 54 unique lipid subspecies from 15 unique lipid classes were annotated. Lysophosphatidylcholines (LPC) and ceramides (Cer) showed opposite effects in subjects with T1D and subjects with T2D, LPCs being mainly up-regulated in T1D and down-regulated in T2D, and Cer being up-regulated in T2D and down-regulated in T1D. Also, Phosphatidylcholines were clearly down-regulated in subjects with T1D. Regarding sex-specific differences, ceramides and phosphatidylcholines exhibited important diabetes-associated differences due to sex. Concerning the glycaemic state, we found a gradual increase of a panel of 1-deoxyceramides from normoglycemia to prediabetes to T2D.

Conclusions: Our findings revealed an extensive disruption of lipid metabolism in both T1D and T2D. Additionally, we found sex-specific lipidome changes associated with diabetes, and lipids associated with the glycaemic state that can be linked to previously described molecular mechanisms in diabetes.

Keywords: Sex-specific differences; Type 1 diabetes; Type 2 diabetes; Untargeted lipidomics.

Fig. 1

Figure 1 shows the lipid classes that differ in the comparisons according to diabetes status. When comparing both diabetic conditions, lysophosphatidylcholines (LPC) and ceramides (Cer) were more importantly altered than other lipid classes (Fig. 1A). In a similar way, LPCs, phosphatidylcholines (PC), phosphatidylethanolamines (PE) and TGs were especially altered in T1D (Fig. 1B), as well as Cer in T2D (Fig. 1C). Additional File 2 (Table S3) reports the mass-to-charge ratio (mz) and retention time (rt) for each lipid ion significantly associated with one of these conditions in at least one of the analyses. Moreover, the range of corrected p-values, ionization mode and the list of analyses corresponding to the significant corrected p-value is also shown in Additional File 2 (Table S3)

Fig. 2

Fold-change values and statistical significance obtained for each lipid determined as being significantly different in at least one of the nine analyses conducted. Statistical significance is indicated using asterisks: corrected p-value (p) < 0.05 (*), p < 0.01 (**), p < 0.001 (***), p < 0.0001 (****). Bars in the right side of each panel indicate a positive fold-change value, while bars in the left indicate a negative one. A positive fold-change indicates that the lipid is increased in the first group (e.g. in T1D vs. T2D, TG(18:1_18:1_18:2) is significantly increased in T1D with respect to T2D). The different colours in the background of the plot show the different lipid classes. In the left, the names of the lipid subspecies are shown. The nomenclatures of the type 16:1e indicate that the fatty acid (FA) of the glycerophospholipid is linked to the glycerol moiety by an ether bond, therefore, the mentioned glycerophospholipid is an ether-glycerophospholipid

Fig. 3

Boxplots of lipids that are significantly associated with T2D in men or women. The nomenclatures of the type 16:1e indicate that the fatty acid (FA) of the glycerophospholipid is linked to the glycerol moiety by an ether bond, therefore, the mentioned glycerophospholipid is an ether-glycerophospholipid

Fig. 4

Boxplots of 20 selected lipids significantly associated with T1D in men or women

Fig. 5

Boxplots of lipids significantly associated with the numeric variable defined as 0 for normoglycemia, 1 for prediabetes and 2 for T2D