Sex-specific lipidome changes associated with diabetes

Didac Mauricio's et al. recent publication in Cardiovascular Diabetology reported the findings of a study aiming to explore lipidomic alterations in individuals with type 1 diabetes (T1D) and type 2 diabetes (T2D). We are providing a brief overview about main findings, and potential implications.
Sex-specific lipidome changes associated with diabetes
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Lipidome characterisation and sex-specific differences in type 1 and type 2 diabetes mellitus - Cardiovascular Diabetology

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.

The research involved 360 participants: 91 with T1D, 91 with T2D, 74 prediabetic individuals, and 104 controls. All participants were free from previous cardiovascular or chronic kidney disease. The study utilized untargeted lipidomic analysis through Ultra-high performance liquid chromatography-electrospray ionization mass spectrometry (UHPLC-ESI-MS) to assess lipid profiles. Multiple linear regression models were employed to examine the associations of different lipid classes with diabetes, while considering both sex-specific differences and glycemic states.

 Study findings

 The study identified 54 unique lipid subspecies from 15 unique lipid classes, highlighting a diverse lipidomic profile associated with diabetes.

Lysophosphatidylcholines (LPC) and ceramides showed opposite effects in subjects with T1D and subjects with T2D. Lysophosphatidylcholines were significantly up-regulated in T1D participants but down-regulated in those with T2D. This suggests that LPC metabolism differs markedly between these two types of diabetes. This increase in LPC levels may correlate with increased LCAT activity, which is involved in lipid metabolism, particularly the synthesis of phosphocholine and cholesteryl esters from LPCs and phosphatidylcholine.

Ceramides displayed the opposite trend compared to LPCs; they were found to be up-regulated in subjects with T2D while showing down-regulation in T1D. Variants such as 1-deoxyceramides exhibited a significant increase in T2D, marking them as important indicators of the disease. These findings indicate a clear alteration in ceramide metabolism in type 2 diabetes that may influence insulin signaling pathways, potentially worsening insulin resistance.

Phosphatidylcholines (PC) were predominantly down-regulated in the subjects with type 1 diabetes; this may have implications for membrane integrity and function. This down-regulation contributes to the overall altered lipid profile observed in T1D.

Interestingly, the study identified sex-specific lipidomic differences. For instance, lipid alterations were notably more pronounced in men regarding certain ceramides. Specifically, specific ceramide molecules were significantly decreased only in men with T1D. Additionally, higher levels of phosphatidylcholines were present in normoglycemic women than in men. These findings point to the role of hormonal factors in determining sex-specific lipid metabolism differences.

We also analyzed possible associations of lipid classes with the glycemic state, i.e. normoglycemia, prediabetes and type 2 diabetes. A gradual increase in 1-deoxyceramides was seen progressing from normoglycemia through prediabetes to T2D, indicating these lipid species might serve as potential early biomarkers for diabetes progression.


Clinical and research implications

 The findings underscore a substantial disruption in lipid metabolism for both types of diabetes, indicating that further investigation into lipidomic profiles may yield critical insights into diabetes pathophysiology. This could lead to enhanced understanding of the disease mechanisms and the identification of novel biomarkers for diabetes. Furthermore, from the clinical point of view, our results suggest the need for sex-specific strategies in diabetes management. This personalized approach to treatment could enhance patient outcomes and open avenues for tailored therapeutic interventions. Moreover, the future potential introduction of lipidomic profiling characterization into routine clinical assessments could contribute to more precise management of diabetes and its complications.

Overall, this study contributes relevant knowledge to the field of diabetes research, emphasizing the potential of lipidomics in personalizing treatment strategies while highlighting the importance of sex differences in metabolic responses.

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Type 2 Diabetes
Life Sciences > Health Sciences > Clinical Medicine > Endocrinology > Endocrine System and Metabolic Diseases > Diabetes > Type 2 Diabetes
Type 1 Diabetes
Life Sciences > Health Sciences > Clinical Medicine > Diseases > Immunological Disorders > Autoimmune Diseases > Type 1 Diabetes
Lipidomics
Life Sciences > Biological Sciences > Chemical Biology > Lipidology > Lipids > Lipidomics

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