Serum dihydroceramides correlate with insulin sensitivity in humans and decrease insulin sensitivity in vitro

Zarini, Simona; Brozinick, Joseph T.; Berry, Karin A. Zemski; Garfield, Amanda; Perreault, Leigh; Kerege, Anna A.; Bui, Hai H.; Sanders, Phil; Siddall, Parker; Kuo, Ming Shang; Bergman, Bryan C.

doi:10.1016/j.jlr.2022.100270

Cited by 14 publications

(17 citation statements)

References 46 publications

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“…Firstly, we found that T2D patients had an increased total plasma DhCer at baseline compared with controls. A similar result has already been reported, but with a smaller number of either T2DM patients or control subjects and with a lower number of quantified DhCer species [ 2 , 23 ]. Thus, Zarini et al .…”

Section: Discussionsupporting

confidence: 87%

“…Thus, Zarini et al . found increased plasma levels of 18:0, 20:0, 22:0 and 24:1 DhCer in T2D patients [ 2 ]. Our results are also consistent with those of Szpigel et al .…”

Section: Discussionmentioning

confidence: 99%

“…Growing evidence suggests that they play a causative role in the pathophysiology of type 2 diabetes (T2D) and cardiovascular diseases [ 1 ]. One of the best-known negative effects of Cer is their ability to promote insulin resistance, and plasma Cer concentrations are positively associated with the degree of insulin resistance in humans [ 2 – 4 ]. In addition, recent studies reveal that circulating Cer levels are also strongly associated with cardiovascular outcomes, independently of traditional risk factors [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…DhCer have long been regarded only as inactive precursors of Cer. However, recent studies suggest that DhCer are directly involved in many processes relative to T2D and atherosclerosis, like insulin resistance [ 2 ]. Interestingly, plasma DhCer concentrations are increased in patients with coronary artery disease [ 7 ], and are linked to cardiovascular risk [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, plasma DhCer concentrations are increased in patients with coronary artery disease [ 7 ], and are linked to cardiovascular risk [ 8 ]. Moreover, circulating DhCer are inversely associated with the degree of insulin sensitivity [ 2 , 9 , 10 ], and are long-term strong predictors of T2D onset [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Liraglutide reduces plasma dihydroceramide levels in patients with type 2 diabetes

Denimal

Bergas

Pais-de-Barros

et al. 2023

Cardiovasc Diabetol

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Background Emerging evidence supports that dihydroceramides (DhCer) and ceramides (Cer) contribute to the pathophysiology of insulin resistance and liver steatosis, and that their circulating concentrations are independently associated with cardiovascular outcomes. Circulating DhCer levels are increased in patients with type 2 diabetes (T2D). On the other hand, the GLP-1 receptor agonist liraglutide reduces major adverse cardiac events, insulin resistance and liver steatosis in T2D patients. The main purpose of the present study was therefore to investigate whether liraglutide decreases circulating levels of DhCer and Cer in T2D patients, which could be a mechanism involved in its cardiometabolic benefits. The secondary purpose was to assess the relationship between liraglutide-induced changes in DhCer/Cer levels and insulin resistance and liver steatosis. Methods Plasma concentrations of 11 DhCer and 15 Cer species were measured by a highly-sensitive mass spectrometry system in 35 controls and 86 T2D patients before and after 6 months of liraglutide (1.2 mg/day). Insulin resistance was estimated by the triglyceride-glucose (TyG) index. Liver fat content (LFC) was assessed in 53 patients by proton magnetic resonance spectroscopy. Results Plasma levels of total DhCer, 7 DhCer and 7 Cer species were increased in T2D patients compared to controls. Liraglutide decreased total DhCer by 15.1% (p = 0.005), affecting 16:0 (p = 0.037), 18:0 (p < 0.0001), 18:1 (p = 0.0005), 20:0 (p = 0.0003), 23:0 (p = 0.005) and 24:1 (p = 0.04) species. Total plasma Cer did not significantly change after liraglutide (p = 0.18), but 5 Cer species decreased significantly, i.e. 18:0 and 18:1 (both p < 0.0001), 19:0 and 24:1 (both p < 0.01) and 26:1 (p = 0.04). In multivariate analysis, the reduction in DhCer after liraglutide was independently associated with the reduction in LFC (p = 0.0005) and in TyG index (p = 0.05). Conclusions Liraglutide reduces plasma levels of numerous DhCer and Cer species in T2D patients, which may contribute to the cardiovascular benefit observed in the LEADER trial. The independent association between the decrease in plasma DhCer level with the reduction in LFC and TyG index adds new insights regarding the relationship between DhCer, liver steatosis and insulin resistance. Trial registration ClinicalTrials.gov identifier: NCT02721888.

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Section: Discussionsupporting

confidence: 87%

“…Thus, Zarini et al . found increased plasma levels of 18:0, 20:0, 22:0 and 24:1 DhCer in T2D patients [ 2 ]. Our results are also consistent with those of Szpigel et al .…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Liraglutide reduces plasma dihydroceramide levels in patients with type 2 diabetes

Denimal

Bergas

Pais-de-Barros

et al. 2023

Cardiovasc Diabetol

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Chewing the fat: How lipidomics is changing our understanding of human health and disease in 2022

Géhin

Fowler

Trivedi

2023

Analytical Science Advances

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Lipids are biological molecules that play vital roles in all living organisms. They perform many cellular functions, such as 1) forming cellular and subcellular membranes, 2) storing and using energy, and 3) serving as chemical messengers during intra‐ and inter‐cellular signal transduction. The large‐scale study of the pathways and networks of cellular lipids in biological systems is called “lipidomics” and is one of the fastest‐growing omics technologies of the last two decades. With state‐of‐the‐art mass spectrometry instrumentation and sophisticated data handling, clinical studies show how human lipid composition changes in health and disease, thereby making it a valuable medium to collect for clinical applications, such as disease diagnostics, therapeutic decision‐making, and drug development. This review gives a comprehensive overview of current workflows used in clinical research, from sample collection and preparation to data and clinical interpretations. This is followed by an appraisal of applications in 2022 and a perspective on the exciting future of clinical lipidomics.

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Adipose Tissue Dysfunction Determines Lipotoxicity and Triggers the Metabolic Syndrome: Current Challenges and Clinical Perspectives

Carobbio,

Pellegrinelli,

Vidal-Puig

2024

Advances in Experimental Medicine and Biology

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Serum dihydroceramides correlate with insulin sensitivity in humans and decrease insulin sensitivity in vitro

Cited by 14 publications

References 46 publications

Liraglutide reduces plasma dihydroceramide levels in patients with type 2 diabetes

Liraglutide reduces plasma dihydroceramide levels in patients with type 2 diabetes

Chewing the fat: How lipidomics is changing our understanding of human health and disease in 2022

Adipose Tissue Dysfunction Determines Lipotoxicity and Triggers the Metabolic Syndrome: Current Challenges and Clinical Perspectives

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