The relationship between phospholipids and insulin resistance: From clinical to experimental studies

Chang, Wenguang; Hatch, Grant M.; Wang, Yu; Yu, Fei; Wang, Man

doi:10.1111/jcmm.13984

Cited by 77 publications

(59 citation statements)

References 91 publications

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“…In a recent study in non-human primates, Polewski et al identified differences in plasma phospholipid composition, most notably perturbations in diacylglycerols that are desaturation products of palmitic acid, as markers of worsening insulin resistance and onset of the metabolic syndrome [56]. While the specific metabolites identified differed from those of the present study, phospholipids are integral components of the cell membrane and plasma and their metabolism influences numerous biochemical pathways, including those involved in glycaemic regulation [57]. The compounds of particular interest in Factor 4 include diacylglycerol derivatives of palmitoleic acid (e.g., palmitoleoyl-linoleoyl-glycerol [16:1/18:2]), an unsaturated monounsaturated fatty acid that has been found to exhibit similar detrimental effects to palmitic acid on cardiovascular traits in adult men [58].…”

Section: Statement Of Principal Findingscontrasting

confidence: 49%

A prospective study of associations between in utero exposure to gestational diabetes mellitus and metabolomic profiles during late childhood and adolescence

et al. 2019

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Aims/hypothesis This study aimed to: (1) identify metabolite patterns during late childhood that differ with respect to exposure to maternal gestational diabetes mellitus (GDM); (2) examine the persistence of GDM/metabolite associations 5 years later, during adolescence; and (3) investigate the associations of metabolite patterns with adiposity and metabolic biomarkers from childhood through adolescence. Methods This study included 592 mother-child pairs with information on GDM exposure (n = 92 exposed), untargeted metabolomics data at age 6-14 years (T1) and at 12-19 years (T2), and information on adiposity and metabolic risk biomarkers at T1 and T2. We first consolidated 767 metabolites at T1 into factors (metabolite patterns) via principal component analysis (PCA) and used multivariable regression to identify factors that differed by GDM exposure, at α = 0.05. We then examined associations of GDM with individual metabolites within factors of interest at T1 and T2, and investigated associations of GDM-related factors at T1 with adiposity and metabolic risk throughout T1 and T2 using mixed-effects linear regression models. Results Of the six factors retained from PCA, GDM exposure was associated with greater odds of being in quartile (Q)4 (vs Q1-3) of 'Factor 4' at T1 after accounting for age, sex, race/ethnicity, maternal smoking habits during pregnancy, Tanner stage, physical activity and total energy intake, at α = 0.05 (OR 1.78 [95% CI 1.04, 3.04]; p = 0.04). This metabolite pattern comprised phosphatidylcholines, diacylglycerols and phosphatidylethanolamines. GDM was consistently associated with elevations in a subset of individual compounds within this pattern at T1 and T2. While this metabolite pattern was not related to the health outcomes in boys, it corresponded with greater adiposity and a worse metabolic profile among girls throughout the follow-up period. Each 1-unit increment in Factor 4 corresponded with 0.17 (0.08, 0.25) units higher BMI z score, 8.83 (5.07, 12.59) pmol/l higher fasting insulin, 0.28 (0.13, 0.43) units higher HOMA-IR, and 4.73 (2.15, 7.31) nmol/l higher leptin. Conclusions/interpretation Exposure to maternal GDM was nominally associated with a metabolite pattern characterised by elevated serum phospholipids in late childhood and adolescence at α = 0.05. This metabolite pattern was associated with greater Electronic supplementary material The online version of this article (

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Section: Statement Of Principal Findingscontrasting

confidence: 49%

A prospective study of associations between in utero exposure to gestational diabetes mellitus and metabolomic profiles during late childhood and adolescence

et al. 2019

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“…Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are major components of cellular membranes where they are involved with essential cellular processes (1,2). PC and PE are synthesized de novo by CDP-Cho and CDP-Etn branches of the Kennedy pathway in which the extracellular substrates choline (Cho) and ethanolamine (Etn) are actively transported into the cell, phosphorylated and coupled with diacylglycerols (DAG) to form the final phospholipid product.…”

Section: Introductionmentioning

confidence: 99%

The novel roles of choline transporter-like 1 and 2 in ethanolamine transport

Taylor

Grapentine

Ichhpuniani

et al. 2020

Preprint

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We examined a novel function of mammalian Choline-Transporter-Like proteins CTL1/SLC44A1 and CTL2/SLC44A2 in ethanolamine transport. We established two distinct ethanolamine transport systems of a high affinity (K1 = 55.6 - 66.5 μM), mediated by CTL1, and of a low affinity (K2 = 275 - 299 μM), mediated by CTL2. Both types of transport are Na+-independent and mediated in a pH dependent manner, as expected for ethanolamine/H+ antiporters. Primary human fibroblasts with separate frameshift mutations (M1= SLC44A1ΔAsp517 and M2= SLC44A1ΔSer126) are devoid of CTL1 ethanolamine transport but maintain unaffected CTL2 transport. The lack of CTL1 or CTL2 reduced the ethanolamine transport, the flux by the CDP-ethanolamine Kennedy pathway and PE synthesis. Overexpression of CTL1 in SLC44A1ΔSer126 (M2) cells improved the ethanolamine transport and PE synthesis. The SLC44A1ΔSer126 cells are reliant on CTL2 function and CTL2 siRNA almost completely abolished ethanolamine transport in the whole cells and mitochondria. Overexpression of CTL1 and CTL2 cDNAs increased ethanolamine transport in control and SLC44A1ΔSer126 cells. CTL1 and CTL2 facilitated mitochondrial ethanolamine uptake, but the transport mediated by CTL1 is predominant in the whole cells and mitochondria. These data firmly established that CTL1 and CTL2 are the first identified ethanolamine transporters in the whole cells and mitochondria, with intrinsic roles in de novo PE synthesis by the CDP-Etn Kennedy pathway and compartmentation of intracellular ethanolamine.SignificanceThe lack of Choline Transporter Like 1 (SLC44A1/CTL1) is the primary cause of a new neurodegenerative disorder with elements of childhood-onset parkinsonism and mitochondrial dysfunction. SLC44A2/CTL2 encodes the human neutrophil antigen 3, causes autoimmune hearing loss and Meniere’s disease, and has been recently identified as the main risk factor for thrombosis-the major cause of death in Covid-19 patients. Our investigation provides insights into the novel functions of CTL1 and CTL2 as intrinsic ethanolamine transporters. CTL1 and CTL2 are high and low affinity transporters, with direct roles in the membrane phospholipid synthesis. The work contributes to new knowledge for CTL1 and CTL2 independent transport functions and the optimization of prevention and treatment strategies in those various diseases.

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“…Moreover, alterations in the fatty acid composition of glycerophospholipids has been associated to decreased insulin sensitivity. 19 The association between non-bilayer lipids, like palmitoyloleoyl PE (POPE, compound 3) and glucose metabolism has been previously demonstrated, since POPE increases GLUT4 activity, increasing glucose uptake. 20 Accordingly, this phospholipid was significantly (P < .05) lower in all DFU groups as compared to no T2DM (control) group (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, alterations in the fatty acid composition of glycerophospholipids has been associated to decreased insulin sensitivity. 19 …”

Section: Discussionmentioning

confidence: 99%

Non-Targeted Metabolomic Analysis Reveals Serum Phospholipid Alterations in Patients with Early Stages of Diabetic Foot Ulcer

et al. 2020

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Diabetic foot ulcer (DFU) is a common complication of type 2 diabetes mellitus (T2DM) characterized by ulcer formation, which can lead to the amputation of lower extremities. However, the metabolic alterations related to this complication are not completely elucidated. Therefore, we carried out a metabolomic analysis of serum samples obtained from T2DM adult patients diagnosed with diabetic foot ulcer in a cross-sectional, observational, and comparative study. Eighty-four volunteers were classified into the following groups: without T2DM (control group, n = 30) and with T2DM and different stages of diabetic foot ulcer according to Wagner-Meggitt classification system: DFU G0 (n = 11), DFU G1 (n = 14), DFU G2 (n = 16), and DFU G3 (n = 13). The non-target metabolomic profile followed by chemometric analysis revealed that lysophosphatidylethanolamine (16:1) could be proposed as key metabolite related to the onset of diabetic foot ulcer; however, this phospholipid was not affected by diabetic foot ulcer progression. Therefore, further studies are necessary to validate these phospholipids as biomarker candidates for the early diagnosis of diabetic foot ulcer in T2DM patients.

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The relationship between phospholipids and insulin resistance: From clinical to experimental studies

Cited by 77 publications

References 91 publications

A prospective study of associations between in utero exposure to gestational diabetes mellitus and metabolomic profiles during late childhood and adolescence

A prospective study of associations between in utero exposure to gestational diabetes mellitus and metabolomic profiles during late childhood and adolescence

The novel roles of choline transporter-like 1 and 2 in ethanolamine transport

Non-Targeted Metabolomic Analysis Reveals Serum Phospholipid Alterations in Patients with Early Stages of Diabetic Foot Ulcer

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