Defining lipid mediators of insulin resistance: controversies and challenges

Metcalfe, Louise; Smith, Greg; Turner, Nigel

doi:10.1530/jme-18-0023

Cited by 26 publications

(25 citation statements)

References 258 publications

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“…The varied concentrations of glycosphingolipids in different microdomains of membranes and cellular compartments could therefore contribute to tuning of the signaling properties of GCGR. It is tempting to speculate that changes in lipid metabolism (as a result of dietary intake ( 70 ) and/or pharmacological intervention ( 71 )) may lead to changes in lipid rafts. This in turn may affect the relative proportions of the insulin and GCGRs localized within raft and nonraft membrane microdomains.…”

Section: Discussionmentioning

confidence: 99%

The Glycosphingolipid GM3 Modulates Conformational Dynamics of the Glucagon Receptor

Ansell

Song

Sansom

2020

Biophysical Journal

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The extracellular domain (ECD) of class B1 G-protein-coupled receptors (GPCRs) plays a central role in signal transduction and is uniquely positioned to sense both the extracellular and membrane environments. Although recent studies suggest a role for membrane lipids in the modulation of class A and class F GPCR signaling properties, little is known about the effect of lipids on class B1 receptors. In this study, we employed multiscale molecular dynamics simulations to access the dynamics of the glucagon receptor (GCGR) ECD in the presence of native-like membrane bilayers. Simulations showed that the ECD could move about a hinge region formed by residues Q122–E126 to adopt both closed and open conformations relative to the transmembrane domain. ECD movements were modulated by binding of the glycosphingolipid GM3. These large-scale fluctuations in ECD conformation may affect the ligand binding and receptor activation properties. We also identify a unique phosphatidylinositol (4,5)-bisphosphate (PIP 2 ) interaction profile near intracellular loop (ICL) 2/TM3 at the G-protein-coupling interface, suggesting a mechanism of engaging G-proteins that may have a distinct dependence on PIP 2 compared with class A GPCRs. Given the structural conservation of class B1 GPCRs, the modulatory effects of GM3 and PIP 2 on GCGR may be conserved across these receptors, offering new insights into potential therapeutic targeting.

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Section: Discussionmentioning

confidence: 99%

The Glycosphingolipid GM3 Modulates Conformational Dynamics of the Glucagon Receptor

Ansell

Song

Sansom

2020

Biophysical Journal

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“…However, when adipose tissue reaches its maximum expansion capacity and can no longer perform its storage function, circulating free FA concentrations are at least doubled in obese and T2D individuals compared with lean and healthy subjects [30], and excess lipids accumulate in other peripheral tissues, such as muscles, liver, and pancreas. In addition, low-grade inflammation is observed in adipose tissue of obese individuals [31], leading to an increase in adipocyte lipolysis, which thus contributes to an increase in plasma FA concentrations [32]. Maintenance of adipose tissue expansion is therefore very important to avoid lipid ectopic accumulation.…”

Section: Lipotoxicity and Muscle Insulin Resistancementioning

confidence: 99%

“…However, the involvement of TG as primary initiators of the onset of insulin resistance in muscle cells is far from clear. Overexpression of the FAT/CD36 FA transporter in skeletal muscle has been shown to counteract insulin resistance induced by a fatty diet via increased myotube oxidative capacities, despite increased TG concentrations in cells [32].…”

Section: Lipotoxicity and Muscle Insulin Resistancementioning

confidence: 99%

Sphingolipid Metabolism: New Insight into Ceramide-Induced Lipotoxicity in Muscle Cells

Bandet

Tan

Bourron

et al. 2019

IJMS

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Insulin-resistance is a characteristic feature of type 2 diabetes (T2D) and plays a major role in the pathogenesis of this disease. Skeletal muscles are quantitatively the biggest glucose users in response to insulin and are considered as main targets in development of insulin-resistance. It is now clear that circulating fatty acids (FA), which are highly increased in T2D, play a major role in the development of muscle insulin-resistance. In healthy individuals, excess FA are stored as lipid droplets in adipocytes. In situations like obesity and T2D, FA from lipolysis and food are in excess and eventually accumulate in peripheral tissues. High plasma concentrations of FA are generally associated with increased risk of developing diabetes. Indeed, ectopic fat accumulation is associated with insulin-resistance; this is called lipotoxicity. However, FA themselves are not involved in insulin-resistance, but rather some of their metabolic derivatives, such as ceramides. Ceramides, which are synthetized de novo from saturated FA like palmitate, have been demonstrated to play a critical role in the deterioration of insulin sensitivity in muscle cells. This review describes the latest progress involving ceramides as major players in the development of muscle insulin-resistance through the targeting of selective actors of the insulin signaling pathway.

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“…Impaired insulin signalling in insulin-resistant muscle has long been attributed to (elevated) presence of bioactive lipid derivatives, commonly thought to originate from excess lipid storage in muscle [23]. Bioactive lipids of a wide variety of species are commonly measured by lipidomics.…”

Section: Discussionmentioning

confidence: 99%

Label-free CARS microscopy reveals similar triacylglycerol acyl chain length and saturation in myocellular lipid droplets of athletes and individuals with type 2 diabetes

et al. 2020

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Aims/hypothesis Intramyocellular lipid (IMCL) content associates with development of insulin resistance, albeit not in insulin-sensitive endurance-trained athletes (trained). Qualitative and spatial differences in muscle lipid composition may underlie this so-called athlete’s paradox. Here we studied triacylglycerol (TAG) composition of individual myocellular lipid droplets (LDs) in trained individuals and individuals with type 2 diabetes mellitus. Methods Trained ($$ \dot{V}{\mathrm{O}}_{2\max } $$ V ̇ O 2 max 71.0 ± 1.6 ml O2 [kg lean body mass (LBM)]−1 min−1), normoglycaemic (fasting glucose 5.1 ± 0.1 mmol/l) individuals and untrained ($$ \dot{V}{\mathrm{O}}_{2\max } $$ V ̇ O 2 max 36.8 ± 1.5 ml O2 [kg LBM]−1 min−1) individuals with type 2 diabetes (fasting glucose 7.4 ± 0.5 mmol/l), with similar IMCL content (3.5 ± 0.7% vs 2.5 ± 0.3%, p = 0.241), but at opposite ends of the insulin sensitivity spectrum (glucose infusion rate 93.8 ± 6.6 vs 25.7 ± 5.3 μmol [kg LBM]−1 min−1 for trained individuals and those with type 2 diabetes, respectively) were included from our database in the present study. We applied in situ label-free broadband coherent anti-Stokes Raman scattering (CARS) microscopy to sections from skeletal muscle biopsies to measure TAG acyl chain length and saturation of myocellular LDs. This approach uniquely permits examination of individual LDs in their native environment, in a fibre-type-specific manner, taking into account LD size and subcellular location. Results Despite a significant difference in insulin sensitivity, we observed remarkably similar acyl chain length and saturation in trained and type 2 diabetic individuals (chain length: 18.12 ± 0.61 vs 18.36 ± 0.43 number of carbons; saturation: 0.37 ± 0.05 vs 0.38 ± 0.06 number of C=C bonds). Longer acyl chains or higher saturation (lower C=C number) could be detected in subpopulations of LDs, i.e. large LDs (chain length: 18.11 ± 0.48 vs 18.63 ± 0.57 carbon number) and subsarcolemmal LDs (saturation: 0.34 ± 0.02 vs 0.36 ± 0.04 C=C number), which are more abundant in individuals with type 2 diabetes. Conclusions/interpretation In contrast to reports of profound differences in the lipid composition of lipids extracted from skeletal muscle from trained and type 2 diabetic individuals, our in situ, LD-specific approach detected only modest differences in TAG composition in LD subpopulations, which were dependent on LD size and subcellular location. If, and to what extent, these modest differences can impact insulin sensitivity remains to be elucidated.

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Defining lipid mediators of insulin resistance: controversies and challenges

Cited by 26 publications

References 258 publications

The Glycosphingolipid GM3 Modulates Conformational Dynamics of the Glucagon Receptor

The Glycosphingolipid GM3 Modulates Conformational Dynamics of the Glucagon Receptor

Sphingolipid Metabolism: New Insight into Ceramide-Induced Lipotoxicity in Muscle Cells

Label-free CARS microscopy reveals similar triacylglycerol acyl chain length and saturation in myocellular lipid droplets of athletes and individuals with type 2 diabetes

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