CM Larsen

J. M. R. Gill

JM Adams

JM Haus

L Pickersgill

M Skovbro

M Straczkowski

N Sattar

N. Sattar

PW Wilson

SA Summers

VD Mello de

WL Holland

English

Crossref

Ceramides: A new player in the inflammation–insulin resistance paradigm?

Gill, J.M.R.

Sattar, N.

Enlighten: Publications

 
 
 
 
 
 
 
Gill, J.M.R. and Sattar, N. (2009) Ceramides: a new player in the 
inflammation-insulin resistance paradigm? Diabetologia, 52 (12). p. 
2475. ISSN 0012-186X 
 
http://eprints.gla.ac.uk/8974/ 
 
Deposited on: 8 December 2009 
 
 
Enlighten – Research publications by members of the University of Glasgow 
http://eprints.gla.ac.uk 
Final author version 
Published in Diabetologia, Diabetologia, 52 (12), 2475-2477 
 
Ceramides: a new player in the inflammation-insulin resistance paradigm? 
 
Jason MR Gill1 and Naveed Sattar2
 
1Integrative and Systems Biology, Faculty of Biomedical and Life Sciences, West Medical Building, 
University of Glasgow, Glasgow, G12 8QQ, United Kingdom.  2BHF Glasgow Cardiovascular Research 
Centre, 126 University Place, University of Glasgow, Glasgow, G12 8TA, United Kingdom. 
 
 
Address for correspondence 
Jason Gill or Naveed Sattar,  
University of Glasgow,  
Email:  j.gill@bio.gla.ac.uk or nsattar@clinmed.gla.ac.uk 
 
 
Ceramides are a family of lipid molecules comprising sphingosine bound to a fatty acid.  They form an 
integral part of cell membranes and, according to cosmetics manufacturers, their inclusion in hair and skin 
care products can help you to maintain a ‘youthful glow’.  In addition to their simple structural role, it has 
become clear that ceramides also act as signalling molecules with multiple roles and, of interest to the 
diabetes field, a potential role for ceramides in the pathogenesis of insulin resistance has become evident 
over recent years.  Increased concentrations of ceramides have been reported in skeletal muscle of obese 
insulin-resistant compared to lean insulin sensitive men [1] and strong correlations have been observed 
between muscle ceramide concentrations and insulin sensitivity across a wide cross-section of insulin 
sensitivity values [2,3]. However, this finding is not unequivocal with another study reporting no 
systematic differences in skeletal muscle ceramide concentrations between endurance trained, lean but 
untrained, obese and type 2 diabetic men, although a weak correlation between ceramide concentration and 
insulin resistance was observed [4].  Ceramides may provide a key link between lipid oversupply, 
inflammation and insulin resistance, as a major determinant of ceramide synthesis is the availability of 
long-chain saturated fatty acids [5] and, in addition, a number of inflammatory cytokines, particularly 
TNF-α and IL-1, have been implicated in the regulation of ceramide production [5,6].  In vitro studies 
indicate that ceramides inhibit insulin signalling in muscle cells, by decreasing insulin-stimulated 
activation of Akt/PKB [5,7], and by facilitating inflammatory signalling pathways known to impair insulin 
signalling [5,6].  Furthermore, studies in human muscle cells [8] and rodents [9] indicate that blocking 
ceramide synthesis can prevent the development of insulin resistance.  Thus, there is accumulating 
evidence that ceramides in skeletal muscle may be causally implicated in the pathogenesis of insulin 
resistance.    
 
In this issue of Diabetologia, de Mello and colleagues [10] report a strong correlation between total plasma 
ceramide (measured by liquid chromatography / mass spectrometry) and serum IL-6 concentrations in a 
cross-sectional study of 33 patients with cardiovascular disease.  A modest, borderline significant 
correlation (r = 0.33, p =0.06) between plasma ceramides and HOMA-estimated insulin resistance was also 
observed.  Ceramide concentrations explained almost 35% of the variance in circulating IL-6 and this 
relationship was independent of serum TNF-α and HOMA-IR in multivariate analysis.  Somewhat 
surprisingly, a significant correlation between plasma ceramides and serum TNF-α was not observed, 
although this may be a consequence of low statistical power to detect a relationship due to the relatively 
small sample size and the relatively high co-efficient of variation in the TNF-α assay. The authors suggest 
that their findings may indicate a role for ceramides in the induction of inflammation associated with the 
insulin resistance that is often evident in patients with CHD, although of course whether inflammation is 
causally related to type 2 diabetes (or indeed CHD) remains to be fully established.   
 
Nevertheless, these findings are in broad agreement with a report published earlier this year by Haus and 
co-workers, who reported strong correlations between plasma concentrations of ceramide sub-species and 
both clamp-derived insulin sensitivity and plasma TNF-α concentrations in adults with and without type 2 
diabetes [11].  IL-6 was not measured in that study, so it is not known whether a relationship between 
circulating IL-6 and ceramides was evident, but nevertheless, two studies, in different populations, have 
now demonstrated relationships between circulating ceramides, inflammation and insulin resistance. 
 
These findings raise a number of important issues and questions: 
 
• Firstly, the de Mello et al study was cross-sectional in nature, so it is not possible to determine the 
direction of causality in the association between circulating IL-6 and ceramide concentrations.  As 
inflammatory factors influence ceramide production and ceramides themselves induce 
inflammation, either direction of effect is potentially plausible.  In this respect, it would be of 
interest to determine whether individuals with autoimmune conditions have raised plasma ceramide 
levels and, in particular, whether such levels are influenced by TNF-α and IL-6 blocking therapies.    
Similarly, it would be interesting to establish whether novel anti-inflammatory agents (e.g. 
anakinra, a IL-1 receptor antagonist [12]), demonstrated to improve glucose control in diabetes, 
induce parallel decreases in plasma ceramide concentrations.   
• Secondly, the biological relevance of plasma ceramides is unknown.  Are they directly implicated 
in the pathogenesis of insulin resistance, possibly via interactions with circulating immune cells? 
Or do they simply serve as a marker of tissue ceramide concentrations, which themselves play a 
direct role in pathogenesis?  The relationship between plasma and tissue ceramide concentrations in 
humans is not currently known.  Similarly, little is known about potential links between dietary and 
lifestyle factors and plasma ceramide concentrations.  Further study to evaluate these issues is 
needed to put the interesting, but preliminary, findings from the present study into a broader 
context.  Of course, should plasma ceramide concentrations adequately reflect tissue levels at key 
sites, this could accelerate studies examining their potential pathophysiological relevance to 
diabetes and related conditions. 
• In addition, the importance of plasma ceramides in terms of clinical endpoints is not known.  
Prospective studies are needed to ascertain whether elevated plasma ceramides predict type 2 
diabetes, coronary heart disease or mortality.  Such data are required to evaluate whether plasma 
ceramides could conceivably be used an effective biomarker to predict risk or evaluate disease 
severity.  However, caution is advised here for two reasons.  Firstly, the methodology used for the 
determination of plasma ceramide concentrations is complex, and likely costly, and in its present 
form unlikely to be feasible for routine clinical practice.  Secondly, a useful biomarker must add 
predictive power over and above factors currently measured routinely [13], and as yet few, if any, 
novel biomarkers have demonstrated a consistent ability to enhance risk prediction for either CVD 
or diabetes beyond established predictors.  Indeed, even common markers of inflammation such as 
CRP, which are predictive of diabetes per se, do not to enhance risk prediction for diabetes beyond 
simple clinical predictors (i.e. fasting glucose, triglycerides, HDL cholesterol, blood pressure, BMI 
and family history) [14].  Thus, the benchmark for any new biomarker is set high.  
 
Thus, the study of de Mello and colleagues [10], particularly when taken together with the earlier study 
from Haus et al [11] provide exciting preliminary clinical data on the emerging topic of ceramides, 
inflammation and insulin resistance.  Nevertheless, considerable further work, as outlined above, is needed 
to determine whether these recent findings offer new fruitful avenues in the investigation of diabetes 
pathogenesis.  
 
 
References 
 [1]  Adams JM, Pratipanawatr T, Berria R et al (2004) Ceramide content is increased in skeletal muscle 
from obese insulin-resistant humans. Diabetes 53: 25-31 
 [2]  Straczkowski M, Kowalska I, Baranowski M et al (2007) Increased skeletal muscle ceramide level in 
men at risk of developing type 2 diabetes. Diabetologia 50: 2366-2373 
 [3]  Straczkowski M, Kowalska I, Nikolajuk A et al (2004) Relationship between insulin sensitivity and 
sphingomyelin signaling pathway in human skeletal muscle. Diabetes 53: 1215-1221 
 [4]  Skovbro M, Baranowski M, Skov-Jensen C et al (2008) Human skeletal muscle ceramide content is 
not a major factor in muscle insulin sensitivity. Diabetologia 51: 1253-1260 
 [5]  Summers SA (2006) Ceramides in insulin resistance and lipotoxicity. Prog.Lipid Res. 45: 42-72 
 [6]  Holland WL, Summers SA (2008) Sphingolipids, insulin resistance, and metabolic disease: new 
insights from in vivo manipulation of sphingolipid metabolism. Endocr.Rev. 29: 381-402 
 [7]  Straczkowski M, Kowalska I (2008) The role of skeletal muscle sphingolipids in the development of 
insulin resistance. Rev.Diabet.Stud. 5: 13-24 
 [8]  Pickersgill L, Litherland GJ, Greenberg AS, Walker M, Yeaman SJ (2007) Key role for ceramides in 
mediating insulin resistance in human muscle cells. J.Biol.Chem. 282: 12583-12589 
 [9]  Holland WL, Brozinick JT, Wang LP et al (2007) Inhibition of ceramide synthesis ameliorates 
glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab 5: 167-179 
[10]  de Mello VD, Lankinen M, Schwab U et al (2009) Link between plasma ceramides, inflammation 
and insulin resistance: association with serum IL-6 concentration in patients with coronary heart 
disease. Diabetologia 
[11]  Haus JM, Kashyap SR, Kasumov T et al (2009) Plasma ceramides are elevated in obese subjects with 
type 2 diabetes and correlate with the severity of insulin resistance. Diabetes 58: 337-343 
[12]  Larsen CM, Faulenbach M, Vaag A et al (2007) Interleukin-1-receptor antagonist in type 2 diabetes 
mellitus. N.Engl.J.Med. 356: 1517-1526 
[13]  Sattar N, Wannamethee SG, Forouhi NG (2008) Novel biochemical risk factors for type 2 diabetes: 
pathogenic insights or prediction possibilities? Diabetologia 51: 926-940 
[14]  Wilson PW, Meigs JB, Sullivan L, Fox CS, Nathan DM, D'Agostino RB, Sr. (2007) Prediction of 
incident diabetes mellitus in middle-aged adults: the Framingham Offspring Study. Arch.Intern.Med. 
167: 1068-1074 
 
 


Ceramides: a new player in the inflammation-insulin resistance paradigm?

Enlighten

       Gill, J.M.R. and Sattar, N. (2009) Ceramides: a new player in the inflammation-insulin resistance paradigm? Diabetologia, 52 (12). p. 2475. ISSN 0012-186X  http://eprints.gla.ac.uk/8974/  Deposited on: 8 December 2009   Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk Final author version Published in Diabetologia, Diabetologia, 52 (12), 2475-2477  Ceramides: a new player in the inflammation-insulin resistance paradigm?  Jason MR Gill1 and Naveed Sattar2 1Integrative and Systems Biology, Faculty of Biomedical and Life Sciences, West Medical Building, University of Glasgow, Glasgow, G12 8QQ, United Kingdom.  2BHF Glasgow Cardiovascular Research Centre, 126 University Place, University of Glasgow, Glasgow, G12 8TA, United Kingdom.   Address for correspondence Jason Gill or Naveed Sattar,  University of Glasgow,  Email:  j.gill@bio.gla.ac.uk or nsattar@clinmed.gla.ac.uk   Ceramides are a family of lipid molecules comprising sphingosine bound to a fatty acid.  They form an integral part of cell membranes and, according to cosmetics manufacturers, their inclusion in hair and skin care products can help you to maintain a ‘youthful glow’.  In addition to their simple structural role, it has become clear that ceramides also act as signalling molecules with multiple roles and, of interest to the diabetes field, a potential role for ceramides in the pathogenesis of insulin resistance has become evident over recent years.  Increased concentrations of ceramides have been reported in skeletal muscle of obese insulin-resistant compared to lean insulin sensitive men [1] and strong correlations have been observed between muscle ceramide concentrations and insulin sensitivity across a wide cross-section of insulin sensitivity values [2,3]. However, this finding is not unequivocal with another study reporting no systematic differences in skeletal muscle ceramide concentrations between endurance trained, lean but untrained, obese and type 2 diabetic men, although a weak correlation between ceramide concentration and insulin resistance was observed [4].  Ceramides may provide a key link between lipid oversupply, inflammation and insulin resistance, as a major determinant of ceramide synthesis is the availability of long-chain saturated fatty acids [5] and, in addition, a number of inflammatory cytokines, particularly TNF-α and IL-1, have been implicated in the regulation of ceramide production [5,6].  In vitro studies indicate that ceramides inhibit insulin signalling in muscle cells, by decreasing insulin-stimulated activation of Akt/PKB [5,7], and by facilitating inflammatory signalling pathways known to impair insulin signalling [5,6].  Furthermore, studies in human muscle cells [8] and rodents [9] indicate that blocking ceramide synthesis can prevent the development of insulin resistance.  Thus, there is accumulating evidence that ceramides in skeletal muscle may be causally implicated in the pathogenesis of insulin resistance.     In this issue of Diabetologia, de Mello and colleagues [10] report a strong correlation between total plasma ceramide (measured by liquid chromatography / mass spectrometry) and serum IL-6 concentrations in a cross-sectional study of 33 patients with cardiovascular disease.  A modest, borderline significant correlation (r = 0.33, p =0.06) between plasma ceramides and HOMA-estimated insulin resistance was also observed.  Ceramide concentrations explained almost 35% of the variance in circulating IL-6 and this relationship was independent of serum TNF-α and HOMA-IR in multivariate analysis.  Somewhat surprisingly, a significant correlation between plasma ceramides and serum TNF-α was not observed, although this may be a consequence of low statistical power to detect a relationship due to the relatively small sample size and the relatively high co-efficient of variation in the TNF-α assay. The authors suggest that their findings may indicate a role for ceramides in the induction of inflammation associated with the insulin resistance that is often evident in patients with CHD, although of course whether inflammation is causally related to type 2 diabetes (or indeed CHD) remains to be fully established.    Nevertheless, these findings are in broad agreement with a report published earlier this year by Haus and co-workers, who reported strong correlations between plasma concentrations of ceramide sub-species and both clamp-derived insulin sensitivity and plasma TNF-α concentrations in adults with and without type 2 diabetes [11].  IL-6 was not measured in that study, so it is not known whether a relationship between circulating IL-6 and ceramides was evident, but nevertheless, two studies, in different populations, have now demonstrated relationships between circulating ceramides, inflammation and insulin resistance.  These findings raise a number of important issues and questions:  • Firstly, the de Mello et al study was cross-sectional in nature, so it is not possible to determine the direction of causality in the association between circulating IL-6 and ceramide concentrations.  As inflammatory factors influence ceramide production and ceramides themselves induce inflammation, either direction of effect is potentially plausible.  In this respect, it would be of interest to determine whether individuals with autoimmune conditions have raised plasma ceramide levels and, in particular, whether such levels are influenced by TNF-α and IL-6 blocking therapies.    Similarly, it would be interesting to establish whether novel anti-inflammatory agents (e.g. anakinra, a IL-1 receptor antagonist [12]), demonstrated to improve glucose control in diabetes, induce parallel decreases in plasma ceramide concentrations.   • Secondly, the biological relevance of plasma ceramides is unknown.  Are they directly implicated in the pathogenesis of insulin resistance, possibly via interactions with circulating immune cells? Or do they simply serve as a marker of tissue ceramide concentrations, which themselves play a direct role in pathogenesis?  The relationship between plasma and tissue ceramide concentrations in humans is not currently known.  Similarly, little is known about potential links between dietary and lifestyle factors and plasma ceramide concentrations.  Further study to evaluate these issues is needed to put the interesting, but preliminary, findings from the present study into a broader context.  Of course, should plasma ceramide concentrations adequately reflect tissue levels at key sites, this could accelerate studies examining their potential pathophysiological relevance to diabetes and related conditions. • In addition, the importance of plasma ceramides in terms of clinical endpoints is not known.  Prospective studies are needed to ascertain whether elevated plasma ceramides predict type 2 diabetes, coronary heart disease or mortality.  Such data are required to evaluate whether plasma ceramides could conceivably be used an effective biomarker to predict risk or evaluate disease severity.  However, caution is advised here for two reasons.  Firstly, the methodology used for the determination of plasma ceramide concentrations is complex, and likely costly, and in its present form unlikely to be feasible for routine clinical practice.  Secondly, a useful biomarker must add predictive power over and above factors currently measured routinely [13], and as yet few, if any, novel biomarkers have demonstrated a consistent ability to enhance risk prediction for either CVD or diabetes beyond established predictors.  Indeed, even common markers of inflammation such as CRP, which are predictive of diabetes per se, do not to enhance risk prediction for diabetes beyond simple clinical predictors (i.e. fasting glucose, triglycerides, HDL cholesterol, blood pressure, BMI and family history) [14].  Thus, the benchmark for any new biomarker is set high.   Thus, the study of de Mello and colleagues [10], particularly when taken together with the earlier study from Haus et al [11] provide exciting preliminary clinical data on the emerging topic of ceramides, inflammation and insulin resistance.  Nevertheless, considerable further work, as outlined above, is needed to determine whether these recent findings offer new fruitful avenues in the investigation of diabetes pathogenesis.    References  [1]  Adams JM, Pratipanawatr T, Berria R et al (2004) Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes 53: 25-31  [2]  Straczkowski M, Kowalska I, Baranowski M et al (2007) Increased skeletal muscle ceramide level in men at risk of developing type 2 diabetes. Diabetologia 50: 2366-2373  [3]  Straczkowski M, Kowalska I, Nikolajuk A et al (2004) Relationship between insulin sensitivity and sphingomyelin signaling pathway in human skeletal muscle. Diabetes 53: 1215-1221  [4]  Skovbro M, Baranowski M, Skov-Jensen C et al (2008) Human skeletal muscle ceramide content is not a major factor in muscle insulin sensitivity. Diabetologia 51: 1253-1260  [5]  Summers SA (2006) Ceramides in insulin resistance and lipotoxicity. Prog.Lipid Res. 45: 42-72  [6]  Holland WL, Summers SA (2008) Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocr.Rev. 29: 381-402  [7]  Straczkowski M, Kowalska I (2008) The role of skeletal muscle sphingolipids in the development of insulin resistance. Rev.Diabet.Stud. 5: 13-24  [8]  Pickersgill L, Litherland GJ, Greenberg AS, Walker M, Yeaman SJ (2007) Key role for ceramides in mediating insulin resistance in human muscle cells. J.Biol.Chem. 282: 12583-12589  [9]  Holland WL, Brozinick JT, Wang LP et al (2007) Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab 5: 167-179 [10]  de Mello VD, Lankinen M, Schwab U et al (2009) Link between plasma ceramides, inflammation and insulin resistance: association with serum IL-6 concentration in patients with coronary heart disease. Diabetologia [11]  Haus JM, Kashyap SR, Kasumov T et al (2009) Plasma ceramides are elevated in obese subjects with type 2 diabetes and correlate with the severity of insulin resistance. Diabetes 58: 337-343 [12]  Larsen CM, Faulenbach M, Vaag A et al (2007) Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N.Engl.J.Med. 356: 1517-1526 [13]  Sattar N, Wannamethee SG, Forouhi NG (2008) Novel biochemical risk factors for type 2 diabetes: pathogenic insights or prediction possibilities? Diabetologia 51: 926-940 [14]  Wilson PW, Meigs JB, Sullivan L, Fox CS, Nathan DM, D'Agostino RB, Sr. (2007) Prediction of incident diabetes mellitus in middle-aged adults: the Framingham Offspring Study. Arch.Intern.Med. 167: 1068-1074   

Ceramide content is increased in skeletal muscle from obese insulin-resistant humans.

Ceramides in insulin resistance and lipotoxicity.

Human skeletal muscle ceramide content is not a major factor in muscle insulin sensitivity.

Increased skeletal muscle ceramide level in men at risk of developing type 2 diabetes.

Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab 5: 167-179 [10] de Mello VD,

Key role for ceramides in mediating insulin resistance in human muscle cells.

Nikolajuk A et al (2004) Relationship between insulin sensitivity and sphingomyelin signaling pathway in human skeletal muscle.

Novel biochemical risk factors for type 2 diabetes: pathogenic insights or prediction possibilities?

Plasma ceramides are elevated in obese subjects with type 2 diabetes and correlate with the severity of insulin resistance.

Prediction of incident diabetes mellitus in middle-aged adults: the Framingham Offspring Study.

Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism.

The role of skeletal muscle sphingolipids in the development of insulin resistance.

Vaag A et al (2007) Interleukin-1-receptor antagonist in type 2 diabetes mellitus.

https://link.springer.com/content/pdf/10.1007%2Fs00125-009-1546-x.pdf

Ceramides: a new player in the inflammation-insulin resistance paradigm?

Abstract

Similar works

Full text

Available Versions

Crossref

Enlighten: Publications

Enlighten