Ceramide: a contributor to insulin resistance or an innocent bystander?

Many studies in humans and animals have clearly demonstrated that obesity predisposes to the development of insulin resistance. Despite years of investigational efforts, however, it is still not completely known why and how this happens. One currently popular hypothesis is that obesity triggers a low-grade, chronic inflammation and the release of proinflammatory cytokines from adipose tissue and macrophages, which can antagonise insulin action [1]. According to another hypothesis, chronic excessive nutrient intake results in accumulation of fat not only in the physiological storage sites, i.e. in adipose tissue, but also in other tissues such as liver and skeletal muscle, where it causes problems [2]. This model is supported by studies demonstrating that experimental manipulations promoting lipid deposition in muscle and/or liver such as i.v. lipid/heparin infusions or overproduction of lipoprotein lipase in muscle and/or liver of transgenic mice, cause insulin resistance [3]. It has been shown, however, that intramyocellular or intrahepatic accumulation of triacylglycerol is not directly responsible for decreased insulin action, but is likely to be the source for accumulation of several lipid metabolites that can inhibit insulin signalling. For instance, experiments in animals and humans have shown that short-term lipid/ heparin infusions not only increase intramyocellular triacylglycerol concentrations, but also result in intracellular accumulation of long-chain acyl-CoA and diacylglycerol and activation of several serine/threonine kinases, including several protein kinase C isoforms, inhibitor of kappa-B kinase and c-jun N-terminal kinase [4]. Some of these kinases have been shown to interfere with insulin signalling by decreasing tyrosine phosphorylation of IRS-1/2. Diacylglycerol, rather than long-chain acyl-CoA, has been implicated as the most likely lipid metabolite responsible for the lipid-induced insulin resistance [5] (Fig. 1). The ceramides, a family of molecules consisting of variable length fatty acids linked to sphingosine or related bases, are another type of lipid metabolite postulated to be a link between nutrient excess, inflammatory cytokine production and development of insulin resistance (Fig. 1). Supporting this notion are many in vitro and animal studies showing that ceramide can induce insulin resistance [6]. One of the mechanisms by which ceramide can inhibit insulin action in isolated cells involves inhibition of Akt. This can occur through several mechanisms, including dephosphorylation of Akt by increased protein phosphatase 2 activity, or by inhibition of translocation of Akt to the cell membrane [6]. Whether ceramide is involved in the development of obesity-related insulin resistance in humans is less clear. The paper by Skovbro et al. [7] in this issue of Diabetologia addresses this question. Ceramide content was measured in muscle biopsy samples taken from 33 men with a wide range of insulin sensitivities (determined by euglycaemic– hyperinsulinaemic clamp), ranging from very low (patients with type 2 diabetes) to very high (endurance-trained healthy men). The authors found that basal muscle ceramide concentration was similar in all men, regardless of the large differences in insulin sensitivity, and did not change in response to hyperinsulinaemia. They concluded that muscle ceramide content could not be a major factor in the pathogenesis of the insulin resistance in these men. Their results, however, are in disagreement with human studies by others. For instance, Straczkowski et al. [8] Diabetologia (2008) 51:1095–1096 DOI 10.1007/s00125-008-1015-y