Body fat distribution and insulin resistance Skeletal muscle intramyocellular lipids

Overabundance of plasma triglycerides and free fatty acids entering the circulation by lipol-ysis from adipose tissue or by ingestion from food is frequently associated with pathophys-iology of insulin resistance and diabetes mellitus (Defronzo 2004). Results of radioactive tracer and stable isotope dilution studies have suggested that both hepatic and peripheral muscle tissues are involved in the development of insulin resistance (Defronzo 1988). Focusing on glucose uptake in skeletal muscle, based on the results of his experimental studies series, Sir Randle (Randle et al. 1963) postulated the hypothesis that the substrate competition for mitochondrial oxidation is the major mechanism involved in the impairment of glucose uptake into skeletal muscle. Recent studies applying 13C and 31P MRS methods (reviewed in Chapter 11 of this book) and analysis of skeletal muscle biopsy have shown that direct impairment of insulin signalling cascade (Griffin et al. 1999), and therefore direct impairment of glucose transport (Cline et al. 1999), phosphorylation (Roden et al. 1996, 1999; Krebs et al. 2001) and glycogen synthesis (Roden et al. 1996; Delmas-Beauvieux et al. 1999) are the effect of circulating FFA on the glucose metabolism. These and other studies (Boden & Chen 1995; Boden et al. 1995) have shown that experimental elevation of free fatty acids causes similar defects in the skeletal muscle glucose metabolism as those found in various pathologically insulin-resistant states - T2DM, offspring, IR (Shulman et al. 1990; Rothman et al. 1991, 1992; Perseghin et al. 1996; Petersen et al. 1998). On the other hand, it is still under debate whether or not - and why - persistent suppression of plasma FFA concentration is necessary to improve skeletal muscle insulin sensitivity (Bajaj et al. 2004, 2005; Johnson et al. 2006; Santomauro et al. 1999).

Another metabolically active source of triglycerides that could influence cellular glucose uptake is the lipids stored in the cytosol of non-adipose tissue. Such lipid vesicles can be found in the skeletal muscle, myocardum, liver and pancreatic P-cells. These fat depots are not released into the circulation, but may influence glucose utilisation directly. Early evidence from histological and biochemical skeletal muscle biopsy analysis have shown a correlation between skeletal muscle triglyceride aggregation and insulin resistance (Phillips et al. 1996; Pan et al. 1997; Ebeling et al. 1998). These techniques, however, could not sufficiently discriminate between intramyocellular (IMCL) and extramyocellular (EMCL) lipid stores and so the question about the direct effect of intracellular lipids remained open. Consequent correlative studies, using localised MRS of skeletal muscle, have shown increased IMCL content in different insulin resistant - lean, obese, adolescent, type 1 and type 2 diabetic - populations (Jacob et al. 1999; Krssak et al. 1999; Perseghin et al. 1999, 2003; Sinha et al. 2002; Larson-Meyer et al. 2006a) (Figure 13.9). These findings are supported by the results of studies using CT measurement of skeletal muscle fat content (Goodpaster et al. 2000a,b). Further experiments have revealed differences in IMCL content in different muscle groups (Jacob et al. 1999; Perseghin et al. 1999; Hwang et al. 2001; Anderwald et al. 2002; Schick et al. 2002; Kautzky-Willer et al. 2003; Vermathen et al. 2004) (Figure 13.7), highlighting the different relationships between insulin sensitivity and IMCL content in predominantly oxidative or predominantly glycolytic muscles. These studies showed lower IMCL content in glycolytic, fibre type II - tibialis anterior muscle, as compared to the oxida-tive fibre type I - soleus muscle (Jacob et al.1999; Perseghin et al. 1999; Hwang et al. 2001; Anderwald et al. 2002; Kautzky-Willer et al. 2003; Vermathen et al. 2004). These results (Jacob et al. 1999; Anderwald et al. 2002; Kautzky-Willer et al. 2003) could also show that IMCL content in tibialis anterior muscle is a better predictor of peripheral insulin resistance than IMCL content in soleus muscle, which is more tightly associated with the indexes of whole body adiposity such as body mass index (BMI). Taken together, these studies suggested the hypothesis that IMCLs, especially in glycolytic tibialis anterior muscle, influence directly skeletal muscle glucose uptake and therefore that its content is a good marker of insulin resistance. However, increased IMCL content was also observed in endurance-

Figure 13.9 Differences in IntramyoceUular Fat Accumulation Single voxel JH MR spectra of the soleus muscle obtained at magnetic field strength of 3T in three different subjects. Spectrum A is from the solues muscle, with low IMCL content (0.70 % of water resonance); spectrum B is from muscle with average IMCL content (1.47 %); and spectrum C is from muscle with high IMCL content (1.94 %). EMCL denotes extramyocellular lipids. Upper panel shows cross-sectional image of human calf muscle, with a typical volume of the area of interest for single voxel localised MR spectroscopy of soleus muscle.

Figure 13.9 Differences in IntramyoceUular Fat Accumulation Single voxel JH MR spectra of the soleus muscle obtained at magnetic field strength of 3T in three different subjects. Spectrum A is from the solues muscle, with low IMCL content (0.70 % of water resonance); spectrum B is from muscle with average IMCL content (1.47 %); and spectrum C is from muscle with high IMCL content (1.94 %). EMCL denotes extramyocellular lipids. Upper panel shows cross-sectional image of human calf muscle, with a typical volume of the area of interest for single voxel localised MR spectroscopy of soleus muscle.

trained athletes (Goodpaster et al. 2001; Thamer et al. 2003), who are also highly insulin sensitive.

Revealing this paradox demanded systematic explanation. Recent papers using histo-chemical analysis of muscle biopsies focusing on muscle fibre type specific triglyceride content and fibre type distribution in insulin sensitive, insulin resistant and endurance trained states, show a shift in muscle fibre distribution towards oxidative type 1 muscle fibres (Hickey et al. 1995; Anderson et al. 1997; Nyholm et al. 1997; Clore et al. 1998), increased type 1 fibre specific IMCL content in trained individuals and increased skeletal muscle and whole-body oxidative capacity in those with endurance training (Essen & Haggmark 1975; He et al. 2001; Goodpaster et al. 2003). The observation of IMCL depletion during prolonged sub-maximal exercise (Krssak et al. 2000; Brechtel et al. 2001; Larson-Meyer et al. 2002; White et al. 2003), suggesting the idea that increased IMCL stores could be of substantial benefit for endurance runners, sparked the question of whether the increased muscular triglyceride concentrations are the cause of insulin resistance or rather the result of impaired oxidative capacity in the skeletal muscle of insulin-resistant individuals.

Further studies were designed to assess the regulation of IMCL stores in various conditions. First of all it was hypothesised that experimental elevation of IMCL content would cause or at least would be associated with increased insulin resistance. At the same time, diet or pharmacologically introduced increase in insulin sensitivity should be mirrored by a decrease in IMCL content.

The first part was shown to be true in the case of a three days (Bachmann et al. 2001) high fat diet and intravenous intralipid/heparin infusion induced peripheral insulin resistance (Bachmann et al. 2001; Boden et al. 2001). Researchers could observe a parallel increase of IMCL content, relatively more pronounced in the tibialis anterior muscle of young healthy humans (Bachmann et al. 2001; Boden et al. 2001). Similar results, accompanied by molecular adaptations favouring fat storage in muscle, were found in another study after one week of high fat diet (Schrauwen-Hinderling et al. 2005). Inducing insulin resistance by i.v. amino acid infusion during euglycaemic-hyperinsulinaemia (Krebs et al. 2001) was met by a subtle increase of IMCL content in soleus muscle. IMCL content decreased with increasing insulin sensitivity due to 8-10 months of leptin replacement in patients generalised lipodystrophy (Simha et al. 2003) and 6 months of caloric restriction with or without exercise in an overweight population (Larson-Meyer et al. 2006a).

On the other hand, similar (Bachmann et al. 2001; Boden et al. 2001) but shorter intralipid infusion in young healthy men decreased the glucose uptake but did not increase the IMCL content in the soleus muscle (Brehm et al. 2006). Another study showed that increased plasma FFA elevated by three days of fasting induced increase of IMCL level in the vastus lateralis muscle (Stannard et al. 2002) of young healthy males. Prolonged tight glycaemic control by i.v. insulin infusion did not improve peripheral insulin sensitivity in T2DM, and increased IMCL content in soleus but not tibialis anterior muscle (Anderwald et al. 2002). IMCL stores also increased with the endurance exercise training programme, despite obvious increase of insulin sensitivity (Schrauwen-Hinderling et al. 2003), and remained stable despite improving insulin sensitivity by diet intervention in young healthy humans (Frost et al. 2003), or three months of glitazone treatment in T2DM (Mayerson et al. 2002).

These, to some extent controversial, findings shifted the focus back to the skeletal muscle lipid oxidation pathway, as it was hypothesised that mitochondrial oxidative and phosphoryla-tion capacity might be a contributing factor to insulin resistance and increased IMCL content (Shulman 2000). One of the key intermediate metabolites of lipid oxidation long-chain acyl-CoA was found to be involved in the regulation of skeletal muscle glucose transport and utilisation (Wititsuwannakul & Kim 1977; Faergeman & Knudsen 1997; Tippett & Neet 1982), and its intracellular content was negatively correlated with whole-body insulin sensitivity (Ellis et al. 2000). in vitro studies also found that accelerated beta-oxidation in muscle cells exerts an insulin-sensitising effect independently of changes in intracellular lipid content (Perdomo et al. 2004) and that increased stearoyl-CoA desaturase 1 activity protects against fatty acid induced skeletal muscle insulin resistance (Pinnamaneni et al. 2006). Recent studies found that skeletal muscle mitochondrial phosphorylation capacity and/or ATP demand is associated with decrease of peripheral insulin sensitivity and increased IMCL content in elderly sedentary individuals (Petersen et al. 2003) and insulin-resistant offspring of T2DM patients (Petersen et al. 2005). Skeletal muscle oxidative capacity was identified as a better predictor of insulin sensitivity than either IMCL concentration or long-chain fatty acyl-CoA content in a population spanning from older T2DM to young, well trained athletes (Bruce et al. 2003), and in another, slightly overweight (BMI ~29 kg/m-2) type 2 diabetic population (Schrauwen-Hinderling et al. 2006). It was also shown that experimental elevation of circulating FFA diminishes the effect of insulin stimulation on skeletal muscle ATP synthesis in the parallel, with the effect on glucose transport and phosphorylation but without an influence on IMCL content in skeletal muscle (Brehm et al. 2006). Physical activity induced enhancement of lipid oxidation is also associated with improvements in insulin sensitivity in overweight and obese sedentary humans (Gan et al. 2003; Goodpaster et al. 2003; Larson-Meyer et al. 2006a).

To summarise, recent studies have revealed increased IMCL content in sedentary and insulin-resistant individuals. However, the result also supports the hypothesis that increased intramyocellular fat accumulation is a result of defects in lipid oxidation and/or lipid over-supply, rather than a direct cause of insulin resistance, and that IMCL stores are an efficient energy storage pool, which is increased in endurance trained individuals.

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