Insulin resistance plays an important role in the pathogenesis of human type 2 diabetes. In humans, a negative correlation between insulin sensitivity and intramyocellular lipid (IMCL) content has been shown; thus, IMCL becomes a marker for insulin resistance. Recently, magnetic resonance spectroscopy (MRS) has been established as a dependable method for selective detection and quantification of IMCL in humans. To validate the interrelation between insulin sensitivity and IMCL in an animal model of type 2 diabetes, we established volume selective 1 H-MRS at 7 Tesla to noninvasively assess IMCL in the rat. In male obese Zucker Diabetic Fatty rats and their lean littermates, IMCL levels were determined repeatedly over 4 months, and insulin sensitivity was measured by the euglycemic-hyperinsulinemic clamp method at 6 -7 and at 22-24 weeks of age. A distinct relation between IMCL and insulin sensitivity was demonstrated as well as age dependence for both parameters. Rosiglitazone treatment caused a clear reduction of IMCL and hepatic fat despite increased body weight, and a marked improvement of insulin sensitivity. Thus, the insulin sensitizing properties of rosiglitazone were consistent with a redistribution of lipids from nonadipocytic (skeletal muscle, liver) back into fat tissue. Diabetes 52:138 -144, 2003

Increased supply of fatty acids to muscle and liver is causally involved in the insulin resistance syndrome. Using a tissue microdialysis technique in Wistar and Zucker fatty (ZF) rats, we determined tissue glycerol levels as a marker of lipolysis in gastrocnemius muscle (gMT), subcutaneous adipose (SAT), and visceral adipose tissue (VAT) as well as the reduction of plasma free fatty acids, glycerol, and triglycerides caused by the antilipolysis-specific adenosine-A1 receptor agonist (ARA). In Wistar and ZF rats, ARA significantly lowered dialysate glycerol levels in SAT, VAT, and gMT. Whereas in SAT and VAT the decrease in dialysate glycerol indicated adipocytic antilipolysis, this decrease in gMT was not caused by a direct effect of ARA on intramyocellular lipolysis, as demonstrated by the lack of inhibition of the protein kinase A activity ratio in gMT. In addition, no differences of the fed-starved-refed dynamics of intramyocellular triglyceride levels compared with untreated controls were measured by in vivo 1 Hspectroscopy, excluding any adenylate cyclase-independent antilipolysis in muscle. Treatment with ARA resulted in pronounced reductions of plasma free fatty acids, glycerol, and triglycerides. Furthermore, in ZF rats, ARA treatment caused an immediate improvement of peripheral insulin sensitivity measured by the euglycemic-hyperinsulinemic glucose clamp technique.

Increased intramyocellular lipid (IMCL) content has been proposed as biomarker for insulin resistance (IR). An inverse correlation between IMCL and insulin sensitivity (IS) was found in nonathletic humans, whereas in animal models only a few validation studies have been performed. The aim of this study was to investigate the interrelation between IS indices determined by the glucose clamp technique (glucose disposal (GD), exogenous glucose infusion rates (GIR)) and IMCL content in the tibialis (TIB) and the soleus (SOL) muscle obtained by magnetic resonance spectroscopy in different rat models of IR. Dietinduced insulin-resistant Wistar rats as well as genetic disease models (ZDF rats) were used. In both muscles, elevated IMCL correlated with an impaired IS in all models of IR. The correlation of IMCL with both parameters for IS was comparable in TIB and SOL. The best fit between IMCL and IS was obtained using TIB and GIR data (r ‫؍‬ -0.69, P < 0.001). Diabetic male ZDF rats exhibited comparatively low IMCL levels due to their catabolic state: exclusion of this group improved r.

. Muscle-type specific fatty acid metabolism in insulin resistance: an integrated in vivo study in Zucker diabetic fatty rats.

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The investigation of intramyocellular lipids (IMCLs) with proton MR spectroscopy ( 1 H-MRS) in humans has recently received increasing attention. IMCL levels correlate with insulin resistance and are affected by diet and exercise, making IMCL an interesting marker for metabolic investigations. In the present in vivo study, the feasibility of using 1 H MRS for the detection of IMCL in rats is demonstrated, and the influence of various factors, such as age, gender, muscle type, and rat strain, on IMCL levels is systematically analyzed. In healthy Wistar and Sprague Dawley (SD) rats, the highest ratios of IMCL/tCr were found in young rats, and IMCL/tCr decreased with increasing age. In addition, IMCL concentration was clearly influenced by gender and muscle type. Insulin-resistant, male, obese, Zucker diabetic fatty (ZDF) rats showed significantly higher IMCL levels than Wistar or SD rats. Proton MR spectroscopy ( 1 H-MRS) has been applied successfully to human muscle in vivo, both in investigations of muscle lipid metabolism in healthy volunteers, and in studies of patients with muscular diseases. The most relevant spectroscopic signals of muscle tissue stem from total creatin (tCr, 3.05 ppm) and from the methylene and methyl protons of lipid resonances (1.0 -1.6 ppm (1,2)).In human muscle, localized MRS can identify two sets of proton resonances from fatty acyl chains-one from intramyocellular (IMCL) and one from extramyocellular (EMCL) lipids (1), which are separated by a frequency shift of 0.2 ppm. The frequency shift has been explained by magnetic susceptibility differences between these two compartments, and the anisotropic spatial arrangement of muscle fibers. The chemical shift of the EMCL resonance has been shown to be orientation-dependent (3), which is most likely due to the arrangement of adipocytes along muscle fibers. IMCL, on the other hand, is stored in the cytoplasm of muscle cells within spherical droplets (4), resulting in no spatial dependence of their chemical shift on the main magnetic field direction (3). This orientation dependency is essential for the separation of EMCL and IMCL by MRS. The best separation between the two signals is achieved when the investigated muscle lies roughly parallel to the main magnetic field B 0 (3).Volume-selective 1 H-MRS is currently the only methodology that enables noninvasive monitoring of IMCL levels in vivo. The main reason for the recently increased interest in the measurement of IMCL levels stems from the good correlation between the IMCL concentration and insulin resistance (5-7). Insulin resistance is the key feature of type 2 diabetes, but may also be found in other common disorders, such as obesity, dyslipidemia, and arterial hypertension. Recent studies indicate that measurements of IMCL levels may also increase our knowledge of the pathogenesis of noninsulin-dependent type 2 diabetes mellitus (8). Other investigators have analyzed the role of IMCL as an energy depot, and the effects of diet and exercise on IMCL levels (9 -12).Currently, it is still...

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