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

AimsType 2 diabetes mellitus (DM) leads to cardiac dysfunction irrespective of hypertension and coronary artery disease; this is called diabetic cardiomyopathy. Here, we investigated the severity of diabetic cardiomyopathy and myocardial remodelling in aged Zucker diabetic fatty (ZDF) rats. Methods and resultsBody weight, blood glucose and glycated haemoglobin (Hb A1c ) levels, and urinary albumin excretion were monitored regularly in ZDF rats (n ¼ 19) and control littermates (n ¼ 19) up to age 45 weeks. ZDF rats were severely diabetic during the entire study period and demonstrated decreased body and heart weights at sacrifice. Left ventricular (LV) function was determined using magnetic resonance imaging (MRI) at age 44 weeks and revealed similar LV ejection fraction and cardiac output index in control and ZDF rats, indicating preserved systolic function. LV pressure characteristics assessed at age 45 weeks showed significant, but mild elevations of LV end-diastolic pressure (+45%) and relaxation time constant Tau (+54%) in ZDF rats, indicating diastolic dysfunction. Histological analyses revealed a significantly increased LV collagen content (+50%), but no cardiomyocyte hypertrophy in ZDF rats. ConclusionThe present study clearly shows that long term, severe DM in 45-week-old ZDF rats resulted in relatively mild impairment of diastolic LV function, whereas systolic function was well preserved. These data do not support the notion that diabetes per se is a critical factor in the induction of a clinically relevant degree of cardiac dysfunction. Co-morbidities such as hypertension and coronary artery disease probably have larger impacts on myocardial function in diabetic individuals.--

Background and Purpose-Thrombolytic treatment of stroke carries the risk of hemorrhagic transformation. Therefore, the potential of MRI for prediction of recombinant tissue plasminogen activator (rtPA)-induced bleeding is explored to identify patients in whom rtPA treatment may provoke such complications. Methods-Spontaneously hypertensive rats (SHR) (nϭ9) were submitted to middle cerebral artery (MCA) clot embolism, followed 3 hours later by intra-arterial infusion of 10 mg/kg rtPA. Untreated SHR (nϭ9) were infused with saline. MRI imaging was performed before treatment and included apparent diffusion coefficient (ADC), T2, and perfusion mapping and contrast enhancement with gadolinium-DTPA. The distribution of intracerebral hemorrhages was studied 3 days later by histological staining. Results-Clot embolism led to the rapid decline of ADC in the territory of the occluded artery. Tissue lesion volume derived from ADC imaging increased by 155Ϯ69% in the untreated animals and by 168Ϯ87% in the treated animals (PϭNS), determined on the histological sections after 3 days. This same lesion growth in both groups indicated absence of therapeutic effect after 3-hour treatment delay. Hemorrhagic transformations were significantly more frequent in treated SHR (PϽ0.05). In untreated rats, hemorrhages were found in the border zone of the ischemic territory; in treated animals, hemorrhagic transformations occurred in the ischemic core region. rtPA-induced hemorrhages were predicted by a disturbance of the blood-brain barrier in 3 of 4 animals before treatment by Gd-DTPA contrast enhancement but not by ADC, T2, or perfusion imaging. The region of contrast enhancement colocalized with subsequent bleeding in these animals. Conclusions-The disturbance of blood-brain barrier but not of other MR parameters allows risk assessment for hemorrhagic transformation induced by subsequent thrombolytic treatment.

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.

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

Metabolic changes in the hippocampus formation can be investigated with in vivo magnetic resonance spectroscopy (MRS). Learned helplessness (LH) is a well validated animal model of depression which we established in Sprague-Dawley rats defining some as "learned helpless" (LH) or not "learned helpless" (NLH). Helpless and non-helpless rats received a course of daily administered electroconvulsive shocks (ECS) for 6 days. MRS measurements were performed on a 4.7 T animal scanner with an average voxel size within the rat hippocampus of 10 microl. In LH rats hippocampal creatine/NAA rose significantly (14%) whereas creatine/NAA of NLH rats showed no increase at all. A possible connection between hippocampal creatine levels and major depressive disorders as a reflection of changes in energy metabolism is discussed.