Background: Obesity represents a risk factor for insulin resistance, type 2 diabetes mellitus, and atherosclerosis. In addition, for any given amount of total body fat, an excess of visceral fat or fat accumulation in the liver and skeletal muscle augments the risk. Conversely, even in obesity, a metabolically benign fat distribution phenotype may exist.Methods: In 314 subjects, we measured total body, visceral, and subcutaneous fat with magnetic resonance (MR) tomography and fat in the liver and skeletal muscle with proton MR spectroscopy. Insulin sensitivity was estimated from oral glucose tolerance test results. Subjects were divided into 4 groups: normal weight (body mass index [BMI] [calculated as weight in kilograms divided by height in meters squared], Ͻ25.0), overweight (BMI, 25.0-29.9), obese-insulin sensitive (IS) (BMI, Ն30.0 and placement in the upper quartile of insulin sensitivity), and obese-insulin resistant (IR) (BMI, Ն30.0 and placement in the lower 3 quartiles of insulin sensitivity).Results: Total body and visceral fat were higher in the overweight and obese groups compared with the normal-weight group (PϽ.05); however, no differences were observed between the obese groups. In contrast, ectopic fat in skeletal muscle (PϽ.001) and particularly the liver (4.3%±0.6% vs 9.5%±0.8%) and the intima-media thickness of the common carotid artery (0.54±0.02 vs 0.59±0.01 mm) were lower and insulin sensitivity was higher (17.4±0.9 vs 7.3±0.3 arbitrary units) in the obese-IS vs the obese-IR group (PϽ.05). Unexpectedly, the obese-IS group had almost identical insulin sensitivity and the intima-media thickness was not statistically different compared with the normal-weight group (18.2±0.9 AU and 0.51±0.02 mm, respectively). Conclusions:A metabolically benign obesity that is not accompanied by insulin resistance and early atherosclerosis exists in humans. Furthermore, ectopic fat in the liver may be more important than visceral fat in the determination of such a beneficial phenotype in obesity.

Activation of the transcription factor nuclear factor-B (NF-B) has been suggested to participate in chronic disorders, such as diabetes and its complications. In contrast to the short and transient activation of NF-B in vitro, we observed a long-lasting sustained activation of NF-B in the absence of decreased IB␣ in mononuclear cells from patients with type 1 diabetes. This was associated with increased transcription of NF-Bp65. A comparable increase in NF-Bp65 antigen and mRNA was also observed in vascular endothelial cells of diabetic rats. As a mechanism, we propose that binding of ligands such as advanced glycosylation end products (AGEs), members of the S100 family, or amyloid-␤ peptide ( T issue culture models of cellular activation provide easily accessible systems for detailed analysis of mechanisms potentially underlying the pathogenesis of human disease. However, the time course of such in vitro models is usually significantly abbreviated, limited to hours to days, compared with the pace of disorders under study in vivo. This indicates the importance of seeking out mechanisms in cell culture that might bridge the gap that accounts for the chronicity of cellular perturbation observed in the intact organism.The transcription factor nuclear factor-B (NF-B) has been proposed as a critical bridge between oxidant stress and gene expression (1-8). Exposure of cells to inflammatory, infectious, or other stressful stimuli results in rapid phosphorylation and degradation of IB␣ and the subsequent release and translocation of NF-B into the nucleus (1-11). This mechanism ensures quick and finely tuned cellular responses in the absence of de novo protein synthesis. Because transcription of IB␣ is positively autoregulated by NF-B (9 -11), activation of NF-B is usually self-terminated within minutes to hours (1-11). Such a scenario lends itself to analysis by short-term in vitro studies in which stimulus-induced responses are transient and the system returns to the baseline state over hours. Consequently, induction of NF-B and enhanced transcription of its target genes in vitro have been studied mainly in the setting of acute cellular responses.Reactive oxygen intermediates are generated by processes that occur over seconds. However, increasing evidence suggests a role for oxidative stress in chronic degenerative diseases such as atherosclerosis (1,6,12,13), diabetes (14 -16), and Alzheimer's disease (17)(18)(19). This indicates the relevance of signal transduction systems such as NF-B, which are capable of transforming the appearance and disappearance of short-lived oxygen free radicals into more sustained signals for cellular activation

Insulin resistance plays an important role in the pathogenesis of type 2 diabetes; however, the multiple mechanisms causing insulin resistance are not yet fully understood. The aim of this study was to explore the possible contribution of intramyocellular lipid content in the pathogenesis of skeletal muscle insulin resistance. We compared insulin-resistant and insulin-sensitive subjects. To meet stringent matching criteria for other known confounders of insulin resistance, these individuals were selected from an extensively metabolically characterized group of 280 first-degree relatives of type 2 diabetic subjects. Some 13 lean insulin-resistant and 13 lean insulin-sensitive subjects were matched for sex, age, BMI, percent body fat, physical fitness, and waist-to-hip ratio. Insulin sensitivity was determined by the hyperinsulinemic-euglycemic clamp method (for insulin-resistant subjects, glucose metabolic clearance rate [MCR] was 5.77+/-0.28 ml x kg(-1) x min(-1) [mean +/- SE]; for insulin-sensitive subjects, MCR was 10.15+/-0.7 ml x kg(-1) x min(-1); P<0.002). Proton magnetic resonance spectroscopy (MRS) was used to measure intramyocellular lipid content (IMCL) in both groups. MRS studies demonstrated that in soleus muscle, IMCL was increased by 84% (11.8+/-1.6 vs. 6.4+/-0.59 arbitrary units; P = 0.008 ), and in tibialis anterior muscle, IMCL was increased by 57% (3.26+/-0.36 vs. 2.08+/-0.3 arbitrary units; P = 0.017) in the insulin-resistant offspring, whereas the extramyocellular lipid content and total muscle lipid content were not statistically different between the two groups. These data demonstrate that in these well-matched groups of lean subjects, IMCL is increased in insulin-resistant offspring of type 2 diabetic subjects when compared with an insulin-sensitive group matched for age, BMI, body fat distribution, percent body fat, and degree of physical fitness. These results indicate that increased IMCL represents an early abnormality in the pathogenesis of insulin resistance and suggest that increased IMCL may contribute to the defective glucose uptake in skeletal muscle in insulin-resistant subjects.

No abstract