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      Individual Stearoyl-CoA Desaturase 1 Expression Modulates Endoplasmic Reticulum Stress and Inflammation in Human Myotubes and Is Associated With Skeletal Muscle Lipid Storage and Insulin Sensitivity In Vivo

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          Abstract

          OBJECTIVE

          Increased plasma levels of free fatty acids occur in obesity and type 2 diabetes and contribute to the development of insulin resistance. Saturated fatty acids (SFAs) such as palmitate especially have lipotoxic effects leading to endoplasmatic reticulum (ER) stress, inflammation, and insulin resistance. Stearoyl-CoA desaturase 1 (SCD1) plays a key role in preventing lipotoxic effects, as it converts SFAs to less harmful monounsaturated fatty acids. Here, we tested the hypothesis that individual differences in the regulation of SCD1 expression by palmitate exist and influence insulin sensitivity and the cellular response to palmitate.

          RESEARCH DESIGN AND METHODS

          Palmitate-induced gene expression was studied in primary human myotubes of 39 metabolically characterized individuals, as well as in an SCD1-overexpressing cell culture model.

          RESULTS

          SCD1 mRNA expression and inducibility by palmitate in cultured myotubes showed a broad interindividual variation, presumably due to inheritable characteristics of the donors. Overexpression of SCD1 prevented the inflammatory and ER stress response to palmitate exposure. In primary human myotubes, high SCD1 inducibility was associated with a low inflammatory (interleukin [IL]-6, IL-8, and chemokine [CXC motif] ligand 3 [CXCL3]) and ER stress (CCAAT/enhancer binding protein [C/EBP] homologous protein, activating transcription factor 3 [ATF3], and X-box binding protein 1 [XBP1]) response to palmitate exposure. Finally, palmitate-stimulated SCD1 mRNA expression, positively correlated with intramyocellular lipid (IMCL) content of the donors, was measured by 1H-magnetic resonance spectroscopy. After adjustment for IMCL, SCD1 expression and inducibility were positively correlated with insulin sensitivity.

          CONCLUSIONS

          We hypothesize that myocellular SCD1 inducibility by palmitate is an individual characteristic that modulates lipid storage, palmitate-induced inflammation, ER stress, and insulin resistance. This may describe individuals with increased capability of innoxious free fatty acid handling and benign triglyceride storage.

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          Most cited references 37

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          Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp.

          Several methods have been proposed to evaluate insulin sensitivity from the data obtained from the oral glucose tolerance test (OGTT). However, the validity of these indices has not been rigorously evaluated by comparing them with the direct measurement of insulin sensitivity obtained with the euglycemic insulin clamp technique. In this study, we compare various insulin sensitivity indices derived from the OGTT with whole-body insulin sensitivity measured by the euglycemic insulin clamp technique. In this study, 153 subjects (66 men and 87 women, aged 18-71 years, BMI 20-65 kg/m2) with varying degrees of glucose tolerance (62 subjects with normal glucose tolerance, 31 subjects with impaired glucose tolerance, and 60 subjects with type 2 diabetes) were studied. After a 10-h overnight fast, all subjects underwent, in random order, a 75-g OGTT and a euglycemic insulin clamp, which was performed with the infusion of [3-3H]glucose. The indices of insulin sensitivity derived from OGTT data and the euglycemic insulin clamp were compared by correlation analysis. The mean plasma glucose concentration divided by the mean plasma insulin concentration during the OGTT displayed no correlation with the rate of whole-body glucose disposal during the euglycemic insulin clamp (r = -0.02, NS). From the OGTT, we developed an index of whole-body insulin sensitivity (10,000/square root of [fasting glucose x fasting insulin] x [mean glucose x mean insulin during OGTT]), which is highly correlated (r = 0.73, P < 0.0001) with the rate of whole-body glucose disposal during the euglycemic insulin clamp. Previous methods used to derive an index of insulin sensitivity from the OGTT have relied on the ratio of plasma glucose to insulin concentration during the OGTT. Our results demonstrate the limitations of such an approach. We have derived a novel estimate of insulin sensitivity that is simple to calculate and provides a reasonable approximation of whole-body insulin sensitivity from the OGTT.
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            Identification and characterization of metabolically benign obesity in humans.

            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. 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], or = 30.0 and placement in the upper quartile of insulin sensitivity), and obese-insulin resistant (IR) (BMI, > or = 30.0 and placement in the lower 3 quartiles of insulin sensitivity). Total body and visceral fat were higher in the overweight and obese groups compared with the normal-weight group (P < .05); however, no differences were observed between the obese groups. In contrast, ectopic fat in skeletal muscle (P < .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 (P < .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). 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.
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              Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study.

              Recent muscle biopsy studies have shown a relation between intramuscular lipid content and insulin resistance. The aim of this study was to test this relation in humans by using a novel proton nuclear magnetic resonance (1H NMR) spectroscopy technique, which enables non-invasive and rapid (approximately 45 min) determination of intramyocellular lipid (IMCL) content. Normal weight non-diabetic adults (n = 23, age 29+/-2 years. BMI = 24.1+/-0.5 kg/m2) were studied using cross-sectional analysis. Insulin sensitivity was assessed by a 2-h hyperinsulinaemic (approximately 450 pmol/l)-euglycaemic (approximately 5 mmol/l) clamp test. Intramyocellular lipid concentrations were determined by using localized 1H NMR spectroscopy of soleus muscle. Simple linear regression analysis showed an inverse correlation (r = -0.579, p = 0.0037) [corrected] between intramyocellular lipid content and M-value (100-120 min of clamp) as well as between fasting plasma non-esterified fatty acid concentration and M-value (r = -0.54, p = 0.0267). Intramyocellular lipid content was not related to BMI, age and fasting plasma concentrations of triglycerides, non-esterified fatty acids, glucose or insulin. These results show that intramyocellular lipid concentration, as assessed non invasively by localized 1H NMR spectroscopy, is a good indicator of whole body insulin sensitivity in non-diabetic, non-obese humans.
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                Author and article information

                Journal
                Diabetes
                diabetes
                diabetes
                Diabetes
                Diabetes
                American Diabetes Association
                0012-1797
                1939-327X
                August 2009
                28 May 2009
                : 58
                : 8
                : 1757-1765
                Affiliations
                1Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology, and Clinical Chemistry, University of Tübingen, Tübingen, Germany;
                2Section of Experimental Radiology, University of Tübingen, Tübingen, Germany.
                Author notes
                Corresponding author: Andreas Peter, andreas.peter@ 123456med.uni-tuebingen.de .
                Article
                0188
                10.2337/db09-0188
                2712792
                19478146
                © 2009 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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                Categories
                Original Article
                Metabolism

                Endocrinology & Diabetes

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