Skeletal Muscle 11βHSD1 Activity of Nondiabetic Subjects is Unaltered in Central Obesity-associated Insulin Resistance

Abstract

Local activation of glucocorticoids in insulin target tissues by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) has been implicated in the etiology of the metabolic syndrome. In obesity, adipose tissue 11βHSD1 is upregulated, leading to the generation of higher tissue levels of cortisol, which may increase insulin resistance. However, skeletal muscle is the predominant site of insulin-mediated glucose disposal, which is known to be reduced in obesity. We aimed to determine if there is any relationship between skeletal muscle 11βHSD1 and markers of central adiposity and insulin resistance in nondiabetic subjects. 20 nondiabetic volunteers (8 males and 12 females, mean age 55±13 years, body mass index 21.5–47.6, mean 30.4±1.6 kg/m²) underwent a single fasting blood sample followed by a muscle biopsy of vastus lateralis under local anesthetic. Fasting glucose, insulin and adiponectin were measured in serum. Skeletal muscle 11βHSD1 oxoreductase activity was determined by measuring the conversion of radiolabelled ³H-cortisone to cortisol by thin layer chromatography. When subjects were categorised according to abdominal obesity (waist circumference ≥102 cm in men, ≥88 cm in women), there was no difference between the groups in skeletal muscle 11βHSD1 activity. There was no correlation between body mass index or waist circumference and 11βHSD1 activity or between HOMA and 11βHSD1 activity. Skeletal muscle 11βHSD1 oxoreductase activity is not altered in nondiabetic subjects with central obesity-associated insulin resistance. It is therefore unlikely that the in vivo insulin resistance observed in skeletal muscle of centrally obese subjects is mediated by alterations in 11βHSD1.

Key words

insulin resistance - metabolic syndrome - cortisol - adiponectin

References

• 1 Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, Hewison M, Stewart PM. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response.  Endocr Rev. 2004;  25 831-866
• 2 Morton NM, Seckl JR. 11beta-hydroxysteroid dehydrogenase type 1 and obesity.  Front Horm Res. 2008;  36 146-164
• 3 Jang C, Obeyesekere VR, Dilley RJ, Alford FP, Inder WJ. 11Beta hydroxysteroid dehydrogenase type 1 is expressed and is biologically active in human skeletal muscle.  Clin Endocrinol (Oxf). 2006;  65 800-805
• 4 Jang C, Obeyesekere VR, Alford FP, Inder WJ. Skeletal muscle 11beta hydroxysteroid dehydrogenase type 1 activity is upregulated following elective abdominal surgery.  Eur J Endocrinol. 2009;  160 249-255
• 5 Whorwood CB, Donovan SJ, Flanagan D, Phillips DI, Byrne CD. Increased glucocorticoid receptor expression in human skeletal muscle cells may contribute to the pathogenesis of the metabolic syndrome.  Diabetes. 2002;  51 1066-1075
• 6 Jang C, Obeyesekere VR, Dilley RJ, Krozowski Z, Inder WJ, Alford FP. Altered activity of 11beta-hydroxysteroid dehydrogenase Types 1 and 2 in skeletal muscle confers metabolic protection in subjects with Type 2 diabetes.  J Clin Endocrinol Metab. 2007;  92 3314-3320
• 7 DeFronzo RA, Gunnarsson R, Bjorkman O, Olsson M, Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus.  J Clin Invest. 1985;  76 149-155
• 8 Laakso M, Edelman SV, Olefsky JM, Brechtel G, Wallace P, Baron AD. Kinetics of in vivo muscle insulin-mediated glucose uptake in human obesity.  Diabetes. 1990;  39 965-974
• 9 Laine H, Yki-Jarvinen H, Kirvela O, Tolvanen T, Raitakari M, Solin O, Haaparanta M, Knuuti J, Nuutila P. Insulin resistance of glucose uptake in skeletal muscle cannot be ameliorated by enhancing endothelium-dependent blood flow in obesity.  J Clin Invest. 1998;  101 1156-1162
• 10 Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) . Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).  JAMA. 2001;  285 2486-2497
• 11 Carr DB, Utzschneider KM, Hull RL, Kodama K, Retzlaff BM, Brunzell JD, Shofer JB, Fish BE, Knopp RH, Kahn SE. Intra-abdominal fat is a major determinant of the National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome.  Diabetes. 2004;  53 2087-2094
• 12 Tomlinson JW, Sinha B, Bujalska I, Hewison M, Stewart PM. Expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue is not increased in human obesity.  J Clin Endocrinol Metab. 2002;  87 5630-5635
• 13 Livingstone DE, Jones GC, Smith K, Jamieson PM, Andrew R, Kenyon CJ, Walker BR. Understanding the role of glucocorticoids in obesity: tissue-specific alterations of corticosterone metabolism in obese Zucker rats.  Endocrinology. 2000;  141 560-563
• 14 Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, Flier JS. A transgenic model of visceral obesity and the metabolic syndrome.  Science. 2001;  294 2166-2170
• 15 Veilleux A, Rheaume C, Daris M, Luu-The V, Tchernof A. Omental adipose tissue type 1 11 beta-hydroxysteroid dehydrogenase oxoreductase activity, body fat distribution, and metabolic alterations in women.  J Clin Endocrinol Metab. 2009;  94 3550-3557
• 16 Morgan SA, Sherlock M, Gathercole LL, Lavery GG, Lenaghan C, Bujalska IJ, Laber D, Yu A, Convey G, Mayers R, Hegyi K, Sethi JK, Stewart PM, Smith DM, Tomlinson JW. 11beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid-induced insulin resistance in skeletal muscle.  Diabetes. 2009;  58 2506-2515
• 17 Stewart PM, Boulton A, Kumar S, Clark PM, Shackleton CH. Cortisol metabolism in human obesity: impaired cortisone–>cortisol conversion in subjects with central adiposity.  J Clin Endocrinol Metab. 1999;  84 1022-1027
• 18 Bonora E, Targher G, Alberiche M, Bonadonna RC, Saggiani F, Zenere MB, Monauni T, Muggeo M. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity.  Diabetes Care. 2000;  23 57-63
• 19 Pouliot MC, Despres JP, Lemieux S, Moorjani S, Bouchard C, Tremblay A, Nadeau A, Lupien PJ. Waist circumference and abdominal sagittal diameter: best simple anthropometric indexes of abdominal visceral adipose tissue accumulation and related cardiovascular risk in men and women.  Am J Cardiol. 1994;  73 460-468
• 20 Jensen MD, Kanaley JA, Reed JE, Sheedy PF. Measurement of abdominal and visceral fat with computed tomography and dual-energy X-ray absorptiometry.  Am J Clin Nutr. 1995;  61 274-278
• 21 Scherzer R, Shen W, Bacchetti P, Kotler D, Lewis CE, Shlipak MG, Heymsfield SB, Grunfeld C. Simple anthropometric measures correlate with metabolic risk indicators as strongly as magnetic resonance imaging-measured adipose tissue depots in both HIV-infected and control subjects.  Am J Clin Nutr. 2008;  87 1809-1817
• 22 Schnackenberg CG. 11beta-hydroxysteroid dehydrogenase type 1 inhibitors for metabolic syndrome.  Curr Opin Investig Drugs. 2008;  9 295-300
• 23 Kotelevtsev Y, Holmes MC, Burchell A, Houston PM, Schmoll D, Jamieson P, Best R, Brown R, Edwards CR, Seckl JR, Mullins JJ. 11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress.  Proc Natl Acad Sci U S A. 1997;  94 14924-14929
• 24 Morton NM, Holmes MC, Fievet C, Staels B, Tailleux A, Mullins JJ, Seckl JR. Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11beta-hydroxysteroid dehydrogenase type 1 null mice.  J Biol Chem. 2001;  276 41293-41300

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