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. 1984 Oct;74(4):1515–1525. doi: 10.1172/JCI111565

Relationship between skeletal muscle insulin resistance, insulin-mediated glucose disposal, and insulin binding. Effects of obesity and body fat topography.

D J Evans, R Murray, A H Kissebah
PMCID: PMC425322  PMID: 6148358

Abstract

Skeletal muscle sensitivity and responsiveness to insulin and their relationship to overall glucose disposal and insulin binding were determined in 89 premenopausal women of varying body fat topography (waist/hips girth ratio [WHR] 0.64-1.02) and obesity level (percentage of ideal body weight 92-230). As a marker of insulin action, the percentage of total glycogen synthase present in the I form (glucose-6-phosphate independent) was measured in quadriceps muscle biopsies. The increase in percentage of synthase I 1 h after oral glucose loading was not significantly different between nonobese and obese weight-matched subgroups of increasing WHR, but this response was maintained at the expense of increasing plasma insulin levels as the WHR rose. The increase in percentage of synthase I in response to submaximal steady state plasma insulin (SSPI) of approximately 100 microU/ml achieved by the infusion of somatostatin, insulin, and glucose, however, was significantly lower in obese than in nonobese subjects, and was inversely correlated with WHR. The increase in percentage of synthase I correlated inversely with the steady state plasma glucose (SSPG) concentration, which is an index of the efficiency of overall glucose disposal, and directly with insulin binding to circulating monocytes. Insulin binding also correlated inversely with WHR and with fasting plasma insulin levels. When obese subjects were separated into three weight-matched subgroups on the basis of increasing WHR, significant trends to decreased percentage of synthase I response, increased SSPG, and decreased insulin binding were found. In women with predominantly upper body obesity (WHR greater than 0.85), the increase in percentage of synthase in response to submaximal SSPI was diminished, but there was no impairment of percentage of synthase I responsiveness to supramaximal SSPI of approximately 1,000 microU/ml. At supramaximal SSPI levels, SSPG in four obese women was normal, whereas in five women, SSPG concentrations were markedly increased. Our results suggest that in premenopausal women, impaired skeletal muscle insulin sensitivity that results in decreased glucose storage capacity may contribute to the diminished efficiency of glucose disposal and insulin resistance that are associated with upper body obesity. The impairment in skeletal muscle sensitivity may be overcome in vivo at the expense of increasing plasma insulin levels, with maximal responsiveness remaining unimpaired. This defect may result from a reduction in insulin receptor number which could, in turn, be secondary to persistently elevated fasting plasma insulin levels. In some upper body segment obese women, however, an additional defect affecting other insulin-sensitive pathways may also be present.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Assimacopoulos-Jeannet F., Jeanrenaud B. The hormonal and metabolic basis of experimental obesity. Clin Endocrinol Metab. 1976 Jul;5(2):337–365. doi: 10.1016/s0300-595x(76)80025-4. [DOI] [PubMed] [Google Scholar]
  2. BUTTERFIELD W. J., HANLEY T., WHICHELOW M. J. PERIPHERAL METABOLISM OF GLUCOSE AND FREE FATTY ACIDS DURING ORAL GLUCOSE TOLERANCE TESTS. Metabolism. 1965 Aug;14:851–866. doi: 10.1016/0026-0495(65)90122-8. [DOI] [PubMed] [Google Scholar]
  3. Bar R. S., Gorden P., Roth J., Kahn C. R., De Meyts P. Fluctuations in the affinity and concentration of insulin receptors on circulating monocytes of obese patients: effects of starvation, refeeding, and dieting. J Clin Invest. 1976 Nov;58(5):1123–1135. doi: 10.1172/JCI108565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bar R. S., Harrison L. C., Muggeo M., Gorden P., Kahn C. R., Roth J. Regulation of insulin receptors in normal and abnormal physiology in humans. Adv Intern Med. 1979;24:23–52. [PubMed] [Google Scholar]
  5. Bergström J., Hultman E., Roch-Norlund A. E. Muscle glycogen synthetase in normal subjects. Basal values, effect of glycogen depletion by exercise and of a carbohydrate-rich diet following exercise. Scand J Clin Lab Invest. 1972 Apr;29(2):231–236. doi: 10.3109/00365517209081080. [DOI] [PubMed] [Google Scholar]
  6. Björntorp P., Sjöström L. Carbohydrate storage in man: speculations and some quantitative considerations. Metabolism. 1978 Dec;27(12 Suppl 2):1853–1865. doi: 10.1016/s0026-0495(78)80004-3. [DOI] [PubMed] [Google Scholar]
  7. Böyum A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl. 1968;97:77–89. [PubMed] [Google Scholar]
  8. Ciaraldi T. P., Kolterman O. G., Olefsky J. M. Mechanism of the postreceptor defect in insulin action in human obesity. Decrease in glucose transport system activity. J Clin Invest. 1981 Oct;68(4):875–880. doi: 10.1172/JCI110342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cramp D. G. New automated method for measuring glucose by glucose oxidase. J Clin Pathol. 1967 Nov;20(6):910–912. doi: 10.1136/jcp.20.6.910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Crettaz M., Jeanrenaud B. Postreceptor alterations in the states of insulin resistance. Metabolism. 1980 May;29(5):467–473. doi: 10.1016/0026-0495(80)90172-9. [DOI] [PubMed] [Google Scholar]
  11. DeFronzo R. A., Soman V., Sherwin R. S., Hendler R., Felig P. Insulin binding to monocytes and insulin action in human obesity, starvation, and refeeding. J Clin Invest. 1978 Jul;62(1):204–213. doi: 10.1172/JCI109108. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  12. DeFronzo R. A., Tobin J. D., Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979 Sep;237(3):E214–E223. doi: 10.1152/ajpendo.1979.237.3.E214. [DOI] [PubMed] [Google Scholar]
  13. Durnin J. V., Womersley J. Body fat assessed from total body density and its estimation from skinfold thickness: measurements on 481 men and women aged from 16 to 72 years. Br J Nutr. 1974 Jul;32(1):77–97. doi: 10.1079/bjn19740060. [DOI] [PubMed] [Google Scholar]
  14. Evans D. J., Hoffmann R. G., Kalkhoff R. K., Kissebah A. H. Relationship of androgenic activity to body fat topography, fat cell morphology, and metabolic aberrations in premenopausal women. J Clin Endocrinol Metab. 1983 Aug;57(2):304–310. doi: 10.1210/jcem-57-2-304. [DOI] [PubMed] [Google Scholar]
  15. Evans D. J., Hoffmann R. G., Kalkhoff R. K., Kissebah A. H. Relationship of body fat topography to insulin sensitivity and metabolic profiles in premenopausal women. Metabolism. 1984 Jan;33(1):68–75. doi: 10.1016/0026-0495(84)90164-1. [DOI] [PubMed] [Google Scholar]
  16. Felig P., Wahren J. Symposium I: hormone-fuel interactions in normal and diabetic man. The liver as site of insulin and glucagon action in normal, diabetic and obese humans. Isr J Med Sci. 1975 Jun;11(6):528–539. [PubMed] [Google Scholar]
  17. HUNTER W. M., GREENWOOD F. C. Preparation of iodine-131 labelled human growth hormone of high specific activity. Nature. 1962 May 5;194:495–496. doi: 10.1038/194495a0. [DOI] [PubMed] [Google Scholar]
  18. Harrison L. C., King-Roach A. P. Insulin sensitivity of adipose tissue in vitro and the response to exogenous insulin in obese human subjects. Metabolism. 1976 Oct;25(10):1095–1101. doi: 10.1016/0026-0495(76)90017-2. [DOI] [PubMed] [Google Scholar]
  19. Harrison L. C., Martin F. I., Melick R. A. Correlation between insulin receptor binding in isolated fat cells and insulin sensitivity in obese human subjects. J Clin Invest. 1976 Dec;58(6):1435–1441. doi: 10.1172/JCI108599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Jackson R. A., Peters N., Advani U., Perry G., Rogers J., Brough W. H., Pilkington T. R. Forearm glucose uptake during the oral glucose tolerance test in normal subjects. Diabetes. 1973 Jun;22(6):442–458. doi: 10.2337/diab.22.6.442. [DOI] [PubMed] [Google Scholar]
  21. Kissebah A. H., Vydelingum N., Murray R., Evans D. J., Hartz A. J., Kalkhoff R. K., Adams P. W. Relation of body fat distribution to metabolic complications of obesity. J Clin Endocrinol Metab. 1982 Feb;54(2):254–260. doi: 10.1210/jcem-54-2-254. [DOI] [PubMed] [Google Scholar]
  22. Kolterman O. G., Insel J., Saekow M., Olefsky J. M. Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects. J Clin Invest. 1980 Jun;65(6):1272–1284. doi: 10.1172/JCI109790. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kolterman O. G., Reaven G. M., Olefsky J. M. Relationship between in vivo insulin resistance and decreased insulin receptors in obese man. J Clin Endocrinol Metab. 1979 Mar;48(3):487–494. doi: 10.1210/jcem-48-3-487. [DOI] [PubMed] [Google Scholar]
  24. Larner J., Cheng K., Schwartz C., Kikuchi K., Tamura S., Creacy S., Dubler R., Galasko G., Pullin C., Katz M. Insulin mediators and their control of metabolism through protein phosphorylation. Recent Prog Horm Res. 1982;38:511–556. doi: 10.1016/b978-0-12-571138-8.50017-2. [DOI] [PubMed] [Google Scholar]
  25. Le Marchand-Brustel Y., Jeanrenaud B., Freychet P. Insulin binding and effects in isolated soleus muscle of lean and obese mice. Am J Physiol. 1978 Apr;234(4):E348–E358. doi: 10.1152/ajpendo.1978.234.4.E348. [DOI] [PubMed] [Google Scholar]
  26. Nagulesparan M., Savage P. J., Unger R. H., Bennett P. H. A simplified method using somatostatin to assess in vivo insulin resistance over a range of obesity. Diabetes. 1979 Nov;28(11):980–983. doi: 10.2337/diab.28.11.980. [DOI] [PubMed] [Google Scholar]
  27. Nuttall F. Q., Barbosa J., Gannon M. C. Activation of skeletal muscle glycogen synthase following glucose administration in normal males. Metabolism. 1977 Jul;26(7):719–720. doi: 10.1016/0026-0495(77)90058-0. [DOI] [PubMed] [Google Scholar]
  28. Nuttall F. Q., Barbosa J., Gannon M. C. The glycogen synthase system in skeletal muscle of normal humans and patients with myotonic dystrophy: effect of glucose and insulin administration. Metabolism. 1974 Jun;23(6):561–568. doi: 10.1016/0026-0495(74)90084-5. [DOI] [PubMed] [Google Scholar]
  29. Nuttall F. Q., Gannon M. C., Larner J. Oral glucose effect on glycogen synthetase and phosphorylase in heart. Muscle and liver. Physiol Chem Phys. 1972;4(6):497–415. [PubMed] [Google Scholar]
  30. Olefsky J. M. LIlly lecture 1980. Insulin resistance and insulin action. An in vitro and in vivo perspective. Diabetes. 1981 Feb;30(2):148–162. doi: 10.2337/diab.30.2.148. [DOI] [PubMed] [Google Scholar]
  31. Olefsky J., Reaven G. M., Farquhar J. W. Effects of weight reduction on obesity. Studies of lipid and carbohydrate metabolism in normal and hyperlipoproteinemic subjects. J Clin Invest. 1974 Jan;53(1):64–76. doi: 10.1172/JCI107560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. RABINOWITZ D., ZIERLER K. L. Forearm metabolism in obesity and its response to intra-arterial insulin. Characterization of insulin resistance and evidence for adaptive hyperinsulinism. J Clin Invest. 1962 Dec;41:2173–2181. doi: 10.1172/JCI104676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. RANDLE P. J., GARLAND P. B., HALES C. N., NEWSHOLME E. A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963 Apr 13;1(7285):785–789. doi: 10.1016/s0140-6736(63)91500-9. [DOI] [PubMed] [Google Scholar]
  34. Rabinowitz D. Some endocrine and metabolic aspects of obesity. Annu Rev Med. 1970;21:241–258. doi: 10.1146/annurev.me.21.020170.001325. [DOI] [PubMed] [Google Scholar]
  35. Roch-Norlund A. E., Bergström J., Hultman E. Muscle glycogen and glycogen synthetase in normal subjects and in patients with diabetes mellitus. Effect of intravenous glucose and insulin administration. Scand J Clin Lab Invest. 1972 Sep;30(1):77–84. doi: 10.3109/00365517209081094. [DOI] [PubMed] [Google Scholar]
  36. Salans L. B., Knittle J. L., Hirsch J. The role of adipose cell size and adipose tissue insulin sensitivity in the carbohydrate intolerance of human obesity. J Clin Invest. 1968 Jan;47(1):153–165. doi: 10.1172/JCI105705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Smith U., Hammersten J., Björntorp P., Kral J. G. Regional differences and effect of weight reduction on human fat cell metabolism. Eur J Clin Invest. 1979 Oct;9(5):327–332. doi: 10.1111/j.1365-2362.1979.tb00892.x. [DOI] [PubMed] [Google Scholar]
  38. Thomas J. A., Schlender K. K., Larner J. A rapid filter paper assay for UDPglucose-glycogen glucosyltransferase, including an improved biosynthesis of UDP-14C-glucose. Anal Biochem. 1968 Oct 24;25(1):486–499. doi: 10.1016/0003-2697(68)90127-9. [DOI] [PubMed] [Google Scholar]
  39. Udenfriend S., Stein S., Böhlen P., Dairman W., Leimgruber W., Weigele M. Fluorescamine: a reagent for assay of amino acids, peptides, proteins, and primary amines in the picomole range. Science. 1972 Nov 24;178(4063):871–872. doi: 10.1126/science.178.4063.871. [DOI] [PubMed] [Google Scholar]
  40. YALOW R. S., BERSON S. A. Immunoassay of endogenous plasma insulin in man. J Clin Invest. 1960 Jul;39:1157–1175. doi: 10.1172/JCI104130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. le Marchand-Brustel Y., Freychet P. Alteration of glycogen synthase activation by insulin in soleus muscles of obese mice. FEBS Lett. 1980 Nov 3;120(2):205–208. doi: 10.1016/0014-5793(80)80298-5. [DOI] [PubMed] [Google Scholar]

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