Abstract
To assess the possible effects of lipid metabolism on insulin-mediated glucose disposal, 18 nondiabetic Pima Indian women (age 18-35 yr) were studied using 1-14C-palmitate infusion to measure free fatty acid turnover rate followed by a euglycemic clamp (clamp) to measure in vivo insulin-mediated glucose disposal (M). Indirect calorimetry was performed in the basal state and during the clamp. This was used to assess glucose oxidation rate, lipid oxidation rate, and to calculate nonoxidative glucose disposal (storage). Basal and clamp lipid oxidation rate correlated with basal plasma free fatty acid concentration (r = 0.81, P less than or equal to 0.0001, r = 0.67, P less than 0.003, respectively). The fall in lipid oxidation was highly correlated with the increase in glucose oxidation during the insulin infusion (r = 0.96, P less than or equal to 0.0001). The clamp lipid oxidation rate negatively correlated with the glucose oxidation rate (r = -0.85, P less than 0.0001) and with the M value (r = -0.60, P less than 0.01) but was not correlated with the clamp glucose storage (r = -0.2, P = 0.4). On the other hand, glucose storage appeared to make a greater contribution to the difference in M value between the upper and lower extremes of M than did glucose oxidation, as evidenced by an increase in glucose storage of 0.59 mg/kg fat-free mass times minute per 1 mg/kg fat-free mass times minute increase in glucose disposal. The M value was negatively correlated with obesity as measured by percent body fat (r = -0.64, P less than 0.004), but neither basal free fatty acid concentration, basal free fatty acid turnover, basal lipid oxidation, nor clamp lipid oxidation correlated with percent body fat. We conclude that an interaction of lipid and glucose metabolism in a glucose fatty acid cycle, as proposed by Randle et al. (1), may be operative in the regulation of glucose oxidation in man. The disposal of glucose however has two components. The storage component does not appear to be associated with lipid oxidation in the way that the oxidative component is and may be regulated by a different mechanism. Since the results show that the glucose storage component plays a significant role in distinguishing between those with low and high M values, we suggest that the glucose fatty acid cycle can, at best, only partially explain impaired in vivo insulin-mediated glucose disposal. Furthermore, the data suggest that the impact of obesity on in vivo insulin resistance appears to be mediated by factors other than changes in lipid availability or metabolism.
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Selected References
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- Ashour B., Hansford R. G. Effect of fatty acids and ketones on the activity of pyruvate dehydrogenase in skeletal-muscle mitochondria. Biochem J. 1983 Sep 15;214(3):725–736. doi: 10.1042/bj2140725. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Balasse E. O. Effect of free fatty acids and ketone bodies on glucose uptake and oxidation in the dog. Horm Metab Res. 1971 Nov;3(6):403–409. doi: 10.1055/s-0028-1094129. [DOI] [PubMed] [Google Scholar]
- Balasse E. O., Neef M. A. Influence of nicotinic acid on the rates of turnover and oxidation of plasma glucose in man. Metabolism. 1973 Sep;22(9):1193–1204. doi: 10.1016/0026-0495(73)90207-2. [DOI] [PubMed] [Google Scholar]
- Balasse E. O., Neef M. A. Operation of the "glucose-fatty acid cycle" during experimental elevations of plasma free fatty acid levels in man. Eur J Clin Invest. 1974 Aug;4(4):247–252. doi: 10.1111/j.1365-2362.1974.tb00400.x. [DOI] [PubMed] [Google Scholar]
- Best J. D., Judzewitsch R. G., Pfeifer M. A., Beard J. C., Halter J. B., Porte D., Jr The effect of chronic sulfonylurea therapy on hepatic glucose production in non-insulin-dependent diabetes. Diabetes. 1982 Apr;31(4 Pt 1):333–338. doi: 10.2337/diab.31.4.333. [DOI] [PubMed] [Google Scholar]
- Björntorp P., Bergman H., Varnauskas E., Lindholm B. Lipid mobilization in relation to body composition in man. Metabolism. 1969 Oct;18(10):840–851. doi: 10.1016/0026-0495(69)90059-6. [DOI] [PubMed] [Google Scholar]
- Boden G., Ray T. K., Smith R. H., Owen O. E. Carbohydrate oxidation and storage in obese non-insulin-dependent diabetic patients. Effects of improving glycemic control. Diabetes. 1983 Nov;32(11):982–987. doi: 10.2337/diab.32.11.982. [DOI] [PubMed] [Google Scholar]
- Bogardus C., Thuillez P., Ravussin E., Vasquez B., Narimiga M., Azhar S. Effect of muscle glycogen depletion on in vivo insulin action in man. J Clin Invest. 1983 Nov;72(5):1605–1610. doi: 10.1172/JCI111119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- DEPOCAS F. REGULATION OF GLUCOSE OXIDATION IN THE WHITE RAT. Am J Physiol. 1964 Jan;206:113–118. doi: 10.1152/ajplegacy.1964.206.1.113. [DOI] [PubMed] [Google Scholar]
- DOLE V. P. A relation between non-esterified fatty acids in plasma and the metabolism of glucose. J Clin Invest. 1956 Feb;35(2):150–154. doi: 10.1172/JCI103259. [DOI] [PMC free article] [PubMed] [Google Scholar]
- DeFronzo R. A., Jacot E., Jequier E., Maeder E., Wahren J., Felber J. P. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes. 1981 Dec;30(12):1000–1007. doi: 10.2337/diab.30.12.1000. [DOI] [PubMed] [Google Scholar]
- 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]
- FELBER J. P., VANNOTTI A. EFFECTS OF FAT INFUSION ON GLUCOSE TOLERANCE AND INSULIN PLASMA LEVELS. Med Exp Int J Exp Med. 1964;10:153–156. doi: 10.1159/000135410. [DOI] [PubMed] [Google Scholar]
- Felber J. P., Meyer H. U., Curchod B., Iselin H. U., Rousselle J., Maeder E., Pahud P., Jéquier E. Glucose storage and oxidation in different degrees of human obesity measured by continuous indirect calorimetry. Diabetologia. 1981;20(1):39–44. doi: 10.1007/BF00253814. [DOI] [PubMed] [Google Scholar]
- Ferrannini E., Barrett E. J., Bevilacqua S., DeFronzo R. A. Effect of fatty acids on glucose production and utilization in man. J Clin Invest. 1983 Nov;72(5):1737–1747. doi: 10.1172/JCI111133. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Foss M. C., Vlachokosta F. V., Cunningham L. N., Aoki T. T. Restoration of glucose homeostasis in insulin-dependent diabetic subjects. An inducible process. Diabetes. 1982 Jan;31(1):46–52. doi: 10.2337/diab.31.1.46. [DOI] [PubMed] [Google Scholar]
- Frayn K. N. Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol Respir Environ Exerc Physiol. 1983 Aug;55(2):628–634. doi: 10.1152/jappl.1983.55.2.628. [DOI] [PubMed] [Google Scholar]
- Garland P. B., Newsholme E. A., Randle P. J. Regulation of glucose uptake by muscle. 9. Effects of fatty acids and ketone bodies, and of alloxan-diabetes and starvation, on pyruvate metabolism and on lactate-pyruvate and L-glycerol 3-phosphate-dihydroxyacetone phosphate concentration ratios in rat heart and rat diaphragm muscles. Biochem J. 1964 Dec;93(3):665–678. doi: 10.1042/bj0930665. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gómez F., Jéquier E., Chabot V., Büber V., Felber J. P. Carbohydrate and lipid oxidation in normal human subjects: its influence on glucose tolerance and insulin response to glucose. Metabolism. 1972 May;21(5):381–391. doi: 10.1016/0026-0495(72)90051-0. [DOI] [PubMed] [Google Scholar]
- HAVEL R. J., NAIMARK A., BORCHGREVINK C. F. Turnover rate and oxidation of free fatty acids of blood plasma in man during exercise: studies during continuous infusion of palmitate-1-C14. J Clin Invest. 1963 Jul;42:1054–1063. doi: 10.1172/JCI104791. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hagenfeldt L. Metabolism of free fatty acids and ketone bodies during exercise in normal and diabetic man. Diabetes. 1979 Jan;28 (Suppl 1):66–70. doi: 10.2337/diab.28.1.s66. [DOI] [PubMed] [Google Scholar]
- Hagenfeldt L., Wahren J., Pernow B., Räf L. Uptake of individual free fatty acids by skeletal muscle and liver in man. J Clin Invest. 1972 Sep;51(9):2324–2330. doi: 10.1172/JCI107043. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hagenfeldt L., Wennlung A., Felig P., Wahren J. Turnover and splanchnic metabolism of free fatty acids in hyperthyroid patients. J Clin Invest. 1981 Jun;67(6):1672–1677. doi: 10.1172/JCI110204. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Herbert V., Lau K. S., Gottlieb C. W., Bleicher S. J. Coated charcoal immunoassay of insulin. J Clin Endocrinol Metab. 1965 Oct;25(10):1375–1384. doi: 10.1210/jcem-25-10-1375. [DOI] [PubMed] [Google Scholar]
- Hers H. G., Van Schaftingen E. Fructose 2,6-bisphosphate 2 years after its discovery. Biochem J. 1982 Jul 15;206(1):1–12. doi: 10.1042/bj2060001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Howard B. V., Klimes I., Vasquez B., Brady D., Nagulesparan M., Unger R. H. The antilipolytic action of insulin in obese subjects with resistance to its glucoregulatory action. J Clin Endocrinol Metab. 1984 Mar;58(3):544–548. doi: 10.1210/jcem-58-3-544. [DOI] [PubMed] [Google Scholar]
- Howard B. V., Savage P. J., Nagulesparan M., Bennion L. J., Unger R. H., Bennett P. H. Evidence for marked sensitivity to the antilipolytic action of insulin in obese maturity-onset diabetics. Metabolism. 1979 Jul;28(7):744–750. doi: 10.1016/0026-0495(79)90180-x. [DOI] [PubMed] [Google Scholar]
- Issekutz B., Jr, Paul P., Miller H. I., Bortz W. M. Oxidation of plasma FFA in lean and obese humans. Metabolism. 1968 Jan;17(1):62–73. doi: 10.1016/s0026-0495(68)80008-3. [DOI] [PubMed] [Google Scholar]
- Jacot E., Defronzo R. A., Jéquier E., Maeder E., Felber J. P. The effect of hyperglycemia, hyperinsulinemia, and route of glucose administration on glucose oxidation and glucose storage. Metabolism. 1982 Sep;31(9):922–930. doi: 10.1016/0026-0495(82)90183-4. [DOI] [PubMed] [Google Scholar]
- KEYS A., BROZEK J. Body fat in adult man. Physiol Rev. 1953 Jul;33(3):245–325. doi: 10.1152/physrev.1953.33.3.245. [DOI] [PubMed] [Google Scholar]
- Katz L. D., Glickman M. G., Rapoport S., Ferrannini E., DeFronzo R. A. Splanchnic and peripheral disposal of oral glucose in man. Diabetes. 1983 Jul;32(7):675–679. doi: 10.2337/diab.32.7.675. [DOI] [PubMed] [Google Scholar]
- Maizels E. Z., Ruderman N. B., Goodman M. N., Lau D. Effect of acetoacetate on glucose metabolism in the soleus and extensor digitorum longus muscles of the rat. Biochem J. 1977 Mar 15;162(3):557–568. doi: 10.1042/bj1620557. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miles J. M., Haymond M. W., Nissen S. L., Gerich J. E. Effects of free fatty acid availability, glucagon excess, and insulin deficiency on ketone body production in postabsorptive man. J Clin Invest. 1983 Jun;71(6):1554–1561. doi: 10.1172/JCI110911. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mosora F., Lacroix M., Luyckx A., Pallikarakis N., Pirnay F., Krzentowski G., Lefèbvre P. Glucose oxidation in relation to the size of the oral glucose loading dose. Metabolism. 1981 Dec;30(12):1143–1149. doi: 10.1016/0026-0495(81)90033-0. [DOI] [PubMed] [Google Scholar]
- NESTEL P. J., CARROLL K. F., SILVERSTEIN M. S. INFLUENCE OF FREE-FATTY-ACID METABOLISM ON GLUCOSE TOLERANCE. Lancet. 1964 Jul 18;2(7351):115–117. doi: 10.1016/s0140-6736(64)90125-4. [DOI] [PubMed] [Google Scholar]
- Nestel P. J. Relationship between FFA flux and TGFA influx in plasma before and during the infusion of insulin. Metabolism. 1967 Dec;16(12):1123–1132. doi: 10.1016/0026-0495(67)90058-3. [DOI] [PubMed] [Google Scholar]
- Newman W. P., Brodows R. G. Insulin action during acute starvation: evidence for selective insulin resistance in normal man. Metabolism. 1983 Jun;32(6):590–596. doi: 10.1016/0026-0495(83)90029-x. [DOI] [PubMed] [Google Scholar]
- Newsholme E. A. Carbohydrate metabolism in vivo: regulation of the blood glucose level. Clin Endocrinol Metab. 1976 Nov;5(3):543–578. doi: 10.1016/s0300-595x(76)80040-0. [DOI] [PubMed] [Google Scholar]
- OPIE L. H., WALFISH P. G. Plasma free fatty acid concentrations in obesity. N Engl J Med. 1963 Apr 4;268:757–760. doi: 10.1056/NEJM196304042681404. [DOI] [PubMed] [Google Scholar]
- Owen O. E., Trapp V. E., Reichard G. A., Jr, Mozzoli M. A., Moctezuma J., Paul P., Skutches C. L., Boden G. Nature and quantity of fuels consumed in patients with alcoholic cirrhosis. J Clin Invest. 1983 Nov;72(5):1821–1832. doi: 10.1172/JCI111142. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Paul P., Issekutz B., Jr, Miller H. I. Interrelationship of free fatty acids and glucose metabolism in the dog. Am J Physiol. 1966 Dec;211(6):1313–1320. doi: 10.1152/ajplegacy.1966.211.6.1313. [DOI] [PubMed] [Google Scholar]
- Pelkonen R., Miettinen T. A., Taskinen M. R., Nikkilä E. A. Effect of acute elevation of plasma glycerol, triglyceride and FFA levels on glucose utilization and plasma insulin. Diabetes. 1968 Feb;17(2):76–82. doi: 10.2337/diab.17.2.76. [DOI] [PubMed] [Google Scholar]
- 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]
- Randle P. J., Garland P. B., Hales C. N., Newsholme E. A., Denton R. M., Pogson C. I. Interactions of metabolism and the physiological role of insulin. Recent Prog Horm Res. 1966;22:1–48. doi: 10.1016/b978-1-4831-9825-5.50004-x. [DOI] [PubMed] [Google Scholar]
- Randle P. J., Sugden P. H., Kerbey A. L., Radcliffe P. M., Hutson N. J. Regulation of pyruvate oxidation and the conservation of glucose. Biochem Soc Symp. 1978;(43):47–67. [PubMed] [Google Scholar]
- Rennie M. J., Holloszy J. O. Inhibition of glucose uptake and glycogenolysis by availability of oleate in well-oxygenated perfused skeletal muscle. Biochem J. 1977 Nov 15;168(2):161–170. doi: 10.1042/bj1680161. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Robinson A. M., Williamson D. H. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev. 1980 Jan;60(1):143–187. doi: 10.1152/physrev.1980.60.1.143. [DOI] [PubMed] [Google Scholar]
- Rousselle J., Bückert A., Pahud P., Jéquier E., Felber J. P. Relationship between glucose oxidation and glucose tolerance in man. Metabolism. 1982 Sep;31(9):866–870. doi: 10.1016/0026-0495(82)90174-3. [DOI] [PubMed] [Google Scholar]
- Ruderman N. B., Toews C. J., Shafrir E. Role of free fatty acids in glucose homeostasis. Arch Intern Med. 1969 Mar;123(3):299–313. [PubMed] [Google Scholar]
- STEELE R. Influences of glucose loading and of injected insulin on hepatic glucose output. Ann N Y Acad Sci. 1959 Sep 25;82:420–430. doi: 10.1111/j.1749-6632.1959.tb44923.x. [DOI] [PubMed] [Google Scholar]
- Schalch D. S., Kipnis D. M. Abnormalities in carbohydrate tolerance associated with elevated plasma nonesterified fatty acids. J Clin Invest. 1965 Dec;44(12):2010–2020. doi: 10.1172/JCI105308. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shulman G. I., Williams P. E., Liljenquist J. E., Lacy W. W., Keller U., Cherrington A. D. Effect of hyperglycemia independent of changes in insulin or glucagon on lipolysis in the conscious dog. Metabolism. 1980 Apr;29(4):317–320. doi: 10.1016/0026-0495(80)90004-9. [DOI] [PubMed] [Google Scholar]
- Soloni F. G., Sardina L. C. Colorimetric microdetermination of free fatty acids. Clin Chem. 1973 Apr;19(4):419–424. [PubMed] [Google Scholar]
- TROUT D. L., ESTES E. H., Jr, FRIEDBERG S. J. Titration of free fatty acids of plasma: a study of current methods and a new modification. J Lipid Res. 1960 Apr;1:199–202. [PubMed] [Google Scholar]
- Thiebaud D., Jacot E., DeFronzo R. A., Maeder E., Jequier E., Felber J. P. The effect of graded doses of insulin on total glucose uptake, glucose oxidation, and glucose storage in man. Diabetes. 1982 Nov;31(11):957–963. doi: 10.2337/diacare.31.11.957. [DOI] [PubMed] [Google Scholar]
- Thiébaud D., DeFronzo R. A., Jacot E., Golay A., Acheson K., Maeder E., Jéquier E., Felber J. P. Effect of long chain triglyceride infusion on glucose metabolism in man. Metabolism. 1982 Nov;31(11):1128–1136. doi: 10.1016/0026-0495(82)90163-9. [DOI] [PubMed] [Google Scholar]
- Verdonk C. A., Rizza R. A., Gerich J. E. Effects of plasma glucose concentration on glucose utilization and glucose clearance in normal man. Diabetes. 1981 Jun;30(6):535–537. doi: 10.2337/diab.30.6.535. [DOI] [PubMed] [Google Scholar]
- Wolfe R. R., Allsop J. R., Burke J. F. Glucose metabolism in man: responses to intravenous glucose infusion. Metabolism. 1979 Mar;28(3):210–220. doi: 10.1016/0026-0495(79)90066-0. [DOI] [PubMed] [Google Scholar]
- 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]
- ZIERLER K. L., RABINOWITZ D. EFFECT OF VERY SMALL CONCENTRATIONS OF INSULIN ON FOREARM METABOLISM. PERSISTENCE OF ITS ACTION ON POTASSIUM AND FREE FATTY ACIDS WITHOUT ITS EFFECT ON GLUCOSE. J Clin Invest. 1964 May;43:950–962. doi: 10.1172/JCI104981. [DOI] [PMC free article] [PubMed] [Google Scholar]