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J Clin Invest. 1996 November 1; 98(9): 2008–2017.
PMCID: PMC507644

Contributions of de novo synthesis of fatty acids to total VLDL-triglyceride secretion during prolonged hyperglycemia/hyperinsulinemia in normal man.


Triglycerides (TG) are synthesized in the liver principally from two sources of fatty acids (FA): FA synthesized de novo in the liver and preformed FA. We have measured the rate of secretion of de novo synthesized FA and total secretion of FA bound to VLDL-TG in healthy men (n = 5) in the basal state, and after 1 (day 1) and 4 d (day 4) of a hypercaloric carbohydrate diet (approximately 2.5 times energy expenditure) that generated a moderate endogenous hyperinsulinemia (plasma insulin approximately 60 microU/ml). Prolonged carbohydrate hyperalimentation/hyperinsulinemia increased plasma VLDL-TG approximately 10-fold in part due to a 3.4-fold increase in total VLDL-TG secretion rate (basal state = 72+/-23, day 4 = 242+/-78 micromol TG/kg/d). Although the secretion of de novo synthesized FA increased throughout the study (basal state = 1.1+/-0.4, day 1 = 15.9+/-7.9, day 4 = 50.0+/-18.8 micromol TG/ kg/d), the 2.7-fold increase in secretion rate of preformed FA (basal state = 70+/-23, day 4 = 191+/-57 micromol TG/kg/d) quantitatively contributed the most to total VLDL-TG secretion rate. Decreased catabolism of VLDL-TG also contributed to the hypertriglyceridemia as reflected by an approximately fourfold decrease in both fractional turnover rate (basal state = 9.2+/-3.8, day 1 = 2.1+/-0.2, day 4 = 2.1+/-0.3 pools/d) and rate of clearance (basal state = 0.35+/-0.08, day 1 = 0.11+/-0.01, day 4 = 0.09+/-0.01 liter/kg/d) of VLDL-TG. Thus, the primary difference between 1 and 4 d of hyperinsulinemia in conjunction with carbohydrate hyperalimentation is the increase in hepatic secretion of preformed FA into VLDL-TG.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Steiner G. Hyperinsulinemia and VLDL kinetics. Adv Exp Med Biol. 1993;334:287–294. [PubMed]
  • Howard BV. Lipoprotein metabolism in diabetes mellitus. J Lipid Res. 1987 Jun;28(6):613–628. [PubMed]
  • Steiner G. Diabetes and atherosclerosis: an overview. Diabetes. 1981;30(Suppl 2):1–7. [PubMed]
  • Taskinen MR. Hyperinsulinism and dyslipidemias as coronary heart disease risk factors in NIDDM. Adv Exp Med Biol. 1993;334:295–301. [PubMed]
  • Carlson LA, Böttiger LE, Ahfeldt PE. Risk factors for myocardial infarction in the Stockholm prospective study. A 14-year follow-up focussing on the role of plasma triglycerides and cholesterol. Acta Med Scand. 1979;206(5):351–360. [PubMed]
  • Castelli WP. The triglyceride issue: a view from Framingham. Am Heart J. 1986 Aug;112(2):432–437. [PubMed]
  • Reaven GM, Chen YD. Role of insulin in regulation of lipoprotein metabolism in diabetes. Diabetes Metab Rev. 1988 Nov;4(7):639–652. [PubMed]
  • Taskinen MR. Lipoprotein lipase in diabetes. Diabetes Metab Rev. 1987 Apr;3(2):551–570. [PubMed]
  • Berthezene F. Hypertriglyceridemia: cause or consequence of insulin resistance? Horm Res. 1992;38(1-2):39–40. [PubMed]
  • Gibbons GF. Insulin, diabetes and hepatic very-low-density lipoprotein metabolism. Biochem Soc Trans. 1989 Feb;17(1):49–51. [PubMed]
  • Woodside WF, Heimberg M. Effects of anti-insulin serum, insulin, and glucose on output of triglycerides and on ketogenesis by the perfused rat liver. J Biol Chem. 1976 Jan 10;251(1):13–23. [PubMed]
  • Shumak SL, Zinman B, Zuniga-Guarjardo S, Poapst M, Steiner G. Triglyceride-rich lipoprotein metabolism during acute hyperinsulinemia in hypertriglyceridemic humans. Metabolism. 1988 May;37(5):461–466. [PubMed]
  • Havel RJ, Kane JP, Balasse EO, Segel N, Basso LV. Splanchnic metabolism of free fatty acids and production of triglycerides of very low density lipoproteins in normotriglyceridemic and hypertriglyceridemic humans. J Clin Invest. 1970 Nov;49(11):2017–2035. [PMC free article] [PubMed]
  • Coppack SW, Jensen MD, Miles JM. In vivo regulation of lipolysis in humans. J Lipid Res. 1994 Feb;35(2):177–193. [PubMed]
  • Lewis GF, Uffelman KD, Szeto LW, Weller B, Steiner G. Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans. J Clin Invest. 1995 Jan;95(1):158–166. [PMC free article] [PubMed]
  • Kazumi T, Vranic M, Steiner G. Triglyceride kinetics: effects of dietary glucose, sucrose, or fructose alone or with hyperinsulinemia. Am J Physiol. 1986 Mar;250(3 Pt 1):E325–E330. [PubMed]
  • Hellerstein MK, Christiansen M, Kaempfer S, Kletke C, Wu K, Reid JS, Mulligan K, Hellerstein NS, Shackleton CH. Measurement of de novo hepatic lipogenesis in humans using stable isotopes. J Clin Invest. 1991 May;87(5):1841–1852. [PMC free article] [PubMed]
  • Wolfe RR, Shaw JH, Durkot MJ. Effect of sepsis on VLDL kinetics: responses in basal state and during glucose infusion. Am J Physiol. 1985 Jun;248(6 Pt 1):E732–E740. [PubMed]
  • Hellerstein MK, Neese RA. Mass isotopomer distribution analysis: a technique for measuring biosynthesis and turnover of polymers. Am J Physiol. 1992 Nov;263(5 Pt 1):E988–1001. [PubMed]
  • Kelleher JK, Masterson TM. Model equations for condensation biosynthesis using stable isotopes and radioisotopes. Am J Physiol. 1992 Jan;262(1 Pt 1):E118–E125. [PubMed]
  • Lee WN, Bassilian S, Guo Z, Schoeller D, Edmond J, Bergner EA, Byerley LO. Measurement of fractional lipid synthesis using deuterated water (2H2O) and mass isotopomer analysis. Am J Physiol. 1994 Mar;266(3 Pt 1):E372–E383. [PubMed]
  • Wolfe RR, O'Donnell TF, Jr, Stone MD, Richmand DA, Burke JF. Investigation of factors determining the optimal glucose infusion rate in total parenteral nutrition. Metabolism. 1980 Sep;29(9):892–900. [PubMed]
  • Wolfe RR, Allsop JR, Burke JF. Glucose metabolism in man: responses to intravenous glucose infusion. Metabolism. 1979 Mar;28(3):210–220. [PubMed]
  • Grundy SM, Mok HY, Zech L, Steinberg D, Berman M. Transport of very low density lipoprotein triglycerides in varying degrees of obesity and hypertriglyceridemia. J Clin Invest. 1979 Jun;63(6):1274–1283. [PMC free article] [PubMed]
  • McGuire EA, Helderman JH, Tobin JD, Andres R, Berman M. Effects of arterial versus venous sampling on analysis of glucose kinetics in man. J Appl Physiol. 1976 Oct;41(4):565–573. [PubMed]
  • HAVEL RJ, EDER HA, BRAGDON JH. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest. 1955 Sep;34(9):1345–1353. [PMC free article] [PubMed]
  • McGowan MW, Artiss JD, Strandbergh DR, Zak B. A peroxidase-coupled method for the colorimetric determination of serum triglycerides. Clin Chem. 1983 Mar;29(3):538–542. [PubMed]
  • Wolfe RR, Peters EJ. Lipolytic response to glucose infusion in human subjects. Am J Physiol. 1987 Feb;252(2 Pt 1):E218–E223. [PubMed]
  • Newsholme EA, Taylor K. Glycerol kinase activities in muscles from vertebrates and invertebrates. Biochem J. 1969 May;112(4):465–474. [PubMed]
  • Wasserman DH, Lacy DB, Goldstein RE, Williams PE, Cherrington AD. Exercise-induced fall in insulin and increase in fat metabolism during prolonged muscular work. Diabetes. 1989 Apr;38(4):484–490. [PubMed]
  • Hellerstein MK, Kletke C, Kaempfer S, Wu K, Shackleton CH. Use of mass isotopomer distributions in secreted lipids to sample lipogenic acetyl-CoA pool in vivo in humans. Am J Physiol. 1991 Oct;261(4 Pt 1):E479–E486. [PubMed]
  • Chinkes DL, Aarsland A, Rosenblatt J, Wolfe RR. Comparison of mass isotopomer dilution methods used to compute VLDL production in vivo. Am J Physiol. 1996 Aug;271(2 Pt 1):E373–E383. [PubMed]
  • Foster DM, Barrett PH, Toffolo G, Beltz WF, Cobelli C. Estimating the fractional synthetic rate of plasma apolipoproteins and lipids from stable isotope data. J Lipid Res. 1993 Dec;34(12):2193–2205. [PubMed]
  • Dagher FJ, Lyons JH, Finlayson DC, Shamsai J, Moore FD. Blood volume measurement: a critical study prediction of normal values: controlled measurement of sequential changes: choice of a bedside method. Adv Surg. 1965;1:69–109. [PubMed]
  • Ajie HO, Connor MJ, Lee WN, Bassilian S, Bergner EA, Byerley LO. In vivo study of the biosynthesis of long-chain fatty acids using deuterated water. Am J Physiol. 1995 Aug;269(2 Pt 1):E247–E252. [PubMed]
  • Gibbons GF, Wiggins D. Intracellular triacylglycerol lipase: its role in the assembly of hepatic very-low-density lipoprotein (VLDL). Adv Enzyme Regul. 1995;35:179–198. [PubMed]
  • Steiner G, Reardon MF. A new model of human VLDL metabolism based on simultaneous studies of its APOB and triglyceride. Metabolism. 1983 Apr;32(4):342–347. [PubMed]
  • Grundy SM, Mok HY, Zech L, Berman M. Influence of nicotinic acid on metabolism of cholesterol and triglycerides in man. J Lipid Res. 1981 Jan;22(1):24–36. [PubMed]
  • Kissebah AH, Alfarsi S, Evans DJ, Adams PW. Integrated regulation of very low density lipoprotein triglyceride and apolipoprotein-B kinetics in non-insulin-dependent diabetes mellitus. Diabetes. 1982 Mar;31(3):217–225. [PubMed]
  • Boberg J, Carlson LA, Freyschuss U. Determination of splanchnic secretion rate of plasma triglycerides and of total and splanchnic turnover of plasma free fatty acids in man. Eur J Clin Invest. 1972 Mar;2(3):123–132. [PubMed]
  • Kissebah AH, Alfarsi S, Adams PW. Integrated regulation of very low density lipoprotein triglyceride and apolipoprotein-B kinetics in man: normolipemic subjects, familial hypertriglyceridemia and familial combined hyperlipidemia. Metabolism. 1981 Sep;30(9):856–868. [PubMed]
  • Harris WS, Connor WE, Illingworth DR, Rothrock DW, Foster DM. Effects of fish oil on VLDL triglyceride kinetics in humans. J Lipid Res. 1990 Sep;31(9):1549–1558. [PubMed]
  • Cryer PE. Glucose counterregulation: prevention and correction of hypoglycemia in humans. Am J Physiol. 1993 Feb;264(2 Pt 1):E149–E155. [PubMed]
  • Radziuk J, Inculet R. The effects of ingested and intravenous glucose on forearm uptake of glucose and glucogenic substrate in normal man. Diabetes. 1983 Nov;32(11):977–981. [PubMed]
  • DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988 Jun;37(6):667–687. [PubMed]
  • Taskinen MR, Packard CJ, Shepherd J. Effect of insulin therapy on metabolic fate of apolipoprotein B-containing lipoproteins in NIDDM. Diabetes. 1990 Sep;39(9):1017–1027. [PubMed]
  • Durrington PN, Newton RS, Weinstein DB, Steinberg D. Effects of insulin and glucose on very low density lipoprotein triglyceride secretion by cultured rat hepatocytes. J Clin Invest. 1982 Jul;70(1):63–73. [PMC free article] [PubMed]
  • Vogelberg KH, Gries FA, Moschinski D. Hepatic production of VLDL-triglycerides. Dependence of portal substrate and insulin concentration. Horm Metab Res. 1980 Dec;12(12):688–694. [PubMed]
  • Lewis GF, Uffelman KD, Szeto LW, Steiner G. Effects of acute hyperinsulinemia on VLDL triglyceride and VLDL apoB production in normal weight and obese individuals. Diabetes. 1993 Jun;42(6):833–842. [PubMed]
  • Duerden JM, Bartlett SM, Gibbons GF. Long-term maintenance of high rates of very-low-density-lipoprotein secretion in hepatocyte cultures. A model for studying the direct effects of insulin and insulin deficiency in vitro. Biochem J. 1989 Nov 1;263(3):937–943. [PubMed]
  • Reaven GM. Role of insulin resistance in human disease (syndrome X): an expanded definition. Annu Rev Med. 1993;44:121–131. [PubMed]
  • Fukuda N, Ontko JA. Interactions between fatty acid synthesis, oxidation, and esterification in the production of triglyceride-rich lipoproteins by the liver. J Lipid Res. 1984 Aug;25(8):831–842. [PubMed]
  • Gibbons GF, Burnham FJ. Effect of nutritional state on the utilization of fatty acids for hepatitic triacylglycerol synthesis and secretion as very-low-density lipoprotein. Biochem J. 1991 Apr 1;275(Pt 1):87–92. [PubMed]
  • Baba H, Zhang XJ, Kunkel K, Wolfe RR. Effect of hepatectomy on glucose metabolism in the dog. Metabolism. 1994 Jun;43(6):670–676. [PubMed]

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