This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 25/8/1697    most recent 01.ATV.0000172689.53992.25v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Adiels, M. Articles by Taskinen, M.-R. Search for Related Content PubMed PubMed Citation Articles by Adiels, M. Articles by Taskinen, M.-R.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1697.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Overproduction of VLDL₁ Driven by Hyperglycemia Is a Dominant Feature of Diabetic Dyslipidemia

Martin Adiels; Jan Borén; Muriel J. Caslake; Philip Stewart; Aino Soro; Jukka Westerbacka; Bernt Wennberg; Sven-Olof Olofsson; Chris Packard; Marja-Riitta Taskinen

From the Department of Mathematical Sciences (M.A., B.W.), Chalmers University of Technology, Göteborg, Sweden; the Wallenberg Laboratory (M.A., J.B., S.-O.O.), Göteborg University, Sweden; the Department of Pathological Biochemistry (A.S., J.W., M.-R.T.), Glasgow Royal Infirmary, Scotland; and the Division of Cardiology (M.J.C., P.S., C.P.), Helsinki University Central Hospital, Biomedicum, Finland.

Correspondence to Jan Borén, MD, PhD, Wallenberg Laboratory, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. E-mail Jan.Boren{at}wlab.gu.se

Objective— We sought to compare the synthesis and metabolism of VLDL₁ and VLDL₂ in patients with type 2 diabetes mellitus (DM2) and nondiabetic subjects.

Methods and Results— We used a novel multicompartmental model to simultaneously determine the kinetics of apolipoprotein (apo) B and triglyceride (TG) in VLDL₁ and VLDL₂ after a bolus injection of [²H₃]leucine and [²H₅]glycerol and to follow the catabolism and transfer of the lipoprotein particles. Our results show that the overproduction of VLDL particles in DM2 is explained by enhanced secretion of VLDL₁ apoB and TG. Direct production of VLDL₂ apoB and TG was not influenced by diabetes per se. The production rates of VLDL₁ apoB and TG were closely related, as were the corresponding pool sizes. VLDL₁ and VLDL₂ compositions did not differ in subjects with DM2 and controls, and the TG to apoB ratio of newly synthesized particles was very similar in the 2 groups. Plasma glucose, insulin, and free fatty acids together explained 55% of the variation in VLDL₁ TG production rate.

Conclusion— Insulin resistance and DM2 are associated with excess hepatic production of VLDL₁ particles similar in size and composition to those in nondiabetic subjects. We propose that hyperglycemia is the driving force that aggravates overproduction of VLDL₁ in DM2.

Analysis of the synthesis and metabolism of VLDL₁ and VLDL₂ in patients with type 2 diabetes and healthy controls revealed that type 2 diabetes and insulin resistance are associated with excess hepatic production of VLDL₁ particles similar in size and composition to those of nondiabetic subjects.

Key Words: diabetes • dyslipidemia • VLDL • apolipoprotein B • triglycerides • compartmental modeling • kinetics • stable isotope

This article has been cited by other articles:

				E. T. Parlevliet, J. P. S.-v. d. Elst, E. P. M. Corssmit, K. Picha, K. O'Neil, V. Stojanovic-Susulic, T. Ort, L. M. Havekes, J. A. Romijn, and H. Pijl CNTO736, a Novel Glucagon-Like Peptide-1 Receptor Agonist, Ameliorates Insulin Resistance and Inhibits Very Low-Density Lipoprotein Production in High-Fat-Fed Mice J. Pharmacol. Exp. Ther., January 1, 2009; 328(1): 240 - 248. [Abstract] [Full Text] [PDF]

				D. C. Chan, G. F. Watts, E. M.M. Ooi, J. Ji, A. G. Johnson, and P. H. R. Barrett Atorvastatin and Fenofibrate Have Comparable Effects on VLDL-Apolipoprotein C-III Kinetics in Men With the Metabolic Syndrome Arterioscler. Thromb. Vasc. Biol., October 1, 2008; 28(10): 1831 - 1837. [Abstract] [Full Text] [PDF]

				R. J. Brown and D. J. Rader When HDL Gets Fat ... Circ. Res., July 18, 2008; 103(2): 131 - 132. [Full Text] [PDF]

				M. Adiels, S.-O. Olofsson, M.-R. Taskinen, and J. Boren Overproduction of Very Low-Density Lipoproteins Is the Hallmark of the Dyslipidemia in the Metabolic Syndrome Arterioscler. Thromb. Vasc. Biol., July 1, 2008; 28(7): 1225 - 1236. [Abstract] [Full Text] [PDF]

				J. M. Stafford, F. Yu, R. Printz, A. H. Hasty, L. L. Swift, and K. D. Niswender Central Nervous System Neuropeptide Y Signaling Modulates VLDL Triglyceride Secretion Diabetes, June 1, 2008; 57(6): 1482 - 1490. [Abstract] [Full Text] [PDF]

				B. Qin, R. A. Anderson, and K. Adeli Tumor necrosis factor-{alpha} directly stimulates the overproduction of hepatic apolipoprotein B100-containing VLDL via impairment of hepatic insulin signaling Am J Physiol Gastrointest Liver Physiol, May 1, 2008; 294(5): G1120 - G1129. [Abstract] [Full Text] [PDF]

				J.-M. Chardigny, F. Destaillats, C. Malpuech-Brugere, J. Moulin, D. E Bauman, A. L Lock, D. M Barbano, R. P Mensink, J.-B. Bezelgues, P. Chaumont, et al. Do trans fatty acids from industrially produced sources and from natural sources have the same effect on cardiovascular disease risk factors in healthy subjects? Results of the trans Fatty Acids Collaboration (TRANSFACT) study Am. J. Clinical Nutrition, March 1, 2008; 87(3): 558 - 566. [Abstract] [Full Text] [PDF]

				I. A. R. Al-Shayji, J. M. R. Gill, J. Cooney, S. Siddiqui, and M. J. Caslake Development of a novel method to determine very low density lipoprotein kinetics J. Lipid Res., September 1, 2007; 48(9): 2086 - 2095. [Abstract] [Full Text] [PDF]

				N. Matikainen, S. Manttari, J. Westerbacka, S. Vehkavaara, N. Lundbom, H. Yki-Jarvinen, and M.-R. Taskinen Postprandial Lipemia Associates with Liver Fat Content J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 3052 - 3059. [Abstract] [Full Text] [PDF]

				F. Magkos, B. W. Patterson, B. S. Mohammed, S. Klein, and B. Mittendorfer Women Produce Fewer but Triglyceride-Richer Very Low-Density Lipoproteins than Men J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1311 - 1318. [Abstract] [Full Text] [PDF]

				Y.-L. Zhang, A. Hernandez-Ono, P. Siri, S. Weisberg, D. Conlon, M. J. Graham, R. M. Crooke, L.-S. Huang, and H. N. Ginsberg Aberrant Hepatic Expression of PPAR{gamma}2 Stimulates Hepatic Lipogenesis in a Mouse Model of Obesity, Insulin Resistance, Dyslipidemia, and Hepatic Steatosis J. Biol. Chem., December 8, 2006; 281(49): 37603 - 37615. [Abstract] [Full Text] [PDF]

				R. Ramakrishnan Studying apolipoprotein turnover with stable isotope tracers: correct analysis is by modeling enrichments J. Lipid Res., December 1, 2006; 47(12): 2738 - 2753. [Abstract] [Full Text] [PDF]

				K. G. Parhofer and P. H. R. Barrett Thematic review series: Patient-Oriented Research. What we have learned about VLDL and LDL metabolism from human kinetics studies J. Lipid Res., August 1, 2006; 47(8): 1620 - 1630. [Abstract] [Full Text] [PDF]

				D. C. Chan, G. F. Watts, M. N. Nguyen, and P. H. R. Barrett Apolipoproteins C-III and A-V as Predictors of Very-Low-Density Lipoprotein Triglyceride and Apolipoprotein B-100 Kinetics Arterioscler. Thromb. Vasc. Biol., March 1, 2006; 26(3): 590 - 596. [Abstract] [Full Text] [PDF]

				H. N. Ginsberg REVIEW: Efficacy and Mechanisms of Action of Statins in the Treatment of Diabetic Dyslipidemia J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 383 - 392. [Abstract] [Full Text] [PDF]

				T. Pulinilkunnil and B. Rodrigues Cardiac lipoprotein lipase: Metabolic basis for diabetic heart disease Cardiovasc Res, February 1, 2006; 69(2): 329 - 340. [Abstract] [Full Text] [PDF]

				M. Myerson, C. Ngai, J. Jones, S. Holleran, R. Ramakrishnan, L. Berglund, and H. N. Ginsberg Treatment with high-dose simvastatin reduces secretion of apolipoprotein B-lipoproteins in patients with diabetic dyslipidemia J. Lipid Res., December 1, 2005; 46(12): 2735 - 2744. [Abstract] [Full Text] [PDF]