Top

Published in:

01-11-2007 | Article

Acute suppression of VLDL₁ secretion rate by insulin is associated with hepatic fat content and insulin resistance

Authors: M. Adiels, J. Westerbacka, A. Soro-Paavonen, A. M. Häkkinen, S. Vehkavaara, M. J. Caslake, C. Packard, S. O. Olofsson, H. Yki-Järvinen, M. R. Taskinen, J. Borén

Published in: Diabetologia | Issue 11/2007

Abstract

Aims/hypothesis

Overproduction of VLDL₁ seems to be the central pathophysiological feature of the dyslipidaemia associated with type 2 diabetes. We explored the relationship between liver fat and suppression of VLDL₁ production by insulin in participants with a broad range of liver fat content.

Methods

A multicompartmental model was used to determine the kinetic parameters of apolipoprotein B and TG in VLDL₁ and VLDL₂ after a bolus of [²H₃]leucine and [²H₅]glycerol during a hyperinsulinaemic–euglycaemic clamp in 20 male participants: eight with type 2 diabetes and 12 control volunteers. The participants were divided into two groups with low or high liver fat. All participants with diabetes were in the high liver-fat group.

Results

The results showed a rapid drop in VLDL₁-apolipoprotein B and -triacylglycerol secretion in participants with low liver fat during the insulin infusion. In contrast, participants with high liver fat showed no significant change in VLDL₁ secretion. The VLDL₁ suppression following insulin infusion correlated with the suppression of NEFA, and the ability of insulin to suppress the plasma NEFA was impaired in participants with high liver fat. A novel finding was an inverse response between VLDL₁ and VLDL₂ secretion in participants with low liver fat: VLDL₁ secretion decreased acutely after insulin infusion whereas VLDL₂ secretion increased.

Conclusions/interpretation

Insulin downregulates VLDL₁ secretion and increases VLDL₂ secretion in participants with low liver fat but fails to suppress VLDL₁ secretion in participants with high liver fat, resulting in overproduction of VLDL₁. Thus, liver fat is associated with lack of VLDL₁ suppression in response to insulin.

Available only for authorised users

Taskinen MR (2003) Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia 46:733–749PubMedCrossRef

Zimmet P, Alberti KG, Shaw J (2001) Global and societal implications of the diabetes epidemic. Nature 414:782–787PubMed

Olofsson SO, Boren J (2005) Apolipoprotein B: a clinically important apolipoprotein which assembles atherogenic lipoproteins and promotes the development of atherosclerosis. J Intern Med 258:395–410PubMedCrossRef

Alexander CA, Hamilton RL, Havel RJ (1976) Subcellular localization of B apoprotein of plasma lipoproteins in rat liver. J Cell Biol 69:241–263PubMedCrossRef

Stillemark P, Boren J, Andersson M et al (2000) The assembly and secretion of apolipoprotein B-48-containing very low density lipoproteins in McA-RH7777 cells. J Biol Chem 275:10506–10513PubMedCrossRef

Adiels M, Taskinen MR, Packard C et al (2006) Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia 49:755–765PubMedCrossRef

Seppala-Lindroos A, Vehkavaara S, Hakkinen AM et al (2002) Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 87:3023–3028PubMedCrossRef

Kelley DE, McKolanis TM, Hegazi RA, Kuller LH, Kalhan SC (2003) Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metab 285:E906–E916PubMedCrossRef

Ryysy L, Hakkinen AM, Goto T et al (2000) Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 49:749–758PubMedCrossRef

10.

Bugianesi E, Gastaldelli A, Vanni E et al (2005) Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia 48:634–642PubMedCrossRef

11.

Targher G, Bertolini L, Poli F et al (2005) Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes 54:3541–3546PubMedCrossRef

12.

Malmstrom R, Packard CJ, Watson TD et al (1997) Metabolic basis of hypotriglyceridemic effects of insulin in normal men. Arterioscler Thromb Vasc Biol 17:1454–1464PubMedCrossRef

13.

Malmstrom R, Packard CJ, Caslake M et al (1999) Effect of heparin-stimulated plasma lipolytic activity on VLDL APO B subclass metabolism in normal subjects. Atherosclerosis 146:381–390PubMedCrossRef

14.

Malmstrom R, Packard CJ, Caslake M et al (1998) Effects of insulin and acipimox on VLDL1 and VLDL2 apolipoprotein B production in normal subjects [published erratum appears in Diabetes 1998, 47:1532]. Diabetes 47:779–787PubMedCrossRef

15.

Lewis GF, Carpentier A, Adeli K, Giacca A (2002) Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 23:201–229PubMedCrossRef

16.

Report of a WHO consultation (1999) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1 Diagnosis and classification of diabetes mellitus. World Health Organization, Department of Noncommunicable Disease Surveillance, Geneva

17.

Adiels M, Boren J, Caslake MJ et al (2005) Overproduction of VLDL1 driven by hyperglycemia is a dominant feature of diabetic dyslipidemia. Arterioscler Thromb Vasc Biol 25:1697–1703PubMedCrossRef

18.

DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214–E223PubMed

19.

Adiels M, Packard C, Caslake MJ et al (2005) A new combined multicompartmental model for apolipoprotein B-100 and triglyceride metabolism in VLDL subfractions. J Lipid Res 46:58–67PubMedCrossRef

20.

Szczepaniak LS, Nurenberg P, Leonard D et al (2005) Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 288:E462–E468PubMedCrossRef

21.

Thomsen C, Becker U, Winkler K, Christoffersen P, Jensen M, Henriksen O (1994) Quantification of liver fat using magnetic resonance spectroscopy. Magn Reson Imaging 12:487–495PubMedCrossRef

22.

Hoyumpa AM Jr, Greene HL, Dunn GD, Schenker S (1975) Fatty liver: biochemical and clinical considerations. Am J Dig Dis 20:1142–1170PubMedCrossRef

23.

Adiels M, Taskinen MR, Packard C et al (2006) Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia 49:755–765PubMedCrossRef

24.

Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ (2005) Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 115:1343–1351PubMedPubMedCentralCrossRef

25.

Adeli K, Taghibiglou C, Van Iderstine SC, Lewis GF (2001) Mechanisms of hepatic very low-density lipoprotein overproduction in insulin resistance. Trends Cardiovasc Med 11:170–176PubMedCrossRef

26.

Lewis GF (1997) Fatty acid regulation of very low density lipoprotein production. Curr Opin Lipidol 8:146–153PubMedCrossRef

27.

Lewis GF, Uffelman KD, Szeto LW, Weller B, Steiner G (1995) Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans. J Clin Invest 95:158–166PubMedPubMedCentralCrossRef

28.

Carpentier A, Taghibiglou C, Leung N et al (2002) Ameliorated hepatic insulin resistance is associated with normalization of microsomal triglyceride transfer protein expression and reduction in very low density lipoprotein assembly and secretion in the fructose-fed hamster. J Biol Chem 277:28795–28802PubMedCrossRef

29.

Au WS, Kung HF, Lin MC (2003) Regulation of microsomal triglyceride transfer protein gene by insulin in HepG2 cells: roles of MAPKerk and MAPKp38. Diabetes 52:1073–1080PubMedCrossRef

30.

Phung TL, Roncone A, Jensen KL, Sparks CE, Sparks JD (1997) Phosphoinositide 3-kinase activity is necessary for insulin-dependent inhibition of apolipoprotein B secretion by rat hepatocytes and localizes to the endoplasmic reticulum. J Biol Chem 272:30693–30702PubMedCrossRef

31.

Brown AM, Gibbons GF (2001) Insulin inhibits the maturation phase of VLDL assembly via a phosphoinositide 3-kinase-mediated event. Arterioscler Thromb Vasc Biol 21:1656–1661PubMedCrossRef

32.

Andersson L, Bostrom P, Ericson J et al (2006) PLD1 and ERK2 regulate cytosolic lipid droplet formation. J Cell Sci 119:2246–2257PubMedCrossRef

33.

Magnusson B, Asp L, Bostrom P et al (2006) Adipocyte differentiation-related protein promotes fatty acid storage in cytosolic triglycerides and inhibits secretion of very low-density lipoproteins. Arterioscler Thromb Vasc Biol 26:1566–1571PubMedCrossRef

34.

Utzschneider KM, Kahn SE (2006) Review: the role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab 91:4753–4761PubMedCrossRef

35.

Bajaj M, Suraamornkul S, Piper P et al (2004) Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazone-treated type 2 diabetic patients. J Clin Endocrinol Metab 89:200–206PubMedCrossRef

36.

Gaemers IC, Groen AK (2006) New insights in the pathogenesis of non-alcoholic fatty liver disease. Curr Opin Lipidol 17:268–273PubMedCrossRef

37.

Westerbacka J, Lammi K, Hakkinen AM et al (2005) Dietary fat content modifies liver fat in overweight nondiabetic subjects. J Clin Endocrinol Metab 90:2804–2809PubMedCrossRef

38.

Kabir M, Catalano KJ, Ananthnarayan S et al (2005) Molecular evidence supporting the portal theory: a causative link between visceral adiposity and hepatic insulin resistance. Am J Physiol Endocrinol Metab 288:E454–E461PubMedCrossRef

39.

Samuel VT, Liu ZX, Qu X et al (2004) Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 279:32345–32353PubMedCrossRef

40.

Boden G, She P, Mozzoli M et al (2005) Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-{kappa}B pathway in rat liver. Diabetes 54:3458–3465PubMedCrossRef

41.

Hammond LE, Neschen S, Romanelli AJ et al (2005) Mitochondrial glycerol-3-phosphate acyltransferase-1 is essential in liver for the metabolism of excess acyl-CoAs. J Biol Chem 280:25629–25636PubMedCrossRef

42.

Shulman GI (2000) Cellular mechanisms of insulin resistance. J Clin Invest 106:171–176PubMedPubMedCentralCrossRef

43.

Samuel VT, Liu ZX, Wang A et al (2007) Inhibition of protein kinase C epsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J Clin Invest 117:739–745PubMedPubMedCentralCrossRef

44.

Savage DB, Choi CS, Samuel VT et al (2006) Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J Clin Invest 116:817–824PubMedPubMedCentralCrossRef

45.

Tiikkainen M, Bergholm R, Vehkavaara S et al (2003) Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content. Diabetes 52:701–707PubMedCrossRef

46.

Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI (2005) Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 54:603–608PubMedCrossRef

47.

Rashid S, Watanabe T, Sakaue T, Lewis GF (2003) Mechanisms of HDL lowering in insulin resistant, hypertriglyceridemic states: the combined effect of HDL triglyceride enrichment and elevated hepatic lipase activity. Clin Biochem 36:421–429PubMedCrossRef

Title: Acute suppression of VLDL1 secretion rate by insulin is associated with hepatic fat content and insulin resistance
Authors: M. Adiels
J. Westerbacka
A. Soro-Paavonen
A. M. Häkkinen
S. Vehkavaara
M. J. Caslake
C. Packard
S. O. Olofsson
H. Yki-Järvinen
M. R. Taskinen
J. Borén
Publication date: 01-11-2007
Publisher: Springer Berlin Heidelberg
Published in: Diabetologia / Issue 11/2007
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-007-0790-1

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Acute suppression of VLDL₁ secretion rate by insulin is associated with hepatic fat content and insulin resistance

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Please log in to get access to this content

Other articles of this Issue 11/2007

Disparate genetic influences on polycystic ovary syndrome (PCOS) and type 2 diabetes revealed by a lack of association between common variants within the TCF7L2 gene and PCOS

Changes in glycaemic control and risk of coronary artery disease in type 1 diabetes mellitus: findings from the Pittsburgh Epidemiology of Diabetes Complications Study (EDC)

Diabetic patients treated with dialysis: complications and quality of life

Modestly increased beta cell apoptosis but no increased beta cell replication in recent-onset type 1 diabetic patients who died of diabetic ketoacidosis

The relationship of retinal vascular calibre to diabetes and retinopathy: the Australian Diabetes, Obesity and Lifestyle (AusDiab) study

The economic burden of out-of-pocket medical expenditures for patients seeking diabetes care in Mexico

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page