Effect of insulin analog initiation therapy on LDL/HDL subfraction profile and HDL associated enzymes in type 2 diabetic patients

Ibrahim Aslan, Ertan Kucuksayan, Mutay Aslan, Ibrahim Aslan, Ertan Kucuksayan, Mutay Aslan

Abstract

Background: Insulin treatment can lead to good glycemic control and result in improvement of lipid parameters in type 2 diabetic patients. This study was designed to evaluate the effect of insulin analog initiation therapy on low-density lipoprotein (LDL)/ high-density lipoprotein (HDL) sub-fractions and HDL associated enzymes in type 2 diabetic patients during early phase.

Methods: Twenty four type 2 diabetic patients with glycosylated hemoglobin (HbA1c) levels above 10% despite ongoing combination therapy with sulphonylurea and metformin were selected. Former treatment regimen was continued for the first day followed by substitution of sulphonylurea therapy with different insulin analogs (0.4 U/kg/day) plus metformin. Glycemic profiles were determined over 72 hours by continuous glucose monitoring system (CGMS) and blood samples were obtained from all patients at 24 and 72 hours. Plasma levels of cholesteryl ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), apolipoprotein B (apoB) and apolipoprotein A-1 (apoA-I) were determined by enzyme-linked immunosorbent assay (ELISA). Measurement of CETP and LCAT activity was performed via fluorometric analysis. Paraoxonase (PON1) enzyme activity was assessed from the rate of enzymatic hydrolysis of phenyl acetate to phenol formation. LDL and HDL subfraction analysis was done by continuous disc polyacrylamide gel electrophoresis.

Results: Mean blood glucose, total cholesterol (TC), triglyceride (TG) and very low-density lipoprotein cholesterol (VLDL-C) levels were significantly decreased while HDL-C levels were significantly increased after insulin treatment. Although LDL-C levels were not significantly different before and after insulin initiation therapy a significant increase in LDL-1 subgroup and a significant reduction in atherogenic LDL-3 and LDL-4 subgroups were observed. Insulin analog initiation therapy caused a significant increase in HDL-large, HDL- intermediate and a significant reduction in HDL-small subfractions. CETP protein level and activity was significantly increased while apoB levels were significantly decreased following insulin analog initiation therapy. No significant difference was found in LCAT mass, LCAT activity, apoA-I and PON-1 arylesterase levels following insulin initiation therapy.

Conclusion: These findings indicate that insulin analog initiation therapy activates lipid metabolism via up-regulating CETP and shows anti-atherogenic effects by increasing HDL-large and decreasing LDL-3 and LDL-4 subfractions in a short time period.

Figures

Figure 1
Figure 1
Electrophoretic separation of lipoproteins on the Quantimetrix Lipoprint Low-Density Lipoprotein System. (A) Image of electrophoretic migration of 6 gel tubes. BT, before treatment; AT, after treatment. (B) Demonstrative densitometric scan of a sample before treatment with insulin analogs (C) Demonstrative densitometric scan of a sample after treatment with insulin analogs.
Figure 2
Figure 2
Electrophoretic separation of lipoproteins on the Quantimetrix Lipoprint High-Density Lipoprotein System. (A) Image of electrophoretic migration of 6 gel tubes. BT, before treatment; AT, after treatment. (B) Demonstrative densitometric scan of a sample before treatment with insulin analogs (C) Demonstrative densitometric scan of a sample after treatment with insulin analogs.
Figure 3
Figure 3
Box plot graph data of (A) plasma cholesteryl ester transfer protein (CETP) levels (B) CETP activity (C) lecithin-cholesterol acyltransferase (LCAT) protein levels (D) LCAT activity.
Figure 4
Figure 4
Box plot graph data of (A) Apolipoprotein B 100 protein levels (B) Apolipoprotein A-1 protein levels (C) paraoxonase (PON1) activity.

References

    1. Juutilainen A, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Type 2 diabetes as a “coronary heart disease equivalent”: an 18-year prospective population-based study in Finnish subjects. Diabetes Care. 2005;28(12):2901–2907. doi: 10.2337/diacare.28.12.2901.
    1. Ginsberg HN. Insulin resistance and cardiovascular disease. J Clin Invest. 2000;106(4):453–458. doi: 10.1172/JCI10762.
    1. American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care. 2000;23(Suppl 1):S57–S60.
    1. Van J, Pan J, Charles MA, Krauss R, Wong N, Wu X. Atherogenic lipid phenotype in a general group of subjects. Arch Pathol Lab Med. 2007;131(11):1679–1685.
    1. Pyŏrälä K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the scandinavian simvastatin survival study (4S) Diabetes Care. 1997;20(4):614–620. doi: 10.2337/diacare.20.4.614.
    1. Föger B. Lipid lowering therapy in type 2 diabetes. Wien Med Wochenschr. 2011;161(11–12):289–296.
    1. Inukai T, Yamamoto R, Suetsugu M, Matsumoto S, Wakabayashi S, Inukai Y, Matsutomo R, Takebayashi K, Aso Y. Small low-density lipoprotein and small low-density lipoprotein/total low-density lipoprotein are closely associated with intima-media thickness of the carotid artery in Type 2 diabetic patients. J Diabetes Complications. 2005;19(5):269–275. doi: 10.1016/j.jdiacomp.2005.03.002.
    1. Chapman MJ, Guérin M, Bruckert E. Atherogenic, dense low-density lipoproteins. Pathophysiology and new therapeutic approaches. Eur Heart J. 1998;19(Suppl A):A24–A30.
    1. Gardner CD, Fortmann SP, Krauss RM. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. JAMA. 1996;276(11):875–881. doi: 10.1001/jama.1996.03540110029028.
    1. Syvänne M, Ahola M, Lahdenperä S, Kahri J, Kuusi T, Virtanen KS, Taskinen MR. High density lipoprotein subfractions in non-insulin-dependent diabetes mellitus and coronary artery disease. J Lipid Res. 1995;36(3):573–582.
    1. Asztalos BF, Cupples LA, Demissie S, Horvath KV, Cox CE, Batista MC, Schaefer EJ. High-density lipoprotein subpopulation profile and coronary heart disease prevalence in male participants of the framingham offspring study. Arterioscler Thromb Vasc Biol. 2004;24(11):2181–2187. doi: 10.1161/01.ATV.0000146325.93749.a8.
    1. Soran H, Hama S, Yadav R, Durrington PN. HDL functionality. Curr Opin Lipidol. 2012;23(4):353–366. doi: 10.1097/MOL.0b013e328355ca25.
    1. Li Y, Xu W, Liao Z, Yao B, Chen X, Huang Z, Hu G, Weng J. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients is associated with improvement of beta-cell function. Diabetes Care. 2004;27(11):2597–2602. doi: 10.2337/diacare.27.11.2597.
    1. Rodbard HW, Blonde L, Braithwaite SS, Brett EM, Cobin RH, Handelsman Y, Hellman R, Jellinger PS, Jovanovic LG, Levy P, Mechanick JI, Zangeneh F. AACE diabetes mellitus clinical practice guidelines task force american association of clinical endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2007;13:1–68. doi: 10.4158/EP.13.S1.1.
    1. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18(6):499–502.
    1. Hoefner DM, Hodel SD, O’Brien JF, Branum EL, Sun D, Meissner I, McConnell JP. Development of a rapid, quantitative method for LDL subfractionation with use of the Quantimetrix Lipoprint LDL System. Clin Chem. 2001;47(2):266–274.
    1. Gazi I, Lourida ES, Filippatos T, Tsimihodimos V, Elisaf M, Tselepis AD. Lipoprotein-associated phospholipase A2 activity is a marker of small, dense LDL particles in human plasma. Clin Chem. 2005;51(12):2264–2273. doi: 10.1373/clinchem.2005.058404.
    1. Filippatos TD, Liberopoulos EN, Kostapanos M, Gazi IF, Papavasiliou EC, Kiortsis DN, Tselepis AD, Elisaf MS. The effects of orlistat and fenofibrate, alone or in combination, on high-density lipoprotein subfractions and pre-beta1-HDL levels in obese patients with metabolic syndrome. Diabetes Obes Metab. 2008;10(6):476–483. doi: 10.1111/j.1463-1326.2007.00733.x.
    1. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c) Diabetes Care. 2003;26:881–885. doi: 10.2337/diacare.26.3.881.
    1. Ceriello A. Postprandial hyperglycemia and diabetes complications: is it time to treat? Diabetes. 2005;54:1–7. doi: 10.2337/diabetes.54.1.1.
    1. Lantus®. Insulin glargine [rDNA origin] injection. Bridgewater, NJ: Sanofi-Aventis; 2007. (Prescribing information).
    1. NovoLog®. Insulin aspart [rDNA origin] injection. Princeton, NJ: Novo Nordisk Inc; 2011. (Prescribing information).
    1. Humalog®. Insulin lispro [rDNA origin] injection. Indianapolis, IN: Eli Lilly and Company; 2011. (Prescribing information).
    1. Morello CM. Pharmacokinetics and pharmacodynamics of insulin analogs in special populations with type 2 diabetes mellitus. Int J Gen Med. 2011;4:827–835.
    1. Roach P. New insulin analogues and routes of delivery: pharmacodynamic and clinical considerations. Clin Pharmacokinet. 2008;47:595–610. doi: 10.2165/00003088-200847090-00003.
    1. Riddle MC, Rosenstock J, Gerich J. Insulin glargine 4002 study ınvestigators. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26:3080–3086. doi: 10.2337/diacare.26.11.3080.
    1. Rodbard HW, Jellinger PS, Davidson JA, Einhorn D, Garber AJ, Grunberger G, Handelsman Y, Horton ES, Lebovitz H, Levy P, Moghissi ES, Schwartz SS. Statement by an american association of clinical endocrinologists/american college of endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009;15:540–559. doi: 10.4158/EP.15.6.540.
    1. Noh YH, Lee SM, Kim EJ, Kim DY, Lee H, Lee JH, Lee JH, Park SY, Koo JH, Wang JH, Lim IJ, Choi SB. Improvement of cardiovascular risk factors in patients with type 2 diabetes after long-term continuous subcutaneous insulin infusion. Diabetes Metab Res Rev. 2008;24(5):384–391. doi: 10.1002/dmrr.849.
    1. Handelsman Y, Mechanick JI, Blonde L, Grunberger G, Bloomgarden ZT, Bray GA, Dagogo-Jack S, Davidson JA, Einhorn D, Ganda O, Garber AJ, Hirsch IB, Horton ES, Ismail-Beigi F, Jellinger PS, Jones KL, Jovanovič L, Lebovitz H, Levy P, Moghissi ES, Orzeck EA, Vinik AI, Wyne KL. AACE task force for developing diabetes comprehensive care plan. American association of clinical endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17(Suppl 2):1–53.
    1. Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJ. A1c-Derived average glucose study group. Translating the A1C assay into estimated average glucose values. Diabetes Care. 2008;31(8):1473–1478. doi: 10.2337/dc08-0545.
    1. Rivellese AA, Patti L, Romano G, Innelli F, Di Marino L, Annuzzi G, Iavicoli M, Coronel GA, Riccardi G. Effect of insulin and sulfonylurea therapy, at the same level of blood glucose control, on low density lipoprotein subfractions in type 2 diabetic patients. J Clin Endocrinol Metab. 2000;85(11):4188–4192. doi: 10.1210/jc.85.11.4188.
    1. Fukui T, Hirano T. High-density lipoprotein subspecies between patients with type 1 diabetes and type 2 diabetes without/with intensive insulin therapy. Endocr J. 2012;59(7):561–569. doi: 10.1507/endocrj.EJ11-0329.
    1. Charles MA, Kane JP. New molecular insights into CETP structure and function: a review. J Lipid Res. 2012;53(8):1451–1458. doi: 10.1194/jlr.R027011.
    1. Geltner C, Lechleitner M, Föger B, Ritsch A, Drexel H, Patsch JR. Insulin improves fasting and postprandial lipemia in type 2 diabetes. Eur J Intern Med. 2002;13(4):256–263. doi: 10.1016/S0953-6205(02)00038-9.
    1. Ai M, Tanaka A, Baba T, Yui K, Numano F. Increased cholesteryl ester transfer protein and changes in lipid metabolism from initiating insulin therapy. Ann N Y Acad Sci. 2001;947:356–361.
    1. Sparks JD, Phung TL, Bolognino M, Sparks CE. Insulin-mediated inhibition of apolipoprotein B secretion requires an intracellular trafficking event and phosphatidylinositol 3-kinase activation: studies with brefeldin A and wortmannin in primary cultures of rat hepatocytes. Biochem J. 1996;313(Pt 2):567–574.
    1. Phung TL, Roncone A, Jensen KL, Sparks CE, Sparks JD. 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. 1997;272(49):30693–30702. doi: 10.1074/jbc.272.49.30693.
    1. Sparks JD, Sparks CE, Adeli K. Selective hepatic insulin resistance, VLDL overproduction, and hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2012;32(9):2104–2112. doi: 10.1161/ATVBAHA.111.241463.
    1. Harel M, Aharoni A, Gaidukov L, Brumshtein B, Khersonsky O, Meged R, Dvir H, Ravelli RB, McCarthy A, Toker L, Silman I, Sussman JL, Tawfik DS. Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes. Nat Struct Mol Biol. 2004;11(5):412–419. doi: 10.1038/nsmb767.
    1. Mackness MI, Mackness B, Durrington PN, Connelly PW, Hegele RA. Paraoxonase: biochemistry, genetics and relationship to plasma lipoproteins. Curr Opin Lipidol. 1996;7:69–76. doi: 10.1097/00041433-199604000-00004.
    1. Gan KN, Smolen A, Eckerson HW, La Du BN. Purification of human serum paraoxonase/arylesterase.Evidence for one esterase catalyzing both activities. Drug Metab Dispos. 1991;19(1):100–106.
    1. Petraki MP, Mantani PT, Tselepis AD. Recent advances on the antiatherogenic effects of HDL-derived proteins and mimetic peptides. Curr Pharm Des. 2009;15(27):3146–3166. doi: 10.2174/138161209789057977.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner