Diabetes Metab J.  2015 Oct;39(5):353-362. 10.4093/dmj.2015.39.5.353.

Interaction between Glucose and Lipid Metabolism: More than Diabetic Dyslipidemia

• Parhofer K

• KMID: 2174008
• DOI: http://doi.org/10.4093/dmj.2015.39.5.353

Abstract

Glucose and lipid metabolism are linked to each other in many ways. The most important clinical manifestation of this interaction is diabetic dyslipidemia, characterized by elevated triglycerides, low high density lipoprotein cholesterol (HDL-C), and predominance of small-dense LDL particles. However, in the last decade we have learned that the interaction is much more complex. Hypertriglyceridemia and low HDL-C cannot only be the consequence but also the cause of a disturbed glucose metabolism. Furthermore, it is now well established that statins are associated with a small but significant increase in the risk for new onset diabetes. The underlying mechanisms are not completely understood but modulation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA)-reductase may play a central role as genetic data indicate that mutations resulting in lower HMG CoA-reductase activity are also associated with obesity, higher glucose concentrations and diabetes. Very interestingly, this statin induced increased risk for new onset type 2 diabetes is not detectable in subjects with familial hypercholesterolemia. Furthermore, patients with familial hypercholesterolemia seem to have a lower risk for type 2 diabetes, a phenomenon which seems to be dose-dependent (the higher the low density lipoprotein cholesterol, the lower the risk). Whether there is also an interaction between lipoprotein(a) and diabetes is still a matter of debate.

Keyword

Diabetes mellitus; Diabetic dyslipidemia; Hyperlipoproteinemia type II; Hyperlipoproteinemias; Statin

MeSH Terms

Cholesterol, HDL
Cholesterol, LDL
Diabetes Mellitus
Dyslipidemias*
Glucose*
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hyperlipoproteinemia Type II
Hyperlipoproteinemias
Hypertriglyceridemia
Lipid Metabolism*
Lipoprotein(a)
Metabolism
Obesity
Triglycerides
Cholesterol, HDL
Cholesterol, LDL
Glucose
Lipoprotein(a)
Triglycerides

Figure

• 

  Fig. 1 High density lipoprotein (HDL) may be linked to glucose metabolism in multiple ways. HDL (at least certain subtypes) have direct anti-inflammatory properties. HDL are also the central component of reverse cholesterol transport and mediate cholesterol efflux from many tissues. This may change the micro environment such that insulin sensitivity and insulin secretion improve.

• 

  Fig. 2 Animal studies indicate that knock-out and overexpression of apolipoprotein A1 (apoA1) affect many metabolic pathways related to diabetes development [21]. Whether the results observed in rodents are also valid in humans is unknown. HDL, high density lipoprotein; HbA1c, glycosylated hemoglobin.

• 

  Fig. 3 Statin therapy is associated with a small increase in new-onset diabetes type 2. The underlying pathophysiology is not well understood. A number of different mechanisms may lead to decreased insulin sensitivity and altered β-cell function. In predisposed subjects this may induce the manifestation of type 2 diabetes. HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A.

Reference

1. Wu L, Parhofer KG. Diabetic dyslipidemia. Metabolism. 2014; 63:1469–1479.

2. Avramoglu RK, Basciano H, Adeli K. Lipid and lipoprotein dysregulation in insulin resistant states. Clin Chim Acta. 2006; 368:1–19.

3. Adiels M, Olofsson SO, Taskinen MR, Boren J. Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2008; 28:1225–1236.

4. Duez H, Lamarche B, Uffelman KD, Valero R, Cohn JS, Lewis GF. Hyperinsulinemia is associated with increased production rate of intestinal apolipoprotein B-48-containing lipoproteins in humans. Arterioscler Thromb Vasc Biol. 2006; 26:1357–1363.

5. Guerin M, Le Goff W, Lassel TS, Van Tol A, Steiner G, Chapman MJ. Atherogenic role of elevated CE transfer from HDL to VLDL(1) and dense LDL in type 2 diabetes: impact of the degree of triglyceridemia. Arterioscler Thromb Vasc Biol. 2001; 21:282–288.

6. Berneis KK, Krauss RM. Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res. 2002; 43:1363–1379.

7. Cholesterol Treatment Trialists' (CTT) Collaborators. Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, Armitage J, Baigent C. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008; 371:117–125.

8. Catapano AL, Reiner Z, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, Chapman M, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, Wood D. European Society of Cardiology (ESC). European Atherosclerosis Society (EAS). ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis. 2011; 217:3–46.

9. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, De Ferrari GM, Ruzyllo W, De Lucca P, Im K, Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA, Braunwald E, Califf RM. IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015; 372:2387–2397.

10. Hegele RA, Ginsberg HN, Chapman MJ, Nordestgaard BG, Kuivenhoven JA, Averna M, Boren J, Bruckert E, Catapano AL, Descamps OS, Hovingh GK, Humphries SE, Kovanen PT, Masana L, Pajukanta P, Parhofer KG, Raal FJ, Ray KK, Santos RD, Stalenhoef AF, Stroes E, Taskinen MR, Tybjaerg-Hansen A, Watts GF, Wiklund O. European Atherosclerosis Society Consensus Panel. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol. 2014; 2:655–666.

11. ORIGIN Trial Investigators. Bosch J, Gerstein HC, Dagenais GR, Diaz R, Dyal L, Jung H, Maggiono AP, Probstfield J, Ramachandran A, Riddle MC, Ryden LE, Yusuf S. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012; 367:309–318.

12. ACCORD Study Group. Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC Jr, Cushman WC, Simons-Morton DG, Byington RP. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010; 362:1563–1574.

13. Kromhout D, Giltay EJ, Geleijnse JM. Alpha Omega Trial Group. n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. 2010; 363:2015–2026.

14. Jun M, Foote C, Lv J, Neal B, Patel A, Nicholls SJ, Grobbee DE, Cass A, Chalmers J, Perkovic V. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet. 2010; 375:1875–1884.

15. Briaud I, Harmon JS, Kelpe CL, Segu VB, Poitout V. Lipotoxicity of the pancreatic beta-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids. Diabetes. 2001; 50:315–321.

16. Lee Y, Hirose H, Ohneda M, Johnson JH, McGarry JD, Unger RH. Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships. Proc Natl Acad Sci U S A. 1994; 91:10878–10882.

17. Rachek LI. Free fatty acids and skeletal muscle insulin resistance. Prog Mol Biol Transl Sci. 2014; 121:267–292.

18. Drew BG, Rye KA, Duffy SJ, Barter P, Kingwell BA. The emerging role of HDL in glucose metabolism. Nat Rev Endocrinol. 2012; 8:237–245.

19. Barter PJ, Rye KA, Tardif JC, Waters DD, Boekholdt SM, Breazna A, Kastelein JJ. Effect of torcetrapib on glucose, insulin, and hemoglobin A1c in subjects in the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial. Circulation. 2011; 124:555–562.

20. Drew BG, Duffy SJ, Formosa MF, Natoli AK, Henstridge DC, Penfold SA, Thomas WG, Mukhamedova N, de Courten B, Forbes JM, Yap FY, Kaye DM, van Hall G, Febbraio MA, Kemp BE, Sviridov D, Steinberg GR, Kingwell BA. High-density lipoprotein modulates glucose metabolism in patients with type 2 diabetes mellitus. Circulation. 2009; 119:2103–2111.

21. Lehti M, Donelan E, Abplanalp W, Al-Massadi O, Habegger KM, Weber J, Ress C, Mansfeld J, Somvanshi S, Trivedi C, Keuper M, Ograjsek T, Striese C, Cucuruz S, Pfluger PT, Krishna R, Gordon SM, Silva RA, Luquet S, Castel J, Martinez S, D'Alessio D, Davidson WS, Hofmann SM. High-density lipoprotein maintains skeletal muscle function by modulating cellular respiration in mice. Circulation. 2013; 128:2364–2371.

22. Mortensen SP, Boushel R. High-density lipoprotein: a new therapeutic target for glucose intolerance? Circulation. 2013; 128:2349–2350.

23. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ. JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008; 359:2195–2207.

24. Freeman DJ, Norrie J, Sattar N, Neely RD, Cobbe SM, Ford I, Isles C, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ, Shepherd J, Gaw A. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation. 2001; 103:357–362.

25. Huptas S, Geiss HC, Otto C, Parhofer KG. Effect of atorvastatin (10 mg/day) on glucose metabolism in patients with the metabolic syndrome. Am J Cardiol. 2006; 98:66–69.

26. Culver AL, Ockene IS, Balasubramanian R, Olendzki BC, Sepavich DM, Wactawski-Wende J, Manson JE, Qiao Y, Liu S, Merriam PA, Rahilly-Tierny C, Thomas F, Berger JS, Ockene JK, Curb JD, Ma Y. Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative. Arch Intern Med. 2012; 172:144–152.

27. Cederberg H, Stancakova A, Yaluri N, Modi S, Kuusisto J, Laakso M. Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort. Diabetologia. 2015; 58:1109–1117.

28. Cai R, Yuan Y, Zhou Y, Xia W, Wang P, Sun H, Yang Y, Huang R, Wang S. Lower intensified target LDL-c level of statin therapy results in a higher risk of incident diabetes: a meta-analysis. PLoS One. 2014; 9:e104922.

29. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SR, McMurray JJ, Freeman DJ, Jukema JW, Macfarlane PW, Packard CJ, Stott DJ, Westendorp RG, Shepherd J, Davis BR, Pressel SL, Marchioli R, Marfisi RM, Maggioni AP, Tavazzi L, Tognoni G, Kjekshus J, Pedersen TR, Cook TJ, Gotto AM, Clearfield MB, Downs JR, Nakamura H, Ohashi Y, Mizuno K, Ray KK, Ford I. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010; 375:735–742.

30. Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, DeMicco DA, Barter P, Cannon CP, Sabatine MS, Braunwald E, Kastelein JJ, de Lemos JA, Blazing MA, Pedersen TR, Tikkanen MJ, Sattar N, Ray KK. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011; 305:2556–2564.

31. Swerdlow DI, Preiss D, Kuchenbaecker KB, Holmes MV, Engmann JE, Shah T, Sofat R, Stender S, Johnson PC, Scott RA, Leusink M, Verweij N, Sharp SJ, Guo Y, Giambartolomei C, Chung C, Peasey A, Amuzu A, Li K, Palmen J, Howard P, Cooper JA, Drenos F, Li YR, Lowe G, Gallacher J, Stewart MC, Tzoulaki I, Buxbaum SG, van der AD, Forouhi NG, Onland-Moret NC, van der Schouw YT, Schnabel RB, Hubacek JA, Kubinova R, Baceviciene M, Tamosiunas A, Pajak A, Topor-Madry R, Stepaniak U, Malyutina S, Baldassarre D, Sennblad B, Tremoli E, de Faire U, Veglia F, Ford I, Jukema JW, Westendorp RG, de Borst GJ, de Jong PA, Algra A, Spiering W, Maitland-van der Zee AH, Klungel OH, de Boer A, Doevendans PA, Eaton CB, Robinson JG, Duggan D, Kjekshus J, Downs JR, Gotto AM, Keech AC, Marchioli R, Tognoni G, Sever PS, Poulter NR, Waters DD, Pedersen TR, Amarenco P, Nakamura H, McMurray JJ, Lewsey JD, Chasman DI, Ridker PM, Maggioni AP, Tavazzi L, Ray KK, Seshasai SR, Manson JE, Price JF, Whincup PH, Morris RW, Lawlor DA, Smith GD, Ben-Shlomo Y, Schreiner PJ, Fornage M, Siscovick DS, Cushman M, Kumari M, Wareham NJ, Verschuren WM, Redline S, Patel SR, Whittaker JC, Hamsten A, Delaney JA, Dale C, Gaunt TR, Wong A, Kuh D, Hardy R, Kathiresan S, Castillo BA, van der Harst P, Brunner EJ, Tybjaerg-Hansen A, Marmot MG, Krauss RM, Tsai M, Coresh J, Hoogeveen RC, Psaty BM, Lange LA, Hakonarson H, Dudbridge F, Humphries SE, Talmud PJ, Kivimaki M, Timpson NJ, Langenberg C, Asselbergs FW, Voevoda M, Bobak M, Pikhart H, Wilson JG, Reiner AP, Keating BJ, Hingorani AD, Sattar N. DIAGRAM Consortium. MAGIC Consortium. InterAct Consortium. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet. 2015; 385:351–361.

32. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, El Shahawy M, Koren MJ, Lepor NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ. ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015; 372:1489–1499.

33. Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, Ballantyne CM, Somaratne R, Legg J, Wasserman SM, Scott R, Koren MJ, Stein EA. Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015; 372:1500–1509.

34. Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, Kuivenhoven JA, Nordestgaard BG, Descamps OS, Steinhagen-Thiessen E, Tybjaerg-Hansen A, Watts GF, Averna M, Boileau C, Boren J, Catapano AL, Defesche JC, Hovingh GK, Humphries SE, Kovanen PT, Masana L, Pajukanta P, Parhofer KG, Ray KK, Stalenhoef AF, Stroes E, Taskinen MR, Wiegman A, Wiklund O, Chapman MJ. European Atherosclerosis Society Consensus Panel on Familial Hypercholesterolaemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014; 35:2146–2157.

35. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Boren J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AF, Stroes E, Taskinen MR, Tybjaerg-Hansen A. European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013; 34:3478–3490a.

36. Umans-Eckenhausen MA, Sijbrands EJ, Kastelein JJ, Defesche JC. Low-density lipoprotein receptor gene mutations and cardiovascular risk in a large genetic cascade screening population. Circulation. 2002; 106:3031–3036.

37. Raal FJ, Pilcher GJ, Panz VR, van Deventer HE, Brice BC, Blom DJ, Marais AD. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation. 2011; 124:2202–2207.

38. Versmissen J, Oosterveer DM, Yazdanpanah M, Defesche JC, Basart DC, Liem AH, Heeringa J, Witteman JC, Lansberg PJ, Kastelein JJ, Sijbrands EJ. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ. 2008; 337:a2423.

39. Besseling J, Kastelein JJ, Defesche JC, Hutten BA, Hovingh GK. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA. 2015; 313:1029–1036.

40. Vohl MC, Gaudet D, Moorjani S, Tremblay G, Perron P, Gagne C, Lesiege D, Bergeron J, Lupien PJ, Despres JP. Comparison of the effect of two low-density lipoprotein receptor class mutations on coronary heart disease among French-Canadian patients heterozygous for familial hypercholesterolaemia. Eur J Clin Invest. 1997; 27:366–373.

41. Brown MS, Goldstein JL. Familial hypercholesterolemia: defective binding of lipoproteins to cultured fibroblasts associated with impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Proc Natl Acad Sci U S A. 1974; 71:788–792.

42. Vuorio A, Strandberg TE, Schneider WJ, Kovanen PT. Statins and new-onset diabetes mellitus: a risk lacking in familial hypercholesterolaemia. J Intern Med. 2015; 08. 11. [Epub]. DOI: 10.1111/joim.12405.

43. Kusters DM, Avis HJ, de Groot E, Wijburg FA, Kastelein JJ, Wiegman A, Hutten BA. Ten-year follow-up after initiation of statin therapy in children with familial hypercholesterolemia. JAMA. 2014; 312:1055–1057.

44. Skoumas J, Liontou C, Chrysohoou C, Masoura C, Aznaouridis K, Pitsavos C, Stefanadis C. Statin therapy and risk of diabetes in patients with heterozygous familial hypercholesterolemia or familial combined hyperlipidemia. Atherosclerosis. 2014; 237:140–145.

45. Mora S, Kamstrup PR, Rifai N, Nordestgaard BG, Buring JE, Ridker PM. Lipoprotein(a) and risk of type 2 diabetes. Clin Chem. 2010; 56:1252–1260.

46. Habib SS, Aslam M. Lipids and lipoprotein(a) concentrations in Pakistani patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2004; 6:338–343.

47. Todoric J, Handisurya A, Leitner K, Harreiter J, Hoermann G, Kautzky-Willer A. Lipoprotein(a) is not related to markers of insulin resistance in pregnancy. Cardiovasc Diabetol. 2013; 12:138.

48. Emerging Risk Factors Collaboration. Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, White IR, Marcovina SM, Collins R, Thompson SG, Danesh J. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009; 302:412–423.