Abstract
Statin therapy is beneficial in reducing LDL cholesterol (LDL-C) levels and cardiovascular events, but it is associated with the risk of incident diabetes mellitus (DM). Familial hypercholesterolemia (FH) is characterized by genetically determined high levels of plasma LDL-C and a low prevalence of DM. LDL-C levels seem then inversely correlated with prevalence of DM. Familial hypobetalipoproteinemia (FHBL) represents the genetic mirror of FH in terms of LDL-C levels, very low in subjects carrying mutations of APOB, PCSK9 (FHBL1) or ANGPTL3 (FHBL2). This review explores the hypothesis that FHBL might represent also the genetic mirror of FH in terms of prevalence of DM and that it is expected to be increased in FHBL in comparison with the general population. A systematic review of published literature on FHBL was made by searching PubMed (1980–2016) for articles presenting clinical data on FHBL probands and relatives. The standardized prevalence rates of DM in FHBL1 were similar to those of the reference population, with a prevalence rate of 8.2 and 9.2%, respectively, while FHBL2 showed a 4.9% prevalence of DM. In conclusion, low LDL-C levels of FHBL do not seem connected to DM as it happens in subjects undergoing statin therapy and the diabetogenic effect of statins has to be explained by mechanisms that do not rely exclusively on the reduced levels of LDL-C. The review also summarizes the published data on the effects of FHBL on insulin sensitivity and the relationships between FH, statin therapy, FHBL1 and intracellular cholesterol metabolism, evaluating possible diabetogenic pathways.
Similar content being viewed by others
References
UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352(9131):837–853
Cholesterol Treatment Trialists’ (CTT) Collaborators, Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, Armitage J, Baigent C (2008) Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 371(9607):117–125
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 (2010) Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 375(9716):735–742. doi:10.1016/S0140-6736(09)61965-6
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 A DL, 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; DIAGRAM Consortium; MAGIC Consortium; InterAct Consortium, 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, Kivimäki M, Timpson NJ, Langenberg C, Asselbergs FW, Voevoda M, Bobak M, Pikhart H, Wilson JG, Reiner AP, Keating BJ, Hingorani AD, Sattar N (2015). HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet 385(9965):351–361. doi:10.1016/S0140-6736(14)61183-1
Beckett RD, Schepers SM, Gordon SK (2015) Risk of new-onset diabetes associated with statin use. SAGE Open Med. doi:10.1177/2050312115605518
Besseling J, Kastelein JJ, Defesche JC, Hutten BA, Hovingh GK (2015) Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA 313(10):1029–1036
Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 34(2):154–156
Minicocci I, Santini S, Cantisani V, Stitziel N, Kathiresan S, Arroyo JA, Martí G, Pisciotta L, Noto D, Cefalù AB, Maranghi M, Labbadia G, Pigna G, Pannozzo F, Ceci F, Ciociola E, Bertolini S, Calandra S, Tarugi P, Averna M, Arca M (2013) Clinical characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled analysis. J Lipid Res 54(12):3481–3490
Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA, PRISMA-P Group (2015) Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 349:g7647
Noto D, Barbagallo CM, Cefalù AB, Falletta A, Sapienza M, Cavera G, Amato S, Pagano M, Maggiore M, Carroccio A, Notarbartolo A, Averna MR (2008) The metabolic syndrome predicts cardiovascular events in subjects with normal fasting glucose: results of a 15 years follow-up in a Mediterranean population. Atherosclerosis 197(1):147–153
Noto D, Cefalù AB, Barbagallo CM, Falletta A, Ganci A, Sapienza M, Cavera G, Nardi I, Pagano M, Notarbartolo A, Averna MR (2012) Prediction of incident type 2 diabetes mellitus based on a twenty-year follow-up of the Ventimiglia heart study. Acta Diabetol 49(2):145–151
Tarugi P, Averna M, Di Leo E, Cefalù AB, Noto D, Magnolo L, Cattin L, Bertolini S, Calandra S (2007) Molecular diagnosis of hypobetalipoproteinemia: an ENID review. Atherosclerosis 195(2):19–27
Burnett JR, Zhong S, Jiang ZG, Hooper AJ, Fisher EA, McLeod RS, Zhao Y, Barrett PH, Hegele RA, van Bockxmeer FM, Zhang H, Vance DE, McKnight CJ, Yao Z (2007) Missense mutations in APOB within the betaalpha1 domain of human APOB-100 result in impaired secretion of ApoB and ApoB-containing lipoproteins in familial hypobetalipoproteinemia. J Biol Chem 282(33):24270–24283
Noto D, Cefalù AB, Cannizzaro A, Minà M, Fayer F, Valenti V, Barbagallo CM, Tuttolomondo A, Pinto A, Sciumè C, Licata G, Averna M (2009) Familial hypobetalipoproteinemia due to apolipoprotein B R463 W mutation causes intestinal fat accumulation and low postprandial lipemia. Atherosclerosis 206(1):193–198
Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, Horton JD, Cohen JC, Hobbs HH (2006) Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 79(3):514–523
Fasano T, Cefalù AB, Di Leo E, Noto D, Pollaccia D, Bocchi L, Valenti V, Bonardi R, Guardamagna O, Averna M, Tarugi P (2007) A novel loss of function mutation of PCSK9 gene in white subjects with low-plasma low-density lipoprotein cholesterol. Arterioscler Thromb Vasc Biol 27(3):677–681
Di Filippo M, Moulin P, Roy P, Samson-Bouma ME, Collardeau-Frachon S, Chebel-Dumont S, Peretti N, Dumortier J, Zoulim F, Fontanges T, Parini R, Rigoldi M, Furlan F, Mancini G, Bonnefont-Rousselot D, Bruckert E, Schmitz J, Scoazec JY, Charrière S, Villar-Fimbel S, Gottrand F, Dubern B, Doummar D, Joly F, Liard-Meillon ME, Lachaux A, Sassolas A (2014) Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia. J Hepatol 61(4):891–902
Tanoli T, Yue P, Yablonskiy D, Schonfeld G (2004) Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity. J Lipid Res 45(5):941–947
Tarugi P, Lonardo A, Ballarini G, Grisendi A, Pulvirenti M, Bagni A, Calandra S (1996) Fatty liver in heterozygous hypobetalipoproteinemia caused by a novel truncated form of apolipoprotein B. Gastroenterology 111(4):1125–1133
Sankatsing RR, Fouchier SW, de Haan S, Hutten BA, de Groot E, Kastelein JJ, Stroes ES (2005) Hepatic and cardiovascular consequences of familial hypobetalipoproteinemia. Arterioscler Thromb Vasc Biol 25(9):1979–1984
Tarugi P, Lonardo A, Ballarini G, Erspamer L, Tondelli E, Bertolini S, Calandra S (2000) A study of fatty liver disease and plasma lipoproteins in a kindred with familial hypobetalipoproteinemia due to a novel truncated form of apolipoprotein B (APO B-54.5). J Hepatol 33(3):361–370
Katsuda S, Kawashiri MA, Inazu A, Tada H, Tsuchida M, Kaneko Y, Nozue T, Nohara A, Okada T, Kobayashi J, Michishita I, Mabuchi H, Yamagishi M (2009) Apolipoprotein B gene mutations and fatty liver in Japanese hypobetalipoproteinemia. Clin Chim Acta 399(1–2):64–68
Welty FK (2014) Hypobetalipoproteinemia and abetalipoproteinemia. Curr Opin Lipidol 25(3):161–168
Lam MC, Singham J, Hegele RA, Riazy M, Hiob MA, Francis G, Steinbrecher UP (2012) Familial hypobetalipoproteinemia-induced nonalcoholic steatohepatitis. Case Rep Gastroenterol 6(2):429–437
Whitfield AJ, Barrett PH, Robertson K, Havlat MF, van Bockxmeer FM, Burnett JR (2005) Liver dysfunction and steatosis in familial hypobetalipoproteinemia. Clin Chem 51(1):266–269
Heeks LV, Hooper AJ, Adams LA, Robbins P, Barrett PH, van Bockxmeer FM, Burnett JR (2013) Non-alcoholic steatohepatitis-related cirrhosis in a patient with APOB L343 V familial hypobetalipoproteinaemia. Clin Chim Acta 421:121–125
Cefalù AB, Pirruccello JP, Noto D, Gabriel S, Valenti V, Gupta N, Spina R, Tarugi P, Kathiresan S, Averna MR (2013) A novel APOB mutation identified by exome sequencing cosegregates with steatosis, liver cancer, and hypocholesterolemia. Arterioscler Thromb Vasc Biol 33(8):2021–2025
Bonnefont-Rousselot D, Condat B, Sassolas A, Chebel S, Bittar R, Federspiel MC, Cazals-Hatem D, Bruckert E (2009) Cryptogenic cirrhosis in a patient with familial hypocholesterolemia due to a new truncated form of apolipoprotein B. Eur J Gastroenterol Hepatol 21(1):104–108
Della Corte C, Fintini D, Giordano U, Cappa M, Brufani C, Majo F, Mennini C, Nobili V (2013) Fatty liver and insulin resistance in children with hypobetalipoproteinemia: the importance of aetiology. Clin Endocrinol (Oxf) 79(1):49–54
Amaro A, Fabbrini E, Kars M, Yue P, Schechtman K, Schonfeld G, Klein S (2010) Dissociation between intrahepatic triglyceride content and insulin resistance in familial hypobetalipoproteinemia. Gastroenterology 139(1):149–153
Visser ME, Lammers NM, Nederveen AJ, van der Graaf M, Heerschap A, Ackermans MT, Sauerwein HP, Stroes ES, Serlie MJ (2011) Hepatic steatosis does not cause insulin resistance in people with familial hypobetalipoproteinaemia. Diabetologia 54(8):2113–2121
Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C, Garimella KV, Fisher S, Abreu J, Barry AJ, Fennell T, Banks E, Ambrogio L, Cibulskis K, Kernytsky A, Gonzalez E, Rudzicz N, Engert JC, DePristo MA, Daly MJ, Cohen JC, Hobbs HH, Altshuler D, Schonfeld G, Gabriel SB, Yue P, Kathiresan S (2010) Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med 363(23):2220–2227
Noto D, Cefalù AB, Valenti V, Fayer F, Pinotti E, Ditta M, Spina R, Vigna G, Yue P, Kathiresan S, Tarugi P, Averna MR (2012) Prevalence of ANGPTL3 and APOB gene mutations in subjects with combined hypolipidemia. Arterioscler Thromb Vasc Biol 32(3):805–809
Mattijssen F, Kersten S (2012) Regulation of triglyceride metabolism by Angiopoietin-like proteins. Biochim Biophys Acta 1821(5):782–789
Inukai K, Nakashima Y, Watanabe M, Kurihara S, Awata T, Katagiri H, Oka Y, Katayama S (2004) ANGPTL3 is increased in both insulin-deficient and -resistant diabetic states. Biochem Biophys Res Commun 317(4):1075–1079
Quagliarini F, Wang Y, Kozlitina J, Grishin NV, Hyde R, Boerwinkle E, Valenzuela DM, Murphy AJ, Cohen JC, Hobbs HH (2012) Atypical angiopoietin-like protein that regulates ANGPTL3. Proc Natl Acad Sci USA 109(48):19751–19756
Köster A, Chao YB, Mosior M, Ford A, Gonzalez-DeWhitt PA, Hale JE, Li D, Qiu Y, Fraser CC, Yang DD, Heuer JG, Jaskunas SR, Eacho P (2005) Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride metabolism. Endocrinology 146(11):4943–4950
Koishi R, Ando Y, Ono M, Shimamura M, Yasumo H, Fujiwara T, Horikoshi H, Furukawa H (2002) Angptl3 regulates lipid metabolism in mice. Nat Genet 30(2):151–157
Mehta N, Qamar A, Qu L, Qasim AN, Mehta NN, Reilly MP, Rader DJ (2014) Differential association of plasma angiopoietin-like proteins 3 and 4 with lipid and metabolic traits. Arterioscler Thromb Vasc Biol 34(5):1057–1063
Wang Y, Gusarova V, Banfi S, Gromada J, Cohen JC, Hobbs HH (2015) Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion. J Lipid Res 56(7):1296–1307
Robciuc MR, Maranghi M, Lahikainen A, Rader D, Bensadoun A, Öörni K, Metso J, Minicocci I, Ciociola E, Ceci F, Montali A, Arca M, Ehnholm C, Jauhiainen M (2013) Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. Arterioscler Thromb Vasc Biol 33(7):1706–1713
Wang X, Wang D, Shan Z (2015) Clinical and genetic analysis of a family diagnosed with familial hypobetalipoproteinemia in which the proband was diagnosed with diabetes mellitus. Atherosclerosis 239(2):552–556
Horton JD, Goldstein JL, Brown MS (2002) SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Investig 109:1125–1131
Shimano H (2001) Sterol regulatory element-binding proteins (SREBPs): transcriptional regulators of lipid synthetic genes. Prog Lipid Res 40(6):439–452
Pramfalk C, Jiang ZY, Cai Q, Hu H, Zhang SD, Han TQ, Eriksson M, Parini P (2010) HNF1alpha and SREBP2 are important regulators of NPC1L1 in human liver. J Lipid Res 51(6):1354–1362
Zhao C, Dahlman-Wright K (2010) Liver X receptor in cholesterol metabolism. J Endocrinol 204(3):233–240
Zelcer N, Hong C, Boyadjian R, Tontonoz P (2009) LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 325(5936):100–104
Goodwin B, Watson MA, Kim H, Miao J, Kemper JK, Kliewer SA (2003) Differential regulation of rat and human CYP7A1 by the nuclear oxysterol receptor liver X receptor-alpha. Mol Endocrinol 17(3):386–394
Calkin AC, Tontonoz P (2010) Liver x receptor signaling pathways and atherosclerosis. Arterioscler Thromb Vasc Biol 30(8):1513–1518
Parikh M, Patel K, Soni S, Gandhi T (2014) Liver X receptor: a cardinal target for atherosclerosis and beyond. J Atheroscler Thromb 21(6):519–531
Hao M, Head WS, Gunawardana SC, Hasty AH, Piston DW (2007) Direct effect of cholesterol on insulin secretion: a novel mechanism for pancreatic beta-cell dysfunction. Diabetes 56(9):2328–2338
Hoeg JM, Edge SB, Demosky SJ Jr, Starzl TE, Triche T, Gregg RE, Brewer HB Jr (1986) Metabolism of low-density lipoproteins by cultured hepatocytes from normal and homozygous familial hypercholesterolemic subjects. Biochim Biophys Acta 876(3):646–657
Telford DE, Sutherland BG, Edwards JY, Andrews JD, Barrett PH, Huff MW (2007) The molecular mechanisms underlying the reduction of LDL apoB-100 by ezetimibe plus simvastatin. J Lipid Res 48(3):699–708
Maejima T, Sugano T, Yamazaki H, Yoshinaka Y, Doi T, Tanabe S, Nishimaki-Mogami T (2011) Pitavastatin increases ABCA expression by dual mechanisms: SREBP2-driven transcriptional activation and PPARα-dependent protein stabilization but without activating LXR in rat hepatoma McARH7777 cells. J Pharmacol Sci 116(1):107–115
Soufi M, Ruppert V, Kurt B, Schaefer JR (2012) The impact of severe LDL receptor mutations on SREBP-pathway regulation in homozygous familial hypercholesterolemia (FH). Gene 499(1):218–222
Chamberlain LH (2001) Inhibition of isoprenoid biosynthesis causes insulin resistance in 3 T3-L1 adipocytes. FEBS Lett 507(3):357–361
Ashcroft FM, Proks P, Smith PA et al (1994) Stimulus–secretion coupling in pancreatic β cells. J Cell Biochem 55(S1994A):54–65
Brault M, Ray J, Gomez YH, Mantzoros CS, Daskalopoulou SS (2014) Statin treatment and new-onset diabetes: a review of proposed mechanisms. Metabolism 63(6):735–745
Vallejo-Vaz AJ, Kondapally Seshasai SR, Kurogi K, Michishita I, Nozue T, Sugiyama S, Tsimikas S, Yoshida H, Ray KK (2015) Effect of pitavastatin on glucose, HbA1c and incident diabetes: a meta-analysis of randomized controlled clinical trials in individuals without diabetes. Atherosclerosis 241(2):409–418
Arnaboldi L, Corsini A (2015) Could changes in adiponectin drive the effect of statins on the risk of new-onset diabetes? The case of pitavastatin. Atheroscler Suppl 16:1–27
Barkas F, Elisaf M, Liberopoulos E, Klouras E, Liamis G, Rizos EC (2016) Statin therapy with or without ezetimibe and the progression to diabetes. J Clin Lipidol 10(2):306–313
Lin X, Chen Z, Yue P, Averna MR, Ostlund RE Jr, Watson MA, Schonfeld G (2006) A targeted apoB38.9 mutation in mice is associated with reduced hepatic cholesterol synthesis and enhanced lipid peroxidation. Am J Physiol Gastrointest Liver Physiol 290(6):G1170–G1176
Miettinen TA, Tilvis RS, Kesäniemi YA (1990) Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population. Am J Epidemiol 131(1):20–31
Miettinen TA, Gylling H, Nissinen MJ (2011) The role of serum non-cholesterol sterols as surrogate markers of absolute cholesterol synthesis and absorption. Nutr Metab Cardiovasc Dis 21(10):765–769
Björkhem I, Miettinen T, Reihnér E, Ewerth S, Angelin B, Einarsson K (1987) Correlation between serum levels of some cholesterol precursors and activity of HMG-CoA reductase in human liver. J Lipid Res 28(10):1137–1143
Noto D, Cefalù AB, Barraco G, Fayer F, Minà M, Yue P, Tarugi P, Schonfeld G, Averna MR (2011) Plasma non-cholesterol sterols in primary hypobetalipoproteinemia. Atherosclerosis 216(2):409–413
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Human and animal rights
This article is a systematic review and it does not contain any studies with human or animal subjects performed by any of the authors.
Informed consent
A formal consent is not required for this type of study.
Additional information
Managed by Massimo Porta.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Noto, D., Arca, M., Tarugi, P. et al. Association between familial hypobetalipoproteinemia and the risk of diabetes. Is this the other side of the cholesterol–diabetes connection? A systematic review of literature. Acta Diabetol 54, 111–122 (2017). https://doi.org/10.1007/s00592-016-0931-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00592-016-0931-4