Drug-induced lipotoxicity: Lipodystrophy associated with HIV-1 infection and antiretroviral treatment

Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids

Volumn 1801, Issue 3, 2010, Pages 392-399

  Villarroya, Francesc ^a   Domingo, Pere ^b   Giralt, Marta ^a  

^a UNIVERSITY OF BARCELONA   (Spain)

^b HOSPITAL DE LA SANTA CREU I SANT PAU   (Spain)

Author keywords

Brown adipose tissue; HIV; Inflammation; Lipodystrophy; Mitochondria

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ANTIRETROVIRUS AGENT; EFAVIRENZ; FATTY ACID; FIBRIC ACID DERIVATIVE; GLUCOSE TRANSPORTER 4; THYMIDINE DERIVATIVE; ZIDOVUDINE;

CARDIAC PATIENT; CARDIOVASCULAR RISK; DIABETES MELLITUS; FATTY LIVER; HOMEOSTASIS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; INSULIN RELEASE; INSULIN RESISTANCE; LIPID METABOLISM; LIPID STORAGE; LIPOATROPHY; LIPODYSTROPHY; LIPOHYPERTROPHY; LIPOLYSIS; METABOLIC DISORDER; PANCREAS; PANCREAS FUNCTION; PRIORITY JOURNAL; REVIEW; SKELETAL MUSCLE; SUBCUTANEOUS FAT;

ADIPOSE TISSUE; ANTI-RETROVIRAL AGENTS; HIV INFECTIONS; HIV-1; HIV-ASSOCIATED LIPODYSTROPHY SYNDROME; HUMANS; HYPERTROPHY; LIPID METABOLISM; LIVER; MUSCLE, SKELETAL; PANCREAS;

HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 76049109697     PISSN: 13881981     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bbalip.2009.09.018     Document Type: Review

References (83)

1. Grinspoon S., and Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N. Engl. J. Med. 352 (2005) 48-62
2. Villarroya F., Domingo P., and Giralt M. Lipodystrophy in HIV 1-infected patients: lessons for obesity research. Int. J. Obes. (Lond). 31 (2007) 1763-1776
3. Flint O.P., Noor M.A., Hruz P.W., Hylemon P.B., Yarasheski K., Kotler D.P., Parker R.A., and Bellamine A. The role of protease inhibitors in the pathogenesis of HIV-associated lipodystrophy: cellular mechanisms and clinical implications. Toxicol. Pathol. 37 (2009) 65-77
4. Gougeon M.L., Penicaud L., Fromenty B., Leclercq P., Viard J.P., and Capeau J. Adipocytes targets and actors in the pathogenesis of HIV-associated lipodystrophy and metabolic alterations. Antivir. Ther. 9 (2004) 161-177
5. Yan Q., and Cruz P.W. Direct comparison of the acute in vivo effects of HIV protease inhibitors on peripheral glucose disposal. J. Acquir. Immune Defic. Syndr. 40 (2005) 398-403
6. Boyd M.A., Carr A., Ruxrungtham K., Srasuebkul P., Bien D., Law M., Wangsuphachart S., Krisanachinda A., Lerdlum S., Lange J.M., Phanuphak P., Cooper D.A., and Reiss P. Changes in body composition and mitochondrial nucleic acid content in patients switched from failed nucleoside analogue therapy to ritonavir-boosted indinavir and efavirenz. J. Infect. Dis. 194 (2006) 642-650
7. Villarroya F., Domingo P., and Giralt M. Lipodystrophy associated with highly active anti-retroviral therapy for HIV infection: the adipocyte as a target of anti-retroviral-induced mitochondrial toxicity. Trends Pharmacol. Sci. 26 (2005) 88-93
8. Villarroya F., Domingo P., and Giralt M. Mechanisms of antiretroviral-induced mitochondrial dysfunction in adipocytes and adipose tissue: in-vitro, animal and human adipose tissue studies. Curr. Opin. HIV AIDS 2 (2007) 261-267
9. Caron M., Auclair M., Lagathu C., Lombes A., Walker U.A., Kornprobst M., and Capeau J. The HIV-1 nucleoside reverse transcriptase inhibitors stavudine and zidovudine alter adipocyte functions in vitro. AIDS 18 (2004) 2127-2136
10. Hadigan C., Borgonha S., Rabe J., Young V., and Grinspoon S. Increased rates of lipolysis among human immunodeficiency virus-infected men receiving highly active antiretroviral therapy. Metabolism 51 (2002) 1143-1147
11. Haubrich R.H., Riddler S.A., DiRienzo A.G., Komarow L., Powderly W.G., Klingman K., Garren K.W., Butcher D.L., Rooney J.F., Haas D.W., Mellors J.W., Havlir D.V., and AIDS Clinical Trials Group (ACTG) A5142 Study Team. Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment. AIDS 23 (2009) 1109-1118
12. El Hadri K., Glorian M., Monsempes C., Dieudonne M.N., Pecquery R., Giudicelli Y., Andreani M., Dugail I., and Fève B. In vitro suppression of the lipogenic pathway by the nonnucleoside reverse transcriptase inhibitor efavirenz in 3T3 and human preadipocytes or adipocytes. J. Biol. Chem. 279 (2004) 15130-15141
13. Peck M.D., Mantero-Atienza E., Miguez-Burbano M.J., Lu Y., Fletcher M.A., Shor-Posner G., and Baum M.K. The esterified plasma fatty acid profile is altered in early HIV-1 infection. Lipids 28 (1993) 593-597
14. Van der Valk M., Reiss P., van Leth F.C., Ackermans M.T., Endert E., Romijn J.A., Heijligenberg R., and Sauerwein H. Highly active antiretroviral therapy-induced lipodystrophy has minor effects on human immunodeficiency virus-induced changes in lipolysis, but normalizes resting energy expenditure. J. Clin. Endocrinol. Metab. 87 (2002) 5066-5071
15. Hadigan C., Liebau J., Torriani M., Andersen R., and Grinspoon S. Improved triglycerides and insulin sensitivity with 3 months of acipimox in human immunodeficiency virus-infected patients with hypertriglyceridemia. J. Clin. Endocrinol. Metab. 91 (2006) 4438-4444
16. Rudich A., Vanounou S., Riesenberg K., Porat M., Tirosh A., Harman-Boehm I., Greenberg A.S., Schlaeffer F., and Bashan N. The HIV protease inhibitor nelfinavir induces insulin resistance and increases basal lipolysis in 3T3-L1 adipocytes. Diabetes 50 (2001) 1425-1431
17. Janneh O., Hoggard P.G., Tjia J.F., Jones S.P., Khoo S.H., Maher B., Back D.J., and Pirmohamed M. Intracellular disposition and metabolic effects of zidovudine, stavudine and four protease inhibitors in cultured adipocytes. Antivir. Ther. 8 (2003) 417-426
18. Ranganathan S., and Kern P.A. The HIV protease inhibitor saquinavir impairs lipid metabolism and glucose transport in cultured adipocytes. J. Endocrinol. 172 (2002) 155-162
19. Van der Valk M., Allick G., Weverling G.J., Romijn J.A., Ackermans M.T., Lange J.M., van Eck-Smit B.L., van Kuijk C., Endert E., Sauerwein H.P., and Reiss P. Markedly diminished lipolysis and partial restoration of glucose metabolism, without changes in fat distribution after extended discontinuation of protease inhibitors in severe lipodystrophic human immunodeficient virus-1-infected patients. J. Clin. Endocrinol. Metab. 89 (2004) 3554-3560
20. Suganami T., Nishida J., and Ogawa Y. A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler. Thromb. Vasc. Biol. 25 (2005) 2062-2068
21. Trujillo M.E., Sullivan S., Harten I., Schneider S.H., Greenberg A.S., and Fried S.K. Interleukin-6 regulates human adipose tissue lipid metabolism and leptin production in vitro. J. Clin. Endocrinol. Metab. 89 (2004) 5577-5582
22. Gasic S., Tian B., and Green A. Tumor necrosis factor alpha stimulates lipolysis in adipocytes by decreasing Gi protein concentrations. J. Biol. Chem. 274 (1999) 6770-6775
23. Bastard J.P., Caron M., Vidal H., Jan V., Auclair M., Vigouroux C., Luboinski J., Laville M., Maachi M., Girard P.M., Rozenbaum W., Levan P., and Capeau J. Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance. Lancet 359 (2002) 1026-1031
24. Giralt M., Domingo P., Guallar J.P., de la Concepcion M.L., Alegre M., Domingo J.C., and Villarroya F. HIV-1 infection alters gene expression in adipose tissue, which contributes to HIV-1/HAART-associated lipodystrophy. Antivir. Ther. 11 (2006) 729-740
25. Tong Q., Sankalé J.L., Hadigan C.M., Tan G., Rosenberg E.S., Kanki P.J., Grinspoon S.K., and Hotamisligil G.S. Regulation of adiponectin in human immunodeficiency virus-infected patients: relationship to body composition and metabolic indices. J. Clin. Endocrinol. Metab. 88 (2003) 1559-1564
26. Kadowaki T., Yamauchi T., Kubota N., Hara K., Ueki K., and Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J. Clin. Invest. 116 (2006) 1784-1792
27. Nolan D., Hammond E., Martin A., Taylor L., Herrmann S., McKinnon E., Metcalf C., Latham B., and Mallal S. Mitochondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase inhibitor therapy. AIDS 17 (2003) 1329-1338
28. Pace C.S., Martin A.M., Hammond E.L., Mamotte C.D., Nolan D.A., and Mallal S.A. Mitochondrial proliferation, DNA depletion and adipocyte differentiation in subcutaneous adipose tissue of HIV-positive HAART recipients. Antivir. Ther. 8 (2003) 323-331
29. Wilson-Fritch L., Burkart A., Bell G., Mendelson K., Leszyk J., Nicoloro S., Czech M., and Corvera S. Mitochondrial biogenesis and remodeling during adipogenesis and in response to the insulin sensitizer rosiglitazone. Mol. Cell. Biol. 23 (2003) 1085-1094
30. Chevillotte E., Giralt M., Miroux B., Ricquier D., and Villarroya F. Uncoupling protein-2 controls adiponectin gene expression in adipose tissue through the modulation of reactive oxygen species production. Diabetes 56 (2007) 1042-1050
31. Jan V., Cervera P., Maachi M., Baudrimont M., Kim M., Vidal H., Girard P.M., Levan P., Rozenbaum W., Lombès A., Capeau J., and Bastard J.P. Altered fat differentiation and adipocytokine expression are inter-related and linked to morphological changes and insulin resistance in HIV-1-infected lipodystrophic patients. Antivir. Ther. 9 (2004) 555-564
32. Lindegaard B., Hansen A.B., Pilegaard H., Keller P., Gerstoft J., and Pedersen B.K. Adipose tissue expression of IL-18 and HIV-associated lipodystrophy. AIDS 18 (2004) 1956-1986
33. Sevastianova K., Sutinen J., Kannisto K., Hamsten A., Pistola M., and Yki-Järvinen H. Adipose tissue inflammation and liver fat in patients with highly active antiretroviral therapy-associated lipodystrophy. Am. J. Physiol. Endocrinol. Metab. 295 (2008) E85-91
34. Guallar J.P., Gallego-Escuredo J.M., Domingo J.C., Alegre M., Fontdevila J., Martínez E., Hammond E.L., Domingo P., Giralt M., and Villarroya F. Differential gene expression indicates that ''buffalo hump' is a distinct adipose tissue disturbance in HIV-1-associated lipodystrophy. AIDS 22 (2008) 575-584
35. Domingo P., Matias-Guiu X., Pujol R.M., Francia E., Lagarda E., Sambeat M.A., and Vázquez G. Subcutaneous adipocyte apoptosis in HIV-1 protease inhibitor-associated lipodystrophy. AIDS 13 (1999) 2261-2267
36. Domingo P., Guallar J.P., Gallego-Escuredo J.M., Díaz-Delfin J., Domingo J.C., Alegre M., Gutiérrez M.M., Mateo M.G., Giralt M., and Villarroya F. Genome-wide transcriptomic análisis reveals distinct patterns of altered gene expression in subcutaneous adipose tissue associated with HIV-1 infection, antiretroviral treatment and lipodystrophy. Antivir. Ther. 13 Suppl 4 (2008) A25
37. Garg A. Acquired and inherited lipodystrophies. N. Engl. J. Med. 350 (2004) 1220-1234
38. Safrin S., and Grunfeld C. Fat distribution and metabolic changes in patients with HIV infection. AIDS 13 (1999) 2493-2505
39. Lafontan M., and Berlan M. Do regional differences in adipocyte biology provide new pathophysiological insights?. Trends Pharmacol. Sci. 24 (2003) 276-283
40. Rodríguez A., Catalán V., Gómez-Ambrosi J., and Frühbeck G. Visceral and subcutaneous adiposity: are both potential therapeutic targets for tackling the metabolic syndrome?. Curr. Pharm. Des. 13 (2007) 2169-2175
41. Kovsan J., Osnis A., Maissel A., Mazor L., Tarnovscki T., Hollander L., Ovadia S., Meier B., Klein J., Bashan N., and Rudich A. Depot-specific adipocyte cell lines reveal differential drug-induced responses of white adipocytes-relevance for partial lipodystrophy. Am. J. Physiol. Endocrinol. Metab. 296 (2009) E315-322
42. Villarroya J., Gallego-Escudero J.M., Domingo J.C., Alegre M., Gutiérrez M.M., Mateo M.G., Villarroya F., Domingo P., and Giralt M. Differential alterations of gene expression in visceral versus subcutaneous adipose tissue from HIV-1-infected, HAART-treated patients with lipodystrophy: a pilot study. Antivir. Ther. 13 (2008) A15
43. Lo J.C., Mulligan K., Tai V.W., Algren H., and Schambelan M. "Buffalo hump" in men with HIV-1 infection. Lancet 351 (1998) 867-870
44. Saint-Marc T., and Touraine J.L. Buffalo hump" in HIV-1 infection. Lancet 352 (1998) 319-320
45. Mallon P.W., Wand H., Law M., Miller J., Cooper D.A., Carr A., and HIV Lipodystrophy Case Definition Study; Australian Lipodystrophy Prevalence Survey Investigators. Buffalo hump seen in HIV-associated lipodystrophy is associated with hyperinsulinemia but not dyslipidemia. J. Acquir. Immune Defic. Syndr. 38 (2005) 156-162
46. Fessel W.J., Follansbee S.B., and Barker B. Ultrastructural findings consistent with brown adipocytes in buffalo humps of HIV-positive patients with fat redistribution syndrome. Antivir. Ther. 5 (2000) 25
47. Rodríguez de la Concepción M.L., Domingo J.C., Domingo P., Giralt M., and Villarroya F. Uncoupling protein 1 gene expression implicates brown adipocytes in highly active antiretroviral therapy-associated lipomatosis. AIDS 18 (2004) 959-960
48. Cypess A.M., Lehman S., Williams G., Tal I., Rodman D., Goldfine A.B., Kuo F.C., Palmer E.L., Tseng Y.H., Doria A., Kolodny G.M., and Kahn C.R. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360 (2009) 1509-1517
49. van Marken Lichtenbelt W.D., Vanhommerig J.W., Smulders N.M., Drossaerts J.M., Kemerink G.J., Bouvy N.D., Schrauwen P., and Teule G.J. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360 (2009) 1500-1508
50. Virtanen K.A., Lidell M.E., Orava J., Heglind M., Westergren R., Niemi T., Taittonen M., Laine J., Savisto N.J., Enerbäck S., and Nuutila P. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360 (2009) 1518-1525
51. Villarroya F., Domingo P., and Giralt M. The importance of brown adipose tissue. N. Engl. J. Med. 361 (2009) 417
52. Bleeker-Rovers C.P., van der Ven A.J., Zomer B., de Geus-Oei L.F., Smits P., Corstens F.H., Koopmans P.P., and Oyen W.J. F-18-fluorodeoxyglucose positron emission tomography for visualization of lipodystrophy in HIV-infected patients. AIDS 18 (2004) 2430-2432
53. Sathekge M., Goethals I., Maes A., and van de Wiele C. Positron emission tomography in patients suffering from HIV-1 infection. Eur. J. Nucl. Med. Mol. Imaging. 36 (2009) 1176-1184
54. Nisoli E., Regianini L., Briscini L., Bulbarelli A., Busetto L., Coin A., Enzi G., and Carruba G.M.O. Multiple symmetric lipomatosis may be the consequence of defective noradrenergic modulation of proliferation and differentiation of brown fat cells. J. Pathol. 198 (2002) 378-387
55. Shimomura I., Hammer R.E., Richardson J.A., Ikemoto S., Bashmakov Y., Goldstein J.L., and Brown M.S. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev. 12 (1998) 3182-3194
56. Bouillaud F., Villarroya F., Hentz E., Raimbault S., Cassard A.M., and Ricquier D. Detection of brown adipose tissue uncoupling protein mRNA in adult patients by a human genomic probe. Clin. Sci. (Lond). 75 (1988) 21-27
57. Cannon B., and Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84 (2004) 277-359
58. Rodriguez de la Concepcion M.L., Yubero P., Domingo J.C., Iglesias R., Domingo P., Villarroya F., and Giralt M. Reverse transcriptase inhibitors alter uncoupling protein-1 and mitochondrial biogenesis in brown adipocytes. Antivir. Ther. 10 (2005) 515-526
59. Guaraldi G., Squillace N., Stentarelli C., Orlando G., D'Amico R., Ligabue G., Fiocchi F., Zona S., Loria P., Esposito R., and Palella F. Nonalcoholic fatty liver disease in HIV-infected patients referred to a metabolic clinic: prevalence, characteristics, and predictors. Clin. Infect. Dis. 47 (2008) 250-257
60. Sutinen J., Häkkinen A.M., Westerbacka J., Seppälä-Lindroos A., Vehkavaara S., Halavaara J., Järvinen A., Ristola M., and Yki-Järvinen H. Increased fat accumulation in the liver in HIV-infected patients with antiretroviral therapy-associated lipodystrophy. AIDS 16 (2002) 2183-2193
61. 1H-MR spectroscopy. Antivir. Ther. 12 (2007) 195-203
62. Mohammed S.S., Aghdassi E., Salit I.E., Avand G., Sherman M., Guindi M., Heathcote J.E., and Allard J.P. HIV-positive patients with nonalcoholic fatty liver disease have a lower body mass index and are more physically active than HIV-negative patients. J. Acquir. Immune Defic. Syndr. 45 (2007) 432-438
63. Lemoine M., Capeau J., and Serfaty L. PPAR and liver injury in HIV-infected patients. PPAR Res. 2009 (2009) 906167
64. Lai K.K., Gang D.L., Zawacki J.K., and Cooley T.P. Fulminant hepatic failure associated with 2′,3′-dideoxyinosine (ddI). Ann. Intern. Med. 115 (1991) 283-284
65. Sulkowski M.S., Thomas D.L., Chaisson R.E., and Moore R.D. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. J. Am. Med. Assoc. 283 (2000) 74-80
66. Carr A., Samaras K., Burton S., Law M., Freund J., Chisholm D.J., and Cooper D.A. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 12 (1998) F51-58
67. Torriani M., Thomas B.J., Barlow R.B., Librizzi J., Dolan S., and Grinspoon S. Increased intramyocellular lipid accumulation in HIV-infected women with fat redistribution. J. Appl. Physiol. 100 (2006) 609-614
68. Luzi L., Perseghin G., Tambussi G., Meneghini E., Scifo P., Pagliato E., Del Maschio A., Testolin G., and Lazzarin A. Intramyocellular lipid accumulation and reduced whole body lipid oxidation in HIV lipodystrophy. Am. J. Physiol. Endocrinol. Metab. 284 (2003) E274-280
69. Haugaard S.B., Andersen O., Madsbad S., Frosig C., Iversen J., Nielsen J.O., and Wojtaszewski J.F. Skeletal muscle insulin signaling defects downstream of phosphatidylinositol 3-kinase at the level of Akt are associated with impaired nonoxidative glucose disposal in HIV lipodystrophy. Diabetes 54 (2005) 3474-3483
70. Nolte L.A., Yarasheski K.E., Kawanaka K., Fisher J., Le N., and Holloszy J.O. The HIV protease inhibitor indinavir decreases insulin- and contraction-stimulated glucose transport in skeletal muscle. Diabetes 50 (2001) 1397-1401
71. Maagaard A., Holberg-Petersen M., Torjesen P.A., Bruun J.N., and Kvale D. Insulin resistance is affected by increased levels of plasma lactate but not mitochondrial alterations in skeletal muscle in NRTI-exposed HIV-infected patients. HIV Clin. Trials 8 (2007) 345-353
72. Abdul-Ghani M.A., Muller F.L., Liu Y., Chavez A.O., Balas B., Zuo P., Chang Z., Tripathy D., Jani R., Molina-Carrion M., Monroy A., Folli F., Van Remmen H., and DeFronzo R.A. Deleterious action of FA metabolites on ATP synthesis: possible link between lipotoxicity, mitochondrial dysfunction, and insulin resistance. Am. J. Physiol. Endocrinol. Metab. 295 (2008) E678-685
73. Samaras K. Prevalence and pathogenesis of diabetes mellitus in HIV-1 infection treated with combined antiretroviral therapy. J. Acquir. Immune Defic. Syndr. 50 (2009) 499-505
74. Haugaard S.B., Andersen O., Volund A., Hansen B.R., Iversen J., Andersen U.B., Nielsen J.O., and Madsbad S. beta-Cell dysfunction and low insulin clearance in insulin-resistant human immunodeficiency virus (HIV)-infected patients with lipodystrophy. Clin. Endocrinol. (Oxf). 62 (2005) 354-361
75. Behrens G., Dejam A., Schmidt H., Balks H.J., Brabant G., Korner T., Stoll M., and Schmidt R.E. Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patients under treatment with protease inhibitors. AIDS 13 (1999) F63-F70
76. Woerle H.J., Mariuz P.R., Meyer C., Reichman R.C., Popa E.M., Dostou J.M., Welle S.L., and Gerich J.E. Mechanisms for the deterioration in glucose tolerance associated with HIV protease inhibitor regimens. Diabetes 52 (2003) 918-925
77. Koster J.C., Remedi M.S., Qiu H., Nichols C.G., and Hruz P.W. HIV protease inhibitors acutely impair glucose-stimulated insulin release. Diabetes 52 (2003) 1695-1700
78. Schütt M., Zhou J., Meier M., and Klein H.H. Long-term effects of HIV-1 protease inhibitors on insulin secretion and insulin signaling in INS-1 beta cells. J. Endocrinol. 183 (2004) 445-454
79. Boden G., Chen X., Ruiz J., White J.V., and Rossetti L. Mechanisms of fatty acid-induced inhibition of glucose uptake. J. Clin. Invest. 93 (1994) 2438-2446
80. Kashyap S., Belfort R., Gastaldelli A., Pratipanawatr T., Berria R., Pratipanawatr W., Bajaj M., Mandarino L., DeFronzo R., and Cusi K. A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes 52 (2003) 2461-2474
81. Dubois M., Kerr-Conte J., Gmyr V., Bouckenooghe T., Muharram G., D'Herbomez M., Martin-Ponthieu A., Vantyghem M.C., Vandewalle B., and Pattou F. Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration. Diabetologia 47 (2004) 463-469
82. del Mar Gutiérrez M., Mateo G., and Domingo P. Strategies in the treatment of HIV-1-associated adipose redistribution syndromes. Expert Opin. Pharmacother. 8 (2007) 1871-1884
83. Slama L., Lanoy E., Valantin M.A., Bastard J.P., Chermak A., Boutekatjirt A., William-Faltaos D., Billaud E., Molina J.M., Capeau J., Costagliola D., and Rozenbaum W. Effect of pioglitazone on HIV-1-related lipodystrophy: a randomized double-blind placebo-controlled trial (ANRS 113). Antivir. Ther. 13 (2008) 67-76