Apoptosis

, Volume 14, Issue 12, pp 1484–1495 | Cite as

Diabetes and apoptosis: lipotoxicity

  • Christine M. Kusminski
  • Shoba Shetty
  • Lelio Orci
  • Roger H. Unger
  • Philipp E. Scherer
Diabetes and Apoptosis

Abstract

Obesity is an established risk factor in the pathogenesis of insulin resistance, type 2 diabetes mellitus and cardiovascular disease; all components that are part of the metabolic syndrome. Traditionally, insulin resistance has been defined in a glucocentric perspective. However, elevated systemic levels of fatty acids are now considered significant contributors towards the pathophysiological aspects associated with the syndrome. An overaccumulation of unoxidized long-chain fatty acids can saturate the storage capacity of adipose tissue, resulting in a lipid ‘spill over’ to non-adipose tissues, such as the liver, muscle, heart, and pancreatic-islets. Under these circumstances, such ectopic lipid deposition can have deleterious effects. The excess lipids are driven into alternative non-oxidative pathways, which result in the formation of reactive lipid moieties that promote metabolically relevant cellular dysfunction (lipotoxicity) and programmed cell-death (lipoapoptosis). Here, we focus on how both of these processes affect metabolically significant cell-types and highlight how lipotoxicity and sequential lipoapoptosis are as major mediators of insulin resistance, diabetes and cardiovascular disease.

Keywords

Diabetes Apoptosis Lipotoxicity Pancreatic β-cells Leptin Adiponectin 

Abbreviations

T2DM

Type 2 diabetes mellitus

CVD

Cardiovascular disease

TG

Triglyceride/triacylglycerol

FFA

Free fatty acid

GLUT4

Glucose transporter-4

NO

Nitric oxide

AMPK

Adenosine monophosphate-activated protein kinase

CoA

Coenzyme-A

SREBP-1c

Sterol regulatory element binding protein-1c

PPAR-γ2

Peroxisome proliferator-activated receptor

ACC

Acetyl coenzyme A carboxylase

FAS

Fatty acid synthetase

GPAT

Glycerol-3-phosphate acyl transferase

CPT-1

Carnitine palmityl transferase-1

ACO

Fatty acyl-CoA oxidase

PGC-1α

Peroxisome proliferator-activated receptor-γ coactivator-1α

UCP-2

Uncoupling protein-2

VLDLs

Very low-density lipoproteins

ROS

Reactive oxygen species

ER

Endoplasmic reticulum

SPT-1

Serine palmitoyl transferase

Bcl2

B-cell lymphoma 2

Bad

Bcl2-antagonist of cell death

Bax

Bcl2-associated X protein

Bid

BH3 interacting domain death agonist

Bim

Bcl2-like 11

NF-κB

Nuclear factor-κB

iNOS

Inducible nitric oxide synthase

ACS

Acyl CoA synthase

ECM

Extracellular matrix

FAT-ATTAC

Fat apoptosis through targeted activation of caspase-8

FKBP

Peptidyl-prolyl cis–trans isomerase

AICAR

5-Amino 4-imidazolecarboxamide riboside

MCD

Malonyl CoA decarboxylase

References

  1. 1.
    Reaven GM (1988) Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37:1595–1607. doi:10.2337/diabetes.37.12.1595 CrossRefPubMedGoogle Scholar
  2. 2.
    Randle PJ, Garland PB, Hales CN et al (1963) The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1:785–789. doi:10.1016/S0140-6736(63)91500-9 CrossRefPubMedGoogle Scholar
  3. 3.
    McGarry JD (1992) What if Minkowski had been ageusic? An alternative angle on diabetes. Science 258:766–770. doi:10.1126/science.1439783 CrossRefPubMedGoogle Scholar
  4. 4.
    Shulman GI (2000) Cellular mechanisms of insulin resistance. J Clin Invest 106:171–176. doi:10.1172/JCI10583 CrossRefPubMedGoogle Scholar
  5. 5.
    Boden G, Cheung P, Stein TP et al (2002) FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis. Am J Physiol Endocrinol Metab 283:E12–E19PubMedGoogle Scholar
  6. 6.
    Charles MA, Eschwege E, Thibult N et al (1997) The role of non-esterified fatty acids in the deterioration of glucose tolerance in caucasian subjects: results of the Paris prospective study. Diabetologia 40:1101–1106. doi:10.1007/s001250050793 CrossRefPubMedGoogle Scholar
  7. 7.
    Schulz LO, Bennett PH, Ravussin E et al (2006) Effects of traditional and western environments on prevalence of type 2 diabetes in Pima Indians in Mexico and the US. Diabetes Care 29:1866–1871. doi:10.2337/dc06-0138 CrossRefPubMedGoogle Scholar
  8. 8.
    Lee Y, Hirose H, Ohneda M et al (1994) 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 USA 91:10878–10882. doi:10.1073/pnas.91.23.10878 CrossRefPubMedGoogle Scholar
  9. 9.
    Unger RH (2003) Lipid overload and overflow: metabolic trauma and the metabolic syndrome. Trends Endocrinol Metab 14:398–403. doi:10.1016/j.tem.2003.09.008 CrossRefPubMedGoogle Scholar
  10. 10.
    Unger RH, Orci L (2001) Diseases of liporegulation: new perspective on obesity and related disorders. FASEB J 15:312–321. doi:10.1096/fj.00-0590 CrossRefPubMedGoogle Scholar
  11. 11.
    Neel JV (1962) Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”? Am J Hum Genet 14:353–362PubMedGoogle Scholar
  12. 12.
    Simha V, Garg A (2006) Lipodystrophy: lessons in lipid and energy metabolism. Curr Opin Lipidol 17:162–169CrossRefPubMedGoogle Scholar
  13. 13.
    Zhang Y, Proenca R, Maffei M et al (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432. doi:10.1038/372425a0 CrossRefPubMedGoogle Scholar
  14. 14.
    Halaas JL, Gajiwala KS, Maffei M et al (1995) Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269:543–546. doi:10.1126/science.7624777 CrossRefPubMedGoogle Scholar
  15. 15.
    Campfield LA, Smith FJ, Guisez Y et al (1995) Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269:546–549. doi:10.1126/science.7624778 CrossRefPubMedGoogle Scholar
  16. 16.
    Shimabukuro M, Koyama K, Chen G et al (1997) Direct antidiabetic effect of leptin through triglyceride depletion of tissues. Proc Natl Acad Sci USA 94:4637–4641. doi:10.1073/pnas.94.9.4637 CrossRefPubMedGoogle Scholar
  17. 17.
    Wang MY, Koyama K, Shimabukuro M et al (1998) OB-Rb gene transfer to leptin-resistant islets reverses diabetogenic phenotype. Proc Natl Acad Sci USA 95:714–718. doi:10.1073/pnas.95.2.714 CrossRefPubMedGoogle Scholar
  18. 18.
    Lee Y, Wang MY, Kakuma T et al (2001) Liporegulation in diet-induced obesity. The antisteatotic role of hyperleptinemia. J Biol Chem 276:5629–5635. doi:10.1074/jbc.M008553200 CrossRefPubMedGoogle Scholar
  19. 19.
    Zhou YT, Grayburn P, Karim A et al (2000) Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci USA 97:1784–1789. doi:10.1073/pnas.97.4.1784 CrossRefPubMedGoogle Scholar
  20. 20.
    Muller-Wieland D, Kotzka J (2005) Correction of insulin resistance and the metabolic syndrome. Handb Exp Pharmacol 170:591–617CrossRefPubMedGoogle Scholar
  21. 21.
    Scherer PE, Williams S, Fogliano M et al (1995) A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 270:26746–26749. doi:10.1074/jbc.270.45.26746 CrossRefPubMedGoogle Scholar
  22. 22.
    Kim JY, van de Wall E, Laplante M et al (2007) Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest 117:2621–2637. doi:10.1172/JCI31021 CrossRefPubMedGoogle Scholar
  23. 23.
    Combs TP, Wagner JA, Berger J et al (2002) Induction of adipocyte complement-related protein of 30 kilodaltons by PPARgamma agonists: a potential mechanism of insulin sensitization. Endocrinology 143:998–1007. doi:10.1210/en.143.3.998 CrossRefPubMedGoogle Scholar
  24. 24.
    Wang ZV, Scherer PE (2008) Adiponectin, cardiovascular function, and hypertension. Hypertension 51:8–14. doi:10.1161/HYPERTENSIONAHA.107.099424 CrossRefPubMedGoogle Scholar
  25. 25.
    Tomas E, Tsao TS, Saha AK et al (2002) Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci USA 99:16309–16313. doi:10.1073/pnas.222657499 CrossRefPubMedGoogle Scholar
  26. 26.
    Yamauchi T, Kamon J, Waki H et al (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946. doi:10.1038/90984 CrossRefPubMedGoogle Scholar
  27. 27.
    Yamauchi T, Kamon J, Minokoshi Y et al (2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 8:1288–1295. doi:10.1038/nm788 CrossRefPubMedGoogle Scholar
  28. 28.
    Brown MS, Goldstein JL (1998) Sterol regulatory element binding proteins (SREBPs): controllers of lipid synthesis and cellular uptake. Nutr Rev 56:S1–S3 discussion S54–75PubMedCrossRefGoogle Scholar
  29. 29.
    Wang X, Sato R, Brown MS et al (1994) SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis. Cell 77:53–62. doi:10.1016/0092-8674(94)90234-8 CrossRefPubMedGoogle Scholar
  30. 30.
    Kakuma T, Wang ZW, Pan W et al (2000) Role of leptin in peroxisome proliferator-activated receptor gamma coactivator-1 expression. Endocrinology 141:4576–4582. doi:10.1210/en.141.12.4576 CrossRefPubMedGoogle Scholar
  31. 31.
    Zhou YT, Shimabukuro M, Koyama K et al (1997) Induction by leptin of uncoupling protein-2 and enzymes of fatty acid oxidation. Proc Natl Acad Sci USA 94:6386–6390. doi:10.1073/pnas.94.12.6386 CrossRefPubMedGoogle Scholar
  32. 32.
    Hardie DG, Pan DA (2002) Regulation of fatty acid synthesis and oxidation by the AMP-activated protein kinase. Biochem Soc Trans 30:1064–1070. doi:10.1042/BST0301064 CrossRefPubMedGoogle Scholar
  33. 33.
    McGarry JD, Mannaerts GP, Foster DW (1977) A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J Clin Invest 60:265–270. doi:10.1172/JCI108764 CrossRefPubMedGoogle Scholar
  34. 34.
    McGarry JD (2002) Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 51:7–18. doi:10.2337/diabetes.51.1.7 CrossRefPubMedGoogle Scholar
  35. 35.
    Lee Y, Yu X, Gonzales F et al (2002) PPAR alpha is necessary for the lipopenic action of hyperleptinemia on white adipose and liver tissue. Proc Natl Acad Sci USA 99:11848–11853. doi:10.1073/pnas.182420899 CrossRefPubMedGoogle Scholar
  36. 36.
    Spiegelman BM (2007) Transcriptional control of mitochondrial energy metabolism through the PGC1 coactivators. Novartis Found Symp 287:60–63. doi:10.1002/9780470725207.ch5 discussion 63–69CrossRefPubMedGoogle Scholar
  37. 37.
    Moitra J, Mason MM, Olive M et al (1998) Life without white fat: a transgenic mouse. Genes Dev 12:3168–3181. doi:10.1101/gad.12.20.3168 CrossRefPubMedGoogle Scholar
  38. 38.
    Florant GL, Porst H, Peiffer A et al (2004) Fat-cell mass, serum leptin and adiponectin changes during weight gain and loss in yellow-bellied marmots (Marmota flaviventris). J Comp Physiol [B] 174:633–639. doi:10.1007/s00360-004-0454-0 Google Scholar
  39. 39.
    Mason TM (1998) The role of factors that regulate the synthesis and secretion of very-low-density lipoprotein by hepatocytes. Crit Rev Clin Lab Sci 35:461–487. doi:10.1080/10408369891234246 CrossRefPubMedGoogle Scholar
  40. 40.
    Shimabukuro M, Zhou YT, Levi M et al (1998) Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci USA 95:2498–2502. doi:10.1073/pnas.95.5.2498 CrossRefPubMedGoogle Scholar
  41. 41.
    Szczepaniak LS, Victor RG, Orci L et al (2007) Forgotten but not gone: the rediscovery of fatty heart, the most common unrecognized disease in America. Circ Res 101:759–767. doi:10.1161/CIRCRESAHA.107.160457 CrossRefPubMedGoogle Scholar
  42. 42.
    Unger RH, Zhou YT, Orci L (1999) Regulation of fatty acid homeostasis in cells: novel role of leptin. Proc Natl Acad Sci USA 96:2327–2332. doi:10.1073/pnas.96.5.2327 CrossRefPubMedGoogle Scholar
  43. 43.
    Unger RH (2005) Longevity, lipotoxicity and leptin: the adipocyte defense against feasting and famine. Biochimie 87:57–64. doi:10.1016/j.biochi.2004.11.014 CrossRefPubMedGoogle Scholar
  44. 44.
    Zhou YT, Shimabukuro M, Lee Y et al (1998) Enhanced de novo lipogenesis in the leptin-unresponsive pancreatic islets of prediabetic Zucker diabetic fatty rats: role in the pathogenesis of lipotoxic diabetes. Diabetes 47:1904–1908. doi:10.2337/diabetes.47.12.1904 CrossRefPubMedGoogle Scholar
  45. 45.
    Quon MJ, Butte AJ, Zarnowski MJ et al (1994) Insulin receptor substrate 1 mediates the stimulatory effect of insulin on GLUT4 translocation in transfected rat adipose cells. J Biol Chem 269:27920–27924PubMedGoogle Scholar
  46. 46.
    McGarry JD, Brown NF (1997) The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur J Biochem 244:1–14. doi:10.1111/j.1432-1033.1997.00001.x CrossRefPubMedGoogle Scholar
  47. 47.
    Summers SA, Garza LA, Zhou H et al (1998) Regulation of insulin-stimulated glucose transporter GLUT4 translocation and Akt kinase activity by ceramide. Mol Cell Biol 18:5457–5464PubMedGoogle Scholar
  48. 48.
    Robertson RP, Harmon JS (2006) Diabetes, glucose toxicity, and oxidative stress: a case of double jeopardy for the pancreatic islet beta cell. Free Radic Biol Med 41:177–184. doi:10.1016/j.freeradbiomed.2005.04.030 CrossRefPubMedGoogle Scholar
  49. 49.
    Maechler P, Jornot L, Wollheim CB (1999) Hydrogen peroxide alters mitochondrial activation and insulin secretion in pancreatic beta cells. J Biol Chem 274:27905–27913. doi:10.1074/jbc.274.39.27905 CrossRefPubMedGoogle Scholar
  50. 50.
    Tiedge M, Lortz S, Drinkgern J et al (1997) Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells. Diabetes 46:1733–1742. doi:10.2337/diabetes.46.11.1733 CrossRefPubMedGoogle Scholar
  51. 51.
    Unger RH, Zhou YT (2001) Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover. Diabetes 50(Suppl 1):S118–S121. doi:10.2337/diabetes.50.2007.S118 CrossRefPubMedGoogle Scholar
  52. 52.
    Ohneda M, Inman LR, Unger RH (1995) Caloric restriction in obese pre-diabetic rats prevents beta-cell depletion, loss of beta-cell GLUT 2 and glucose incompetence. Diabetologia 38:173–179. doi:10.1007/BF00400091 CrossRefPubMedGoogle Scholar
  53. 53.
    Ribaux PG, Iynedjian PB (2003) Analysis of the role of protein kinase B (cAKT) in insulin-dependent induction of glucokinase and sterol regulatory element-binding protein 1 (SREBP1) mRNAs in hepatocytes. Biochem J 376:697–705. doi:10.1042/BJ20031287 CrossRefPubMedGoogle Scholar
  54. 54.
    Koshkin V, Wang X, Scherer PE et al (2003) Mitochondrial functional state in clonal pancreatic beta-cells exposed to free fatty acids. J Biol Chem 278:19709–19715. doi:10.1074/jbc.M209709200 CrossRefPubMedGoogle Scholar
  55. 55.
    Carlsson C, Borg LA, Welsh N (1999) Sodium palmitate induces partial mitochondrial uncoupling and reactive oxygen species in rat pancreatic islets in vitro. Endocrinology 140:3422–3428. doi:10.1210/en.140.8.3422 CrossRefPubMedGoogle Scholar
  56. 56.
    Rakatzi I, Mueller H, Ritzeler O et al (2004) Adiponectin counteracts cytokine- and fatty acid-induced apoptosis in the pancreatic beta-cell line INS-1. Diabetologia 47:249–258. doi:10.1007/s00125-003-1293-3 CrossRefPubMedGoogle Scholar
  57. 57.
    Gu W, Li X, Liu C et al (2006) Globular adiponectin augments insulin secretion from pancreatic islet beta cells at high glucose concentrations. Endocrine 30:217–221. doi:10.1385/ENDO:30:2:217 CrossRefPubMedGoogle Scholar
  58. 58.
    Huypens P, Moens K, Heimberg H et al (2005) Adiponectin-mediated stimulation of AMP-activated protein kinase (AMPK) in pancreatic beta cells. Life Sci 77:1273–1282. doi:10.1016/j.lfs.2005.03.008 CrossRefPubMedGoogle Scholar
  59. 59.
    Staiger K, Stefan N, Staiger H et al (2005) Adiponectin is functionally active in human islets but does not affect insulin secretory function or beta-cell lipoapoptosis. J Clin Endocrinol Metab 90:6707–6713. doi:10.1210/jc.2005-0467 CrossRefPubMedGoogle Scholar
  60. 60.
    Huypens PR (2007) Leptin and adiponectin regulate compensatory beta cell growth in accordance to overweight. Med Hypotheses 68:1134–1137. doi:10.1016/j.mehy.2006.09.046 CrossRefPubMedGoogle Scholar
  61. 61.
    Shimomura I, Bashmakov Y, Ikemoto S et al (1999) Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc Natl Acad Sci USA 96:13656–13661. doi:10.1073/pnas.96.24.13656 CrossRefPubMedGoogle Scholar
  62. 62.
    Shimomura I, Hammer RE, Ikemoto S et al (1999) Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401:73–76. doi:10.1038/43448 CrossRefPubMedGoogle Scholar
  63. 63.
    Ma K, Cabrero A, Saha PK et al (2002) Increased beta-oxidation but no insulin resistance or glucose intolerance in mice lacking adiponectin. J Biol Chem 277:34658–34661. doi:10.1074/jbc.C200362200 CrossRefPubMedGoogle Scholar
  64. 64.
    Wang MY, Orci L, Ravazzola M et al (2005) Fat storage in adipocytes requires inactivation of leptin’s paracrine activity: implications for treatment of human obesity. Proc Natl Acad Sci USA 102:18011–18016. doi:10.1073/pnas.0509001102 CrossRefPubMedGoogle Scholar
  65. 65.
    Chiu HC, Kovacs A, Ford DA et al (2001) A novel mouse model of lipotoxic cardiomyopathy. J Clin Invest 107:813–822. doi:10.1172/JCI10947 CrossRefPubMedGoogle Scholar
  66. 66.
    Obeid LM, Linardic CM, Karolak LA et al (1993) Programmed cell death induced by ceramide. Science 259:1769–1771. doi:10.1126/science.8456305 CrossRefPubMedGoogle Scholar
  67. 67.
    Karaskov E, Scott C, Zhang L et al (2006) Chronic palmitate but not oleate exposure induces endoplasmic reticulum stress, which may contribute to INS-1 pancreatic beta-cell apoptosis. Endocrinology 147:3398–3407. doi:10.1210/en.2005-1494 CrossRefPubMedGoogle Scholar
  68. 68.
    Shimabukuro M, Higa M, Zhou YT et al (1998) Lipoapoptosis in beta-cells of obese prediabetic fa/fa rats. Role of serine palmitoyltransferase overexpression. J Biol Chem 273:32487–32490. doi:10.1074/jbc.273.49.32487 CrossRefPubMedGoogle Scholar
  69. 69.
    Weiss B, Stoffel W (1997) Human and murine serine-palmitoyl-CoA transferase—cloning, expression and characterization of the key enzyme in sphingolipid synthesis. Eur J Biochem 249:239–247. doi:10.1111/j.1432-1033.1997.00239.x CrossRefPubMedGoogle Scholar
  70. 70.
    Maedler K, Oberholzer J, Bucher P et al (2003) Monounsaturated fatty acids prevent the deleterious effects of palmitate and high glucose on human pancreatic beta-cell turnover and function. Diabetes 52:726–733. doi:10.2337/diabetes.52.3.726 CrossRefPubMedGoogle Scholar
  71. 71.
    Kulik G, Klippel A, Weber MJ (1997) Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt. Mol Cell Biol 17:1595–1606PubMedGoogle Scholar
  72. 72.
    Holland WL, Summers SA (2008) Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocr Rev 29:381–402. doi:10.1210/er.2007-0025 CrossRefPubMedGoogle Scholar
  73. 73.
    Datta SR, Dudek H, Tao X et al (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241. doi:10.1016/S0092-8674(00)80405-5 CrossRefPubMedGoogle Scholar
  74. 74.
    El-Assaad W, Buteau J, Peyot ML et al (2003) Saturated fatty acids synergize with elevated glucose to cause pancreatic beta-cell death. Endocrinology 144:4154–4163. doi:10.1210/en.2003-0410 CrossRefPubMedGoogle Scholar
  75. 75.
    Briaud I, Harmon JS, Kelpe CL et al (2001) Lipotoxicity of the pancreatic beta-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids. Diabetes 50:315–321. doi:10.2337/diabetes.50.2.315 CrossRefPubMedGoogle Scholar
  76. 76.
    Shimabukuro M, Ohneda M, Lee Y et al (1997) Role of nitric oxide in obesity-induced beta cell disease. J Clin Invest 100:290–295. doi:10.1172/JCI119534 CrossRefPubMedGoogle Scholar
  77. 77.
    Schonfeld P, Wojtczak L (2007) Fatty acids decrease mitochondrial generation of reactive oxygen species at the reverse electron transport but increase it at the forward transport. Biochim Biophys Acta 1767:1032–1040. doi:10.1016/j.bbabio.2007.04.005 CrossRefPubMedGoogle Scholar
  78. 78.
    Gudz TI, Tserng KY, Hoppel CL (1997) Direct inhibition of mitochondrial respiratory chain complex III by cell-permeable ceramide. J Biol Chem 272:24154–24158. doi:10.1074/jbc.272.39.24154 CrossRefPubMedGoogle Scholar
  79. 79.
    Pi J, Bai Y, Zhang Q et al (2007) Reactive oxygen species as a signal in glucose-stimulated insulin secretion. Diabetes 56:1783–1791. doi:10.2337/db06-1601 CrossRefPubMedGoogle Scholar
  80. 80.
    Cnop M, Welsh N, Jonas JC et al (2005) Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54(Suppl 2):S97–S107. doi:10.2337/diabetes.54.suppl_2.S97 CrossRefPubMedGoogle Scholar
  81. 81.
    Lameloise N, Muzzin P, Prentki M et al (2001) Uncoupling protein 2: a possible link between fatty acid excess and impaired glucose-induced insulin secretion? Diabetes 50:803–809. doi:10.2337/diabetes.50.4.803 CrossRefPubMedGoogle Scholar
  82. 82.
    Joseph JW, Koshkin V, Saleh MC et al (2004) Free fatty acid-induced beta-cell defects are dependent on uncoupling protein 2 expression. J Biol Chem 279:51049–51056. doi:10.1074/jbc.M409189200 CrossRefPubMedGoogle Scholar
  83. 83.
    Shimabukuro M, Wang MY, Zhou YT et al (1998) Protection against lipoapoptosis of beta cells through leptin-dependent maintenance of Bcl-2 expression. Proc Natl Acad Sci USA 95:9558–9561. doi:10.1073/pnas.95.16.9558 CrossRefPubMedGoogle Scholar
  84. 84.
    Cheng L, Ding G, Qin Q et al (2004) Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy. Nat Med 10:1245–1250. doi:10.1038/nm1116 CrossRefPubMedGoogle Scholar
  85. 85.
    Park TS, Hu Y, Noh HL et al (2008) Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. J Lipid Res 49:2101–2112. doi:10.1194/jlr.M800147-JLR200 CrossRefPubMedGoogle Scholar
  86. 86.
    Hickson-Bick DL, Buja LM, McMillin JB (2000) Palmitate-mediated alterations in the fatty acid metabolism of rat neonatal cardiac myocytes. J Mol Cell Cardiol 32:511–519. doi:10.1006/jmcc.1999.1098 CrossRefPubMedGoogle Scholar
  87. 87.
    Sharma S, Adrogue JV, Golfman L et al (2004) Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J 18:1692–1700. doi:10.1096/fj.04-2263com CrossRefPubMedGoogle Scholar
  88. 88.
    Kankaanpaa M, Lehto HR, Parkka JP et al (2006) Myocardial triglyceride content and epicardial fat mass in human obesity: relationship to left ventricular function and serum free fatty acid levels. J Clin Endocrinol Metab 91:4689–4695. doi:10.1210/jc.2006-0584 CrossRefPubMedGoogle Scholar
  89. 89.
    Spalding KL, Arner E, Westermark PO et al (2008) Dynamics of fat cell turnover in humans. Nature 453:783–787. doi:10.1038/nature06902 CrossRefPubMedGoogle Scholar
  90. 90.
    Khan T, Muise ES, Iyengar P et al. (2009) Metabolic dysregulation and adipose tissue fibrosis: the role of collagen VI. Mol Cell Biol 29:1575–1591CrossRefPubMedGoogle Scholar
  91. 91.
    Demeulemeester D, Collen D, Lijnen HR (2005) Effect of matrix metalloproteinase inhibition on adipose tissue development. Biochem Biophys Res Commun 329:105–110. doi:10.1016/j.bbrc.2005.01.103 CrossRefPubMedGoogle Scholar
  92. 92.
    Strissel KJ, Stancheva Z, Miyoshi H et al (2007) Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes 56:2910–2918. doi:10.2337/db07-0767 CrossRefPubMedGoogle Scholar
  93. 93.
    Duffield JS (2003) The inflammatory macrophage: a story of Jekyll and Hyde. Clin Sci (Lond) 104:27–38. doi:10.1042/CS20020240 CrossRefGoogle Scholar
  94. 94.
    Pajvani UB, Trujillo ME, Combs TP et al (2005) Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Nat Med 11:797–803. doi:10.1038/nm1262 CrossRefPubMedGoogle Scholar
  95. 95.
    Saha AK, Ruderman NB (2003) Malonyl-CoA and AMP-activated protein kinase: an expanding partnership. Mol Cell Biochem 253:65–70. doi:10.1023/A:1026053302036 CrossRefPubMedGoogle Scholar
  96. 96.
    Higa M, Zhou YT, Ravazzola M et al (1999) Troglitazone prevents mitochondrial alterations, beta cell destruction, and diabetes in obese prediabetic rats. Proc Natl Acad Sci USA 96:11513–11518. doi:10.1073/pnas.96.20.11513 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Christine M. Kusminski
    • 1
  • Shoba Shetty
    • 1
  • Lelio Orci
    • 3
  • Roger H. Unger
    • 1
  • Philipp E. Scherer
    • 1
    • 2
  1. 1.Department of Internal Medicine, Touchstone Diabetes CenterUniversity of Texas Southwestern Medical CenterDallasUSA
  2. 2.Department of Cell BiologyUniversity of Texas Southwestern Medical CenterDallasUSA
  3. 3.Faculty of Medicine, Department of Cell Physiology and MetabolismCMU, University of GenevaGeneva 4Switzerland

Personalised recommendations