32. Gomez E, Pritchard C, Herbert TP (2002) cAMP-dependent protein kinase and Ca2+ influx through L-type voltage-gated calcium channels mediate Raf- independent activation of extracellular regulated kinase in response to glucagon- like peptide-1 in pancreatic beta-cells. J Biol Chem 277: 48146–48151. 33. Beha A, Juretschke HP, Kuhlmann J, Neumann-Haefelin C, Belz U, et al. (2006) Muscle type-specific fatty acid metabolism in insulin resistance: an integrated in vivo study in Zucker diabetic fatty rats. Am J Physiol 290: E989–E997. 34. Kahn BB, Flier JS (2000) Obesity and insulin resistance. J Clin Invest 106: 473–481. 35. Kharroubi I, Ladriere L, Cardozo AK, Dogusan Z, Cnop M, et al. (2004) Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress. Endocrinology 145: 5087–5096. 36. Boslem E, MacIntosh G, Preston AM, Bartley C, Busch AK, et al. (2011) A lipidomic screen of palmitate-treated MIN6 beta-cells links sphingolipid metabolites with endoplasmic reticulum (ER) stress and impaired protein trafficking. Biochem J 435: 267–276. 37. Thorn K, Bergsten P (2010) Fatty acid-induced oxidation and triglyceride formation is higher in insulin-producing MIN6 cells exposed to oleate compared to palmitate. J Cell Biochem 111: 497–507. 38. Fontes G, Semache M, Hagman DK, Tremblay C, Shah R, et al. (2009) Involvement of Per-Arnt-Sim Kinase and extracellular-regulated kinases-1/2 in palmitate inhibition of insulin gene expression in pancreatic beta-cells. Diabetes 58: 2048–2058. 39. Marchesini N, Hannun YA (2004) Acid and neutral sphingomyelinases: roles and mechanisms of regulation. Biochem Cell Biol 82: 27–44. 40. Da S, X, Leclerc I, Varadi A, Tsuboi T, Moule SK, et al. (2003) Role for AMP- activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression. Biochem J 371: 761–774. 41. Bain J, Plater L, Elliott M, Shpiro N, Hastie CJ, et al. (2007) The selectivity of protein kinase inhibitors: a further update. Biochem J 408: 297–315. 42. Benes C, Poitout V, Marie JC, Martin-Perez J, Roisin MP, et al. (1999) Mode of regulation of the extracellular signal-regulated kinases in the pancreatic beta-cell line MIN6 and their implication in the regulation of insulin gene transcription. Biochem J 340(Pt 1): 219–225. 43. Kowluru A, Veluthakal R, Rhodes CJ, Kamath V, Syed I, et al. (2010) Protein farnesylation-dependent Raf/extracellular signal-related kinase signaling links to Palmitate and Beta Cell Insulin Secretion cytoskeletal remodeling to facilitate glucose-induced insulin secretion in pancreatic beta-cells. Diabetes 59: 967–977. 44. Longuet C, Broca C, Costes S, Hani EH, Bataille D, et al. (2005) Extracellularly regulated kinases 1/2 (p44/42 mitogen-activated protein kinases) phosphorylate synapsin I and regulate insulin secretion in the MIN6 beta-cell line and islets of Langerhans. Endocrinology 146: 643–654. 45. Newsholme P, Gaudel C, McClenaghan NH (2010) Nutrient Regulation of Insulin Secretion and beta-Cell Functional Integrity. Adv Exp Med Biol 654: 91–114. 46. Iizuka K, Nakajima H, Namba M, Miyagawa J, Miyazaki J, et al. (2002) Metabolic consequence of long-term exposure of pancreatic beta cells to free fatty acid with special reference to glucose insensitivity. Biochim Biophys Acta 1586: 23–31. 47. Mynatt RL (2009) Carnitine and type 2 diabetes. Diabetes Metab Res Rev 25 Suppl 1: S45–S49. 48. Briaud I, Harmon JS, Kelpe CL, Segu VB, Poitout V (2001) Lipotoxicity of the pancreatic beta-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids. Diabetes 50: 315–321. 49. Biden TJ, Schmitz-Peiffer C, Burchfield JG, Gurisik E, Cantley J, et al. (2008) The diverse roles of protein kinase C in pancreatic beta-cell function. Biochem Soc Trans 36: 916–919. 50. Cantley J, Burchfield JG, Pearson GL, Schmitz-Peiffer C, Leitges M, et al. (2009) Deletion of PKCepsilon selectively enhances the amplifying pathways of glucose- stimulated insulin secretion via increased lipolysis in mouse beta-cells. Diabetes 58: 1826–1834. 51. Hoppa MB, Collins S, Ramracheya R, Hodson L, Amisten S, et al. (2009) Chronic palmitate exposure inhibits insulin secretion by dissociation of Ca(2+) channels from secretory granules. Cell Metab 10: 455–465. 52. Watson ML, Coghlan M, Hundal HS (2009) Modulating serine palmitoyl transferase (SPT) expression and activity unveils a crucial role in lipid-induced insulin resistance in rat skeletal muscle cells. Biochem J 417: 791–801. 53. Hajduch E, Alessi DR, Hemmings BA, Hundal HS (1998) Constitutive activation of Protein Kinase Ba (PKBa) by membrane targeting promotes glucose and System A amino acid transport, protein synthesis and GSK3 inactivation in L6 muscle cells. Diabetes 47: 1006–1013. PLoS ONE | www.plosone.org 12 October 2011 | Volume 6 | Issue 10 | e25975