Skip to main content

Advertisement

Log in

Lipotoxicity in the Pancreatic Beta Cell: Not Just Survival and Function, but Proliferation as Well?

  • Pathogenesis of Type 2 Diabetes and Insulin Resistance (RM Watanabe, Section Editor)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Free fatty acids (FFAs) exert both positive and negative effects on beta cell survival and insulin secretory function, depending on concentration, duration, and glucose abundance. Lipid signals are mediated not only through metabolic pathways, but also through cell surface and nuclear receptors. Toxicity is modulated by positive signals arising from circulating factors such as hormones, growth factors and incretins, as well as negative signals such as inflammatory mediators and cytokines. Intracellular mechanisms of lipotoxicity include metabolic interference and cellular stress responses such as oxidative stress, endoplasmic reticulum (ER) stress, and possibly autophagy. New findings strengthen an old hypothesis that lipids may also impair compensatory beta cell proliferation. Clinical observations continue to support a role for lipid biology in the risk and progression of both type 1 (T1D) and type 2 diabetes (T2D). This review summarizes recent work in this important, rapidly evolving field.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Poitout V, Robertson RP. Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocr Rev. 2008;29:351–66.

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Prentki M, Matschinsky FM, Madiraju SR. Metabolic signaling in fuel-induced insulin secretion. Cell Metab. 2013;18:162–85.

    CAS  PubMed  Google Scholar 

  3. Kondegowda NG, Mozar A, Chin C, et al. Lactogens protect rodent and human beta cells against glucolipotoxicity-induced cell death through Janus Kinase-2 (Jak2)/signal transducer and activator of transcription-5 (Stat5) Signaling. Diabetologia. 2012;55:1721–32.

    CAS  PubMed  Google Scholar 

  4. Gonzalez-Pertusa JA, Dube J, Valle SR, et al. Novel proapoptotic effect of hepatocyte growth factor: synergy with palmitate to cause pancreatic {Beta}-cell apoptosis. Endocrinology. 2010;151:1487–98.

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Lin HY, Yin Y, Zhang JX, et al. Identification of direct Forkhead Box O1 targets involved in palmitate-induced apoptosis in clonal insulin-secreting cells using chromatin immunoprecipitation coupled to DNA selection and ligation. Diabetologia. 2012;55:2703–12.

    CAS  PubMed  Google Scholar 

  6. Tiano JP, Delghingaro-Augusto V, Le May C, et al. Estrogen receptor activation reduces lipid synthesis in pancreatic islets and prevents beta cell failure in rodent models of type 2 diabetes. J Clin Invest. 2011;121:3331–42. Important work linking lipid metabolism to estradiol signaling in beta cells.

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Kang ZF, Deng Y, Zhou Y, et al. Pharmacological reduction of Nefa restores the efficacy of incretin-based therapies through Glp-1 receptor signalling in the beta cell in mouse models of diabetes. Diabetologia. 2013;56:423–33.

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Kimple ME, Keller MP, Rabaglia MR, et al. Prostaglandin E2 receptor, Ep3, is induced in diabetic islets and negatively regulates glucose- and hormone-stimulated insulin secretion. Diabetes. 2013;62:1904–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Hodson DJ, Mitchell RK, Bellomo EA, et al. Lipotoxicity disrupts incretin-regulated human beta cell connectivity. J Clin Invest. 2013;123:4182–94.

    CAS  PubMed  Google Scholar 

  10. Liu Z, Stanojevic V, Brindamour LJ, Habener JF. Glp1-derived nonapeptide Glp1(28–36) amide protects pancreatic beta-cells from glucolipotoxicity. J Endocrinol. 2012;213:143–54.

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Miao XY, Gu ZY, Liu P, et al. The human glucagon-like peptide-1 analogue liraglutide regulates pancreatic beta-cell proliferation and apoptosis via an Ampk/Mtor/P70s6k signaling pathway. Peptides. 2013;39:71–9.

    CAS  PubMed  Google Scholar 

  12. Wang HW, Mizuta M, Saitoh Y, et al. Glucagon-like peptide-1 and candesartan additively improve glucolipotoxicity in pancreatic beta-cells. Metabolism. 2011;60:1081–9.

    CAS  PubMed  Google Scholar 

  13. Hong SW, Lee J, Park SE, et al. Repression of sterol regulatory element-binding protein 1-C is involved in the protective effects of Exendin-4 in pancreatic beta-cell line. Mol Cell Endocrinol. 2012;362:242–52.

    CAS  PubMed  Google Scholar 

  14. Shimoda M, Kanda Y, Hamamoto S, et al. The human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells via regulation of cell kinetics and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes. Diabetologia. 2011;54:1098–108.

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Shah P, Ardestani A, Dharmadhikari G, et al. The Dpp-4 inhibitor linagliptin restores beta-cell function and survival in human isolated islets through Glp-1 stabilization. J Clin Endocrinol Metab. 2013;98:E1163–72.

    CAS  PubMed  Google Scholar 

  16. Mirmira RG. Saturated free fatty acids: islet beta cell "Stressers". Endocrine. 2012;42:1–2.

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Tang C, Naassan AE, Chamson-Reig A, et al. Susceptibility to fatty acid-induced beta-cell dysfunction is enhanced in prediabetic diabetes-prone biobreeding rats: a potential link between beta-cell lipotoxicity and islet inflammation. Endocrinology. 2013;154:89–101.

    CAS  PubMed  Google Scholar 

  18. Donath MY, Dalmas E, Sauter NS, Boni-Schnetzler M. Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity. Cell Metab. 2013;17:860–72.

    CAS  PubMed  Google Scholar 

  19. Eguchi K, Manabe I, Oishi-Tanaka Y, et al. Saturated fatty acid and Tlr signaling link beta cell dysfunction and islet inflammation. Cell Metab. 2012;15:518–33. This paper shows the critical role inflammation plays in lipotoxicity.

    CAS  PubMed  Google Scholar 

  20. Saksida T, Stosic-Grujicic S, Timotijevic G, et al. Macrophage migration inhibitory factor deficiency protects pancreatic islets from palmitic acid-induced apoptosis. Immunol Cell Biol. 2012;90:688–98.

    CAS  PubMed  Google Scholar 

  21. Amyot J, Semache M, Ferdaoussi M, et al. Lipopolysaccharides impair insulin gene expression in isolated islets of langerhans via toll-like Receptor-4 and Nf-Kappab Signaling. PLoS ONE. 2012;7:e36200.

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Miani M, Colli ML, Ladriere L, et al. Mild endoplasmic reticulum stress augments the proinflammatory effect of Il-1beta in pancreatic rat beta-cells via the Ire1alpha/Xbp1s pathway. Endocrinology. 2012;153:3017–28.

    CAS  PubMed  Google Scholar 

  23. Weaver JR, Holman TR, Imai Y, et al. Integration of pro-inflammatory cytokines, 12-Lipoxygenase and Nox-1 in pancreatic islet beta cell dysfunction. Mol Cell Endocrinol. 2012;358:88–95.

    CAS  PubMed  Google Scholar 

  24. Mohammed AM, Syeda K, Hadden T, Kowluru A. Upregulation of phagocyte-like Nadph oxidase by cytokines in pancreatic beta-cells: attenuation of oxidative and nitrosative stress by 2-Bromopalmitate. Biochem Pharmacol. 2013;85:109–14.

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Poitout V, Lin DC. Modulating Gpr40: therapeutic promise and potential in diabetes. Drug Discov Today. 2013;18:1301–8. Interesting review of progress toward therapeutic use of FFAR1 agonists.

    CAS  PubMed  Google Scholar 

  26. Mancini AD, Poitout V. The fatty acid receptor Ffa1/Gpr40 a decade later: how much do we know? Trends Endocrinol Metab. 2013;24:398–407.

    CAS  PubMed  Google Scholar 

  27. Ferdaoussi M, Bergeron V, Zarrouki B, et al. G protein-coupled receptor (Gpr)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1. Diabetologia. 2012;55:2682–92.

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Xiong Y, Swaminath G, Cao Q, et al. Activation of Ffa1 mediates Glp-1 secretion in mice. Evidence for allosterism at Ffa1. Mol Cell Endocrinol. 2013;369:119–29.

    CAS  PubMed  Google Scholar 

  29. Meidute Abaraviciene S, Muhammed SJ, Amisten S, et al. Gpr40 protein levels are crucial to the regulation of stimulated hormone secretion in pancreatic islets. Lessons from spontaneous obesity-prone and non-obese type 2 diabetes in rats. Mol Cell Endocrinol. 2013;381:150–9.

    CAS  PubMed  Google Scholar 

  30. Tuo Y, Feng DD, Wang DF, et al. Long-term in vitro treatment of Ins-1 rat pancreatic beta-cells by unsaturated free fatty acids protects cells against gluco- and lipotoxicities via activation of Gpr40 receptors. Clin Exp Pharmacol Physiol. 2012;39:423–8.

    CAS  PubMed  Google Scholar 

  31. Wagner R, Kaiser G, Gerst F, et al. Reevaluation of fatty acid receptor 1 as a drug target for the stimulation of insulin secretion in humans. Diabetes. 2013;62:2106–11.

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Lin DC, Guo Q, Luo J, et al. Identification and pharmacological characterization of multiple allosteric binding sites on the free fatty acid 1 receptor. Mol Pharmacol. 2012;82:843–59.

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Yabuki C, Komatsu H, Tsujihata Y, et al. A novel antidiabetic drug, Fasiglifam/Tak-875, acts as an ago-allosteric modulator of Ffar1. PLoS ONE. 2013;8:e76280.

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Ito R, Tsujihata Y, Matsuda-Nagasumi K, et al. Tak-875, a Gpr40/Ffar1 agonist, in combination with metformin prevents progression of diabetes and beta-cell dysfunction in Zucker diabetic fatty rats. Br J Pharmacol. 2013;170:568–80.

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Ou HY, Wu HT, Hung HC, et al. Multiple mechanisms of Gw-9508, a selective G protein-coupled receptor 40 agonist, in the regulation of glucose homeostasis and insulin sensitivity. Am J Physiol Endocrinol Metab. 2013;304:E668–76.

    CAS  PubMed  Google Scholar 

  36. Gowda N, Dandu A, Singh J, et al. Treatment with Cnx-011-67, a novel Gpr40 agonist, delays onset and progression of diabetes and improves beta cell preservation and function in male Zdf rats. BMC Pharmacol Toxicol. 2013;14:28.

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Kristinsson H, Smith DM, Bergsten P, Sargsyan E. Ffar1 is involved in both the acute and chronic effects of palmitate on insulin secretion. Endocrinology. 2013;154:4078–88.

    CAS  PubMed  Google Scholar 

  38. Sun P, Wang T, Zhou Y, et al. Dc260126: a small-molecule antagonist of Gpr40 that protects against pancreatic beta-cells dysfunction in Db/Db mice. PLoS ONE. 2013;8:e66744.

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Wu J, Sun P, Zhang X, et al. Inhibition of Gpr40 protects Min6 beta cells from palmitate-induced Er stress and apoptosis. J Cell Biochem. 2012;113:1152–8.

    CAS  PubMed  Google Scholar 

  40. Prentki M, Madiraju SR. Glycerolipid/free fatty acid cycle and islet beta-cell function in health, obesity and diabetes. Mol Cell Endocrinol. 2012;353:88–100.

    CAS  PubMed  Google Scholar 

  41. Nyren R, Chang CL, Lindstrom P, et al. Localization of lipoprotein lipase and Gpihbp1 in mouse pancreas: effects of diet and leptin deficiency. BMC Physiol. 2012;12:14.

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Klett EL, Chen S, Edin ML, et al. Diminished acyl-coa synthetase isoform 4 activity in Ins 832/13 cells reduces cellular epoxyeicosatrienoic acid levels and results in impaired glucose-stimulated insulin secretion. J Biol Chem. 2013;288:21618–29. Insight into the role of acyl-CoA synthases in beta cell function.

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Sargsyan E, Sol ER, Bergsten P. Upr in palmitate-treated pancreatic beta-cells is not affected by altering oxidation of the fatty acid. Nutr Metab. 2011;8:70.

    CAS  Google Scholar 

  44. Choi SE, Jung IR, Lee YJ, et al. Stimulation of lipogenesis as well as fatty acid oxidation protects against palmitate-induced Ins-1 beta-cell death. Endocrinology. 2011;152:816–27.

    CAS  PubMed  Google Scholar 

  45. Vernier S, Chiu A, Schober J, et al. Beta-cell metabolic alterations under chronic nutrient overload in rat and human islets. Islets. 2012;4:379–92.

    PubMed Central  PubMed  Google Scholar 

  46. Ohtsubo K, Chen MZ, Olefsky JM, Marth JD. Pathway to diabetes through attenuation of pancreatic beta cell glycosylation and glucose transport. Nat Med. 2011;17:1067–75.

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Somesh BP, Verma MK, Sadasivuni MK, et al. Chronic glucolipotoxic conditions in pancreatic islets impair insulin secretion due to dysregulated calcium dynamics, glucose responsiveness and mitochondrial activity. BMC Cell Biol. 2013;14:31.

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Barlow J, Affourtit C. Novel insights into pancreatic beta-cell glucolipotoxicity from real-time functional analysis of mitochondrial energy metabolism in Ins-1e insulinoma cells. Biochem J. 2013;456:417–26.

    CAS  PubMed  Google Scholar 

  49. Zraika S, Koh DS, Barrow BM, et al. Neprilysin deficiency protects against fat-induced insulin secretory dysfunction by maintaining calcium influx. Diabetes. 2013;62:1593–601.

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Malmgren S, Spegel P, Danielsson AP, et al. Coordinate changes in histone modifications, Mrna levels, and metabolite profiles in clonal Ins-1 832/13 beta-cells accompany functional adaptations to lipotoxicity. J Biol Chem. 2013;288:11973–87.

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Baldwin AC, Green CD, Olson LK, et al. A role for aberrant protein Palmitoylation in Ffa-induced Er stress and beta-cell death. Am J Physiol Endocrinol Metab. 2012;302:E1390–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Lam AK, Silva PN, Altamentova SM, Rocheleau JV. Quantitative imaging of electron transfer flavoprotein autofluorescence reveals the dynamics of lipid partitioning in living pancreatic islets. Integr Biol. 2012;4:838–46. Impressive technique for visualizing metabolic pathways.

    CAS  Google Scholar 

  53. Boslem E, Meikle PJ, Biden TJ. Roles of ceramide and sphingolipids in pancreatic beta-cell function and dysfunction. Islets. 2012;4:177–87.

    PubMed Central  PubMed  Google Scholar 

  54. Marcal AC, Camporez JP, Lima-Salgado TM, et al. Changes in food intake, metabolic parameters and insulin resistance are induced by an isoenergetic, medium-chain fatty acid diet and are associated with modifications in insulin signaling in isolated rat pancreatic islets. Br J Nutr. 2013;109:2154–65.

    CAS  PubMed  Google Scholar 

  55. Zhou H, Li C, Li J, et al. Associations of Atp-binding cassette transporter A1 and G1 with insulin secretion in human insulinomas. Pancreas. 2012;41:934–9.

    CAS  PubMed  Google Scholar 

  56. Jelinek D, Castillo JJ, Garver WS. The C57bl/6j Niemann-Pick C1 mouse model with decreased gene dosage has impaired glucose tolerance independent of body weight. Gene. 2013;527:65–70.

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Meng ZX, Yin Y, Lv JH, et al. Aberrant activation of liver X receptors impairs pancreatic beta cell function through upregulation of sterol regulatory element-binding protein 1c in mouse islets and rodent cell lines. Diabetologia. 2012;55:1733–44.

    CAS  PubMed  Google Scholar 

  58. Graciano MF, Valle MM, Kowluru A, et al. Regulation of insulin secretion and reactive oxygen species production by free fatty acids in pancreatic islets. Islets. 2011;3:213–23.

    PubMed  Google Scholar 

  59. MacDonald MJ, Langberg EC, Tibell A, et al. Identification of Atp synthase as a lipid peroxide protein adduct in pancreatic islets from humans with and without type 2 diabetes mellitus. J Clin Endocrinol Metab. 2013;98:E727–31.

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Koulajian K, Ivovic A, Ye K, et al. Overexpression of glutathione peroxidase 4 prevents beta-cell dysfunction induced by prolonged elevation of lipids in vivo. Am J Physiol Endocrinol Metab. 2013;305:E254–62.

    CAS  PubMed  Google Scholar 

  61. Koulajian K, Desai T, Liu GC, et al. Nadph oxidase inhibition prevents beta cell dysfunction induced by prolonged elevation of oleate in rodents. Diabetologia. 2013;56:1078–87.

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Lee SJ, Choi SE, Jung IR, et al. Protective effect of nicotinamide on high glucose/palmitate-induced glucolipotoxicity to Ins-1 beta cells is attributed to its inhibitory activity to sirtuins. Arch Biochem Biophys. 2013;535:187–96.

    CAS  PubMed  Google Scholar 

  63. Back SH, Kaufman RJ. Endoplasmic reticulum stress and type 2 diabetes. Annu Rev Biochem. 2012;81:767–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Schuiki I, Zhang L, Volchuk A. Endoplasmic reticulum redox state is not perturbed by pharmacological or pathological endoplasmic reticulum stress in live pancreatic beta-cells. PLoS ONE. 2012;7:e48626.

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Sommerweiss D, Gorski T, Richter S, et al. Oleate rescues Ins-1e beta-cells from palmitate-induced apoptosis by preventing activation of the unfolded protein response. Biochem Biophys Res Commun. 2013;441:770–6.

    CAS  PubMed  Google Scholar 

  66. Cui W, Ma J, Wang X, et al. Free fatty acid induces endoplasmic reticulum stress and apoptosis of beta-cells by Ca2+/Calpain-2 pathways. PLoS ONE. 2013;8:e59921.

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Vasu S, McClenaghan NH, McCluskey JT, Flatt PR. Effects of lipotoxicity on a novel insulin-secreting human pancreatic beta-cell line, 1.1b4. J Biol Chem. 2013;394:909–18.

    CAS  Google Scholar 

  68. Qi Y, Xia P. Cellular inhibitor of apoptosis protein-1 (Ciap1) plays a critical role in beta-cell survival under endoplasmic reticulum stress: promoting ubiquitination and degradation of C/Ebp homologous protein (Chop). J Biol Chem. 2012;287:32236–45.

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Cunha DA, Igoillo-Esteve M, Gurzov EN, et al. Death protein 5 and P53-upregulated modulator of apoptosis mediate the endoplasmic reticulum stress-mitochondrial dialog triggering lipotoxic rodent and human beta-cell apoptosis. Diabetes. 2012;61:2763–75. Novel pathway implicated in lipotoxic beta cell death.

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Chu KY, Li H, Wada K, Johnson JD. Ubiquitin C-Terminal hydrolase L1 Is required for pancreatic beta cell survival and function in lipotoxic conditions. Diabetologia. 2012;55:128–40.

    CAS  PubMed  Google Scholar 

  71. Wikstrom JD, Israeli T, Bachar-Wikstrom E, et al. Ampk regulates Er morphology and function in stressed pancreatic beta-cells via phosphorylation of Drp1. Mol Endocrinol. 2013;27:1706–23.

    CAS  PubMed  Google Scholar 

  72. Boslem E, Weir JM, MacIntosh G, et al. Alteration of endoplasmic reticulum lipid rafts contributes to lipotoxicity in pancreatic beta-cells. J Biol Chem. 2013;288:26569–82.

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Sabatini PV, Krentz NA, Zarrouki B, et al. Npas4 is a novel activity-regulated cytoprotective factor in pancreatic beta-cells. Diabetes. 2013;62:2808–20.

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Oh YS, Lee YJ, Kang Y, et al. Exendin-4 inhibits glucolipotoxic Er stress in pancreatic beta cells via regulation of Srebp1c and C/Ebpbeta transcription factors. J Endocrinol. 2013;216:343–52.

    CAS  PubMed  Google Scholar 

  75. Martino L, Masini M, Novelli M, et al. Palmitate activates autophagy in Ins-1e beta-cells and in isolated rat and human pancreatic islets. PLoS ONE. 2012;7:e36188.

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Li S, Du L, Zhang L, et al. Cathepsin B contributes to autophagy-related 7 (Atg7)-induced nod-like receptor 3 (Nlrp3)-dependent proinflammatory response and aggravates lipotoxicity in rat insulinoma cell line. J Biol Chem. 2013;288:30094–104.

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Quan W, Hur KY, Lim Y, et al. Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice. Diabetologia. 2012;55:392–403.

    CAS  PubMed  Google Scholar 

  78. Las G, Serada SB, Wikstrom JD, et al. Fatty acids suppress autophagic turnover in beta-cells. J Biol Chem. 2011;286:42534–44.

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Hogh KL, Uy CE, Asadi A, et al. Overexpression of peroxisome proliferator-activated receptor alpha in pancreatic beta-cells improves glucose tolerance in diet-induced obese mice. Exp Physiol. 2013;98:564–75.

    CAS  PubMed  Google Scholar 

  80. da Silva FT, Correia-Junior AL, Dos Anjos TL, et al. Adverse association between obesity and menopause in mice treated with bezafibrate, a pan peroxisome proliferator-activated receptor agonist. Menopause. 2013;20:1264–74.

    Google Scholar 

  81. Vivas Y, Martinez-Garcia C, Izquierdo A, et al. Early peroxisome proliferator-activated receptor gamma regulated genes involved in expansion of pancreatic beta cell mass. BMC Med Genom. 2011;4:86.

    CAS  Google Scholar 

  82. Kim HS, Hwang YC, Koo SH, et al. PPAR-gamma activation increases insulin secretion through the up-regulation of the free fatty acid receptor Gpr40 in pancreatic beta-cells. PLoS ONE. 2013;8:e50128.

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Rhodes CJ. Igf-I and Gh post-receptor signaling mechanisms for pancreatic beta-cell replication. J Mol Endocrinol. 2000;24:303–11.

    CAS  PubMed  Google Scholar 

  84. Cousin SP, Hugl SR, Wrede CE, et al. Free fatty acid-induced inhibition of glucose and insulin-like growth factor I-induced deoxyribonucleic acid synthesis in the pancreatic beta-cell line Ins-1. Endocrinology. 2001;142:229–40.

    CAS  PubMed  Google Scholar 

  85. Maedler K, Oberholzer J, Bucher P, et al. Monounsaturated fatty acids prevent the deleterious effects of palmitate and high glucose on human pancreatic beta-cell turnover and function. Diabetes. 2003;52:726–33.

    CAS  PubMed  Google Scholar 

  86. Layden BT, Durai V, Newman MV, et al. Regulation of pancreatic islet gene expression in mouse islets by pregnancy. J Endocrinol. 2010;207:265–79.

    CAS  PubMed  Google Scholar 

  87. Pascoe J, Hollern D, Stamateris R, et al. Free fatty acids block glucose-induced beta-cell proliferation in mice by inducing cell cycle inhibitors P16 and P18. Diabetes. 2012;61:632–41. Infusion of lipids into mice prevents glucose-induced beta cell proliferation.

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Prentki M, Madiraju SR. Glycerolipid metabolism and signaling in health and disease. Endocr Rev. 2008;29:647–76.

    CAS  PubMed  Google Scholar 

  89. Stamateris RE, Sharma RB, Hollern DA, Alonso LC. Adaptive beta-cell proliferation increases early in high-fat feeding in mice, concurrent with metabolic changes, with induction of islet Cyclin D2 expression. Am J Physiol Endocrinol Metab. 2013;305:E149–59.

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Brelje TC, Bhagroo NV, Stout LE, Sorenson RL. Beneficial effects of lipids and prolactin on insulin secretion and beta-cell proliferation: a role for lipids in the adaptation of islets to pregnancy. J Endocrinol. 2008;197:265–76.

    CAS  PubMed  Google Scholar 

  91. Delghingaro-Augusto V, Nolan CJ, Gupta D, et al. Islet beta cell failure in the 60 % pancreatectomized obese hyperlipidemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass. Diabetologia. 2009;52:1122–32.

    CAS  PubMed  Google Scholar 

  92. Fontes G, Zarrouki B, Hagman DK, et al. Glucolipotoxicity age-dependently impairs beta cell function in rats despite a marked increase in beta cell mass. Diabetologia. 2010;53:2369–79. Infusion of lipids and glucose together into rats results in greatly increased beta cell proliferation.

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Steil GM, Trivedi N, Jonas JC, et al. Adaptation of beta-cell mass to substrate oversupply: enhanced function with normal gene expression. Am J Physiol Endocrinol Metab. 2001;280:E788–96.

    CAS  PubMed  Google Scholar 

  94. Fazio S, Linton MF. Killing two birds with one stone, maybe: Cetp inhibition increases both high-density lipoprotein levels and insulin secretion. Circ Res. 2013;113:94–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Imamura F, Mukamal KJ, Meigs JB, et al. Risk factors for type 2 diabetes mellitus preceded by beta-cell dysfunction, insulin resistance, or both in older adults: the Cardiovascular Health Study. Am J Epidemiol. 2013;177:1418–29.

    PubMed Central  PubMed  Google Scholar 

  96. Zheng T, Gao Y, Tian H. Relationship between blood lipid profiles and pancreatic islet beta cell function in Chinese men and women with normal glucose tolerance: a cross-sectional study. BMC Publ Health. 2012;12:634.

    Google Scholar 

  97. Hughan KS, Bonadonna RC, Lee S, et al. Beta-cell lipotoxicity after an overnight intravenous lipid challenge and free fatty acid elevation in African American versus American White overweight/obese adolescents. J Clin Endocrinol Metab. 2013;98:2062–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Michaliszyn SF, Bonadonna RC, Sjaarda LA, et al. Beta-cell lipotoxicity in response to free fatty acid elevation in prepubertal youth: African American versus Caucasian Contrast. Diabetes. 2013;62:2917–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Salgin B, Ong KK, Thankamony A, et al. Higher fasting plasma free fatty acid levels are associated with lower insulin secretion in children and adults and a higher incidence of type 2 diabetes. J Clin Endocrinol Metab. 2012;97:3302–9.

    CAS  PubMed  Google Scholar 

  100. Lopez X, Cypess A, Manning R, et al. Exogenous insulin enhances glucose-stimulated insulin response in healthy humans independent of changes in free fatty acids. J Clin Endocrinol Metab. 2011;96:3811–21. Potentiation of insulin secretion by insulin is not due to suppression of lipolysis and reduced FFAs.

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Colbert JD, Stone JA. Statin use and the risk of incident diabetes mellitus: a review of the literature. Can J Cardiol. 2012;28:581–9.

    PubMed  Google Scholar 

  102. Strom A, Kolb H, Martin S, et al. Improved preservation of residual beta cell function by atorvastatin in patients with recent onset type 1 diabetes and high Crp levels (Diator Trial). PLoS ONE. 2012;7:e33108.

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Abbasi A, Corpeleijn E, Gansevoort RT, et al. Role of HDL cholesterol and estimates of HDL particle composition in future development of type 2 diabetes in the general population: the prevent study. J Clin Endocrinol Metab. 2013;98:E1352–9.

    CAS  PubMed  Google Scholar 

  104. Siebel AL, Natoli AK, Yap FY, et al. Effects of high-density lipoprotein elevation with cholesteryl ester transfer protein inhibition on insulin secretion. Circ Res. 2013;113:167–75.

    CAS  PubMed  Google Scholar 

  105. Zhang Q, Wan R, Guo R, et al. Long-term high density lipoprotein infusion ameliorates metabolic phenotypes of diabetic Db/Db mice. Diabetes Metab Res Rev. 2013;29:130–8.

    CAS  PubMed  Google Scholar 

  106. Petremand J, Puyal J, Chatton JY, et al. HDLs protect pancreatic beta-cells against Er stress by restoring protein folding and trafficking. Diabetes. 2012;61:1100–11.

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Taylor R. Banting memorial lecture 2012: reversing the twin cycles of type 2 diabetes. Diabet Med. 2013;30:267–75.

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Natali A, Gastaldelli A, Camastra S, et al. Metabolic consequences of adipose triglyceride lipase deficiency in humans: an in vivo study in patients with neutral lipid storage disease with myopathy. J Clin Endocrinol Metab. 2013;98:E1540–8.

    CAS  PubMed  Google Scholar 

  109. Szczepaniak LS, Victor RG, Mathur R, et al. Pancreatic steatosis and its relationship to beta-cell dysfunction in humans: racial and ethnic variations. Diabetes Care. 2012;35:2377–83.

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

Funding supporting this work includes NIH: DK095140 (LCA).

Compliance with Ethics Guidelines

Conflict of Interest

Rohit B. Sharma and Laura C. Alonso declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Laura C. Alonso.

Additional information

This article is part of the Topical Collection on Pathogenesis of Type 2 Diabetes and Insulin Resistance

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sharma, R.B., Alonso, L.C. Lipotoxicity in the Pancreatic Beta Cell: Not Just Survival and Function, but Proliferation as Well?. Curr Diab Rep 14, 492 (2014). https://doi.org/10.1007/s11892-014-0492-2

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11892-014-0492-2

Keywords

Navigation