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Current Diabetes Reports

, 19:81 | Cite as

The Beta Cell in Type 2 Diabetes

  • Ashley A. Christensen
  • Maureen GannonEmail author
Pathogenesis of Type 2 Diabetes and Insulin Resistance (M-E Patti, Section Editor)
  • 108 Downloads
Part of the following topical collections:
  1. Topical Collection on Pathogenesis of Type 2 Diabetes and Insulin Resistance

Abstract

Purpose of Review

This review summarizes the alterations in the β-cell observed in type 2 diabetes (T2D), focusing on changes in β-cell identity and mass and changes associated with metabolism and intracellular signaling.

Recent Findings

In the setting of T2D, β-cells undergo changes in gene expression, reverting to a more immature state and in some cases transdifferentiating into other islet cell types. Alleviation of metabolic stress, ER stress, and maladaptive prostaglandin signaling could improve β-cell function and survival.

Summary

The β-cell defects leading to T2D likely differ in different individuals and include variations in β-cell mass, development, β-cell expansion, responses to ER and oxidative stress, insulin production and secretion, and intracellular signaling pathways. The recent recognition that some β-cells undergo dedifferentiation without dying in T2D suggests strategies to revive these cells and rejuvenate their functionality.

Keywords

β-cell dysfunction Dedifferentiation Disallowed genes ER stress Oxidative stress β-cell metabolism 

Notes

Funding Information

Ashley A. Christensen was supported in part by the Vanderbilt University Training Program in Molecular Endocrinology (5T32 DK7563-30). Maureen Gannon was supported by grants from the NIH/NIDDK (R01 DK105689 and R24DK090964-06) and by a VA Merit award (1 I01 BX003744-01).

Compliance with Ethical Standards

Conflict of Interest

The authors 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.

References

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

  1. 1.
    Ahren B, Pacini G. Insufficient islet compensation to insulin resistance vs. reduced glucose effectiveness in glucose-intolerant mice. Am J Physiol Endocrinol Metab. 2002;283(4):E738–44.PubMedGoogle Scholar
  2. 2.
    Okamoto H, et al. Role of the forkhead protein FoxO1 in beta cell compensation to insulin resistance. J Clin Invest. 2006;116(3):775–82.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Zhang H, Zhang J, Pope CF, Crawford LA, Vasavada RC, Jagasia SM, et al. Gestational diabetes mellitus resulting from impaired beta-cell compensation in the absence of FoxM1, a novel downstream effector of placental lactogen. Diabetes. 2010;59(1):143–52.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Teta M, Long SY, Wartschow LM, Rankin MM, Kushner JA. Very slow turnover of beta-cells in aged adult mice. Diabetes. 2005;54(9):2557–67.PubMedGoogle Scholar
  5. 5.
    Rankin MM, Kushner JA. Adaptive beta-cell proliferation is severely restricted with advanced age. Diabetes. 2009;58(6):1365–72.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Chen H, Gu X, Liu Y, Wang J, Wirt SE, Bottino R, et al. PDGF signalling controls age-dependent proliferation in pancreatic beta-cells. Nature. 2011;478(7369):349–55.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Wong ES, et al. p38MAPK controls expression of multiple cell cycle inhibitors and islet proliferation with advancing age. Dev Cell. 2009;17(1):142–9.PubMedGoogle Scholar
  8. 8.
    Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52(1):102–10.PubMedGoogle Scholar
  9. 9.
    Fontes G, et al. Glucolipotoxicity age-dependently impairs beta cell function in rats despite a marked increase in beta cell mass. Diabetologia. 2010;53(11):2369–79.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Halban PA, Polonsky KS, Bowden DW, Hawkins MA, Ling C, Mather KJ, et al. Beta-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment. Diabetes Care. 2014;37(6):1751–8.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Cerf ME. High fat programming of beta cell compensation, exhaustion, death and dysfunction. Pediatr Diabetes. 2015;16(2):71–8.PubMedGoogle Scholar
  12. 12.
    Sachdeva MM, Claiborn KC, Khoo C, Yang J, Groff DN, Mirmira RG, et al. Pdx1 (MODY4) regulates pancreatic beta cell susceptibility to ER stress. Proc Natl Acad Sci U S A. 2009;106(45):19090–5.Google Scholar
  13. 13.
    Arunagiri A, Haataja L, Cunningham CN, Shrestha N, Tsai B, Qi L, et al. Misfolded proinsulin in the endoplasmic reticulum during development of beta cell failure in diabetes. Ann N Y Acad Sci. 2018;1418(1):5–19.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Saisho Y, Butler AE, Manesso E, Elashoff D, Rizza RA, Butler PC. Beta-cell mass and turnover in humans: effects of obesity and aging. Diabetes Care. 2013;36(1):111–7.PubMedGoogle Scholar
  15. 15.
    Butler AE, Dhawan S, Hoang J, Cory M, Zeng K, Fritsch H, et al. Beta-cell deficit in obese type 2 diabetes, a minor role of beta-cell dedifferentiation and degranulation. J Clin Endocrinol Metab. 2016;101(2):523–32.Google Scholar
  16. 16.
    Deng S, Vatamaniuk M, Huang X, Doliba N, Lian MM, Frank A, et al. Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects. Diabetes. 2004;53(3):624–32.PubMedGoogle Scholar
  17. 17.
    Jurgens CA, Toukatly MN, Fligner CL, Udayasankar J, Subramanian SL, Zraika S, et al. Beta-cell loss and beta-cell apoptosis in human type 2 diabetes are related to islet amyloid deposition. Am J Pathol. 2011;178(6):2632–40.Google Scholar
  18. 18.
    Linnemann AK, Baan M, Davis DB. Pancreatic beta-cell proliferation in obesity. Adv Nutr. 2014;5(3):278–88.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Elsakr JM, Gannon M. Developmental programming of the pancreatic islet by in utero overnutrition. Trends Dev Biol. 2017;10:79–95.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Talchai C, Xuan S, Lin HV, Sussel L, Accili D. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell. 2012;150(6):1223–34.PubMedPubMedCentralGoogle Scholar
  21. 21.
    •• Nordmann TM, Dror E, Schulze F, Traub S, Berishvili E, Barbieux C, et al. The Role of Inflammation in beta-cell dedifferentiation. Sci Rep. 2017;7(1):6285. Findings from this study reveal that inflammatory cytokines associated with chronic inflammation promote beta cell dedifferentiation in mouse and human islets. Google Scholar
  22. 22.
    Weir GC, Aguayo-Mazzucato C, Bonner-Weir S. Beta-cell dedifferentiation in diabetes is important, but what is it? Islets. 2013;5(5):233–7.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Guo S, Dai C, Guo M, Taylor B, Harmon JS, Sander M, et al. Inactivation of specific beta cell transcription factors in type 2 diabetes. J Clin Invest. 2013;123(8):3305–16.Google Scholar
  24. 24.
    Conrad E, Stein R, Hunter CS. Revealing transcription factors during human pancreatic beta cell development. Trends Endocrinol Metab. 2014;25(8):407–14.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Brereton MF, Rohm M, Ashcroft FM. Beta-cell dysfunction in diabetes: a crisis of identity? Diabetes Obes Metab. 2016;18(Suppl 1):102–9.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Remedi MS, Emfinger C. Pancreatic beta-cell identity in diabetes. Diabetes Obes Metab. 2016;18(Suppl 1):110–6.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Zhang C, Moriguchi T, Kajihara M, Esaki R, Harada A, Shimohata H, et al. MafA is a key regulator of glucose-stimulated insulin secretion. Mol Cell Biol. 2005;25(12):4969–76.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Spijker HS, Ravelli RBG, Mommaas-Kienhuis AM, van Apeldoorn AA, Engelse MA, Zaldumbide A, et al. Conversion of mature human beta-cells into glucagon-producing alpha-cells. Diabetes. 2013;62(7):2471–80.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Cieslar-Pobuda A, et al. Transdifferentiation and reprogramming: overview of the processes, their similarities and differences. Biochim Biophys Acta, Mol Cell Res. 2017;1864(7):1359–69.Google Scholar
  30. 30.
    •• Gutierrez GD, et al. Pancreatic beta cell identity requires continual repression of non-beta cell programs. J Clin Invest. 2017;127(1):244–59. In this study, Nkx2.2, a transcription factor important for beta cell differentiation, was also found to be critical for sustained active maintenance of the beta cell phenotype in adulthood. Studies in mouse and human islets revealed that Nkx2.2 actively represses non-beta cell genes in addtion to activating genes involved in beta cell function. PubMedGoogle Scholar
  31. 31.
    Moin AS, Dhawan S, Cory M, Butler PC, Rizza RA, Butler AE. Increased frequency of hormone negative and polyhormonal endocrine cells in lean individuals with type 2 diabetes. J Clin Endocrinol Metab. 2016;101(10):3628–36.Google Scholar
  32. 32.
    Gao T, McKenna B, Li C, Reichert M, Nguyen J, Singh T, et al. Pdx1 maintains beta cell identity and function by repressing an alpha cell program. Cell Metab. 2014;19(2):259–71.Google Scholar
  33. 33.
    Collombat P, Hecksher-Sørensen J, Krull J, Berger J, Riedel D, Herrera PL, et al. Embryonic endocrine pancreas and mature beta cells acquire alpha and PP cell phenotypes upon Arx misexpression. J Clin Invest. 2007;117(4):961–70.Google Scholar
  34. 34.
    Cinti F, Bouchi R, Kim-Muller JY, Ohmura Y, Sandoval PR, Masini M, et al. Evidence of beta-cell dedifferentiation in human type 2 diabetes. J Clin Endocrinol Metab. 2016;101(3):1044–54.Google Scholar
  35. 35.
    Spijker HS, Song H, Ellenbroek JH, Roefs MM, Engelse MA, Bos E, et al. Loss of beta-cell identity occurs in type 2 diabetes and is associated with islet amyloid deposits. Diabetes. 2015;64(8):2928–38.PubMedGoogle Scholar
  36. 36.
    Thorel F, Népote V, Avril I, Kohno K, Desgraz R, Chera S, et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature. 2010;464(7292):1149–54.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Ye L, Robertson MA, Hesselson D, Stainier DYR, Anderson RM. Glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis. Development. 2015;142(8):1407–17.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Lee SH, et al., Insulin acts as a repressive factor to inhibit the ability of PAR2 to induce islet cell transdifferentiation. Islets, 2018: p. 1–12.Google Scholar
  39. 39.
    Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature. 2008;455(7213):627–32.PubMedGoogle Scholar
  40. 40.
    Clayton HW, Osipovich AB, Stancill JS, Schneider JD, Vianna PG, Shanks CM, et al. Pancreatic inflammation redirects acinar to beta cell reprogramming. Cell Rep. 2016;17(8):2028–41.Google Scholar
  41. 41.
    • van der Meulen T, et al. Virgin beta cells persist throughout life at a neogenic niche within pancreatic islets. Cell Metab. 2017;25(4):911–926 e6. This study identified a population of immature beta-like cells within mouse islets that are derived from the transdifferentiation of non-beta cell precursors. These cells are capable of maturing into fully functional, mature beta cells. PubMedGoogle Scholar
  42. 42.
    Quintens R, Hendrickx N, Lemaire K, Schuit F. Why expression of some genes is disallowed in beta-cells. Biochem Soc Trans. 2008;36(Pt 3):300–5.PubMedGoogle Scholar
  43. 43.
    Pullen TJ, Khan AM, Barton G, Butcher SA, Sun G, Rutter GA. Identification of genes selectively disallowed in the pancreatic islet. Islets. 2010;2(2):89–95.PubMedGoogle Scholar
  44. 44.
    Schuit F, van Lommel L, Granvik M, Goyvaerts L, de Faudeur G, Schraenen A, et al. Beta-cell-specific gene repression: a mechanism to protect against inappropriate or maladjusted insulin secretion? Diabetes. 2012;61(5):969–75.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Constantin-Teodosiu D. Regulation of muscle pyruvate dehydrogenase complex in insulin resistance: effects of exercise and dichloroacetate. Diabetes Metab J. 2013;37(5):301–14.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Otonkinski T, et al. Physical exercise-induced hyperglycemia caused by failed silencing of monocarboxylate transporter 1 in pancreatic beta cells. Am J Hum Genet. 2007;81(3):467–74.Google Scholar
  47. 47.
    Becker TC, BeltrandelRio H, Noel RJ, Johnson JH, Newgard CB. Overexpression of hexokinase I in isolated islets of Langerhans via recombinant adenovirus. Enhancement of glucose metabolism and insulin secretion at basal but not stimulatory glucose levels. J Biol Chem. 1994;269(33):21234–8.PubMedGoogle Scholar
  48. 48.
    Lemaire K, Thorrez L, Schuit F. Disallowed and allowed gene expression: two faces of mature islet Beta cells. Annu Rev Nutr. 2016;36:45–71.PubMedGoogle Scholar
  49. 49.
    Cavadas MA, et al. REST is a hypoxia-responsive transcriptional repressor. Sci Rep. 2016;6:31355.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Martin D, Grapin-Botton A. The importance of REST for development and function of beta cells. Front Cell Dev Biol. 2017;5:12.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Lu M, Zheng L, Han B, Wang L, Wang P, Liu H, et al. REST regulates DYRK1A transcription in a negative feedback loop. J Biol Chem. 2011;286(12):10755–63.PubMedGoogle Scholar
  52. 52.
    Wang P, Alvarez-Perez JC, Felsenfeld DP, Liu H, Sivendran S, Bender A, et al. A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nat Med. 2015;21(4):383–8.PubMedPubMedCentralGoogle Scholar
  53. 53.
    • Wang P, et al. Combined inhibition of DYRK1A, SMAD, and trithorax pathways synergizes to induce robust replication in adult human beta cells. Cell Metab. 2018;29(3):638–652.e5. This study suggests that simultaneous inhibition of the DYRK1A kinase and TGF-beta signaling enhances beta cell proliferation in mouse and human islets and is the first to use a methodology to determine actual increases in cell number in isolated human islets in response to a proliferative stimulus. PubMedGoogle Scholar
  54. 54.
    Dirice E, Walpita D, Vetere A, Meier BC, Kahraman S, Hu J, et al. Inhibition of DYRK1A stimulates human beta-cell proliferation. Diabetes. 2016;65(6):1660–71.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Brun T, Maechler P. Beta-cell mitochondrial carriers and the diabetogenic stress response. Biochim Biophys Acta. 2016;1863(10):2540–9.PubMedGoogle Scholar
  56. 56.
    Maechler P. Mitochondrial function and insulin secretion. Mol Cell Endocrinol. 2013;379(1–2):12–8.PubMedGoogle Scholar
  57. 57.
    Bensellam M, Laybutt DR, Jonas JC. The molecular mechanisms of pancreatic beta-cell glucotoxicity: recent findings and future research directions. Mol Cell Endocrinol. 2012;364(1–2):1–27.PubMedGoogle Scholar
  58. 58.
    Poitout V, Robertson RP. Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocr Rev. 2008;29(3):351–66.PubMedGoogle Scholar
  59. 59.
    Affourtit C, Jastroch M, Brand MD. Uncoupling protein-2 attenuates glucose-stimulated insulin secretion in INS-1E insulinoma cells by lowering mitochondrial reactive oxygen species. Free Radic Biol Med. 2011;50(5):609–16.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Rovira-Llopis S, Bañuls C, Diaz-Morales N, Hernandez-Mijares A, Rocha M, Victor VM. Mitochondrial dynamics in type 2 diabetes: pathophysiological implications. Redox Biol. 2017;11:637–45.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Boland BB, et al. Pancreatic beta-cell rest replenishes insulin secretory capacity and attenuates diabetes in an extreme model of obese type 2 diabetes. Diabetes. 2019;68(1):131–40.PubMedGoogle Scholar
  62. 62.
    Pories WJ, Swanson MS, MacDonald KG, Long SB, Morris PG, Brown BM, et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg. 1995;222(3):339–50 discussion 350-2.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Casella G, Abbatini F, Calì B, Capoccia D, Leonetti F, Basso N. Ten-year duration of type 2 diabetes as prognostic factor for remission after sleeve gastrectomy. Surg Obes Relat Dis. 2011;7(6):697–702.PubMedGoogle Scholar
  64. 64.
    Rubino F, Gagner M. Potential of surgery for curing type 2 diabetes mellitus. Ann Surg. 2002;236(5):554–9.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Koliaki C, Roden M. Alterations of mitochondrial function and insulin sensitivity in human obesity and diabetes mellitus. Annu Rev Nutr. 2016;36:337–67.PubMedGoogle Scholar
  66. 66.
    Maechler P, et al. Role of mitochondria in beta-cell function and dysfunction. Adv Exp Med Biol. 2010;654:193–216.PubMedGoogle Scholar
  67. 67.
    Wang J, Yang X, Zhang J. Bridges between mitochondrial oxidative stress, ER stress and mTOR signaling in pancreatic beta cells. Cell Signal. 2016;28(8):1099–104.PubMedGoogle Scholar
  68. 68.
    Stiles L, Shirihai OS. Mitochondrial dynamics and morphology in beta-cells. Best Pract Res Clin Endocrinol Metab. 2012;26(6):725–38.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Anello M, Lupi R, Spampinato D, Piro S, Masini M, Boggi U, et al. Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients. Diabetologia. 2005;48(2):282–9.PubMedGoogle Scholar
  70. 70.
    Leloup C, Tourrel-Cuzin C, Magnan C, Karaca M, Castel J, Carneiro L, et al. Mitochondrial reactive oxygen species are obligatory signals for glucose-induced insulin secretion. Diabetes. 2009;58(3):673–81.PubMedGoogle Scholar
  71. 71.
    Fu J, Cui Q, Yang B, Hou Y, Wang H, Xu Y, et al. The impairment of glucose-stimulated insulin secretion in pancreatic beta-cells caused by prolonged glucotoxicity and lipotoxicity is associated with elevated adaptive antioxidant response. Food Chem Toxicol. 2017;100:161–7.PubMedGoogle Scholar
  72. 72.
    Sigfrid LA, Cunningham JM, Beeharry N, Hakan Borg LA, Rosales Hernandez AL, Carlsson C, et al. Antioxidant enzyme activity and mRNA expression in the islets of Langerhans from the BB/S rat model of type 1 diabetes and an insulin-producing cell line. J Mol Med (Berl). 2004;82(5):325–35.Google Scholar
  73. 73.
    Harmon JS, Bogdani M, Parazzoli SD, Mak SSM, Oseid EA, Berghmans M, et al. Beta-cell-specific overexpression of glutathione peroxidase preserves intranuclear MafA and reverses diabetes in db/db mice. Endocrinology. 2009;150(11):4855–62.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Thielen L, Shalev A. Diabetes pathogenic mechanisms and potential new therapies based upon a novel target called TXNIP. Curr Opin Endocrinol Diabetes Obes. 2018;25(2):75–80.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Gateva AT, Assyov YS, Velikova T, Kamenov ZA. Higher levels of thioredoxin interacting protein (TXNIP) in patients with prediabetes compared to obese normoglycemic subjects. Diabetes Metab Syndr. 2019;13(1):734–7.PubMedGoogle Scholar
  76. 76.
    Back SH, Kaufman RJ. Endoplasmic reticulum stress and type 2 diabetes. Annu Rev Biochem. 2012;81:767–93.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Liu CY, Kaufman RJ. The unfolded protein response. J Cell Sci. 2003;116(Pt 10):1861–2.PubMedGoogle Scholar
  78. 78.
    Lee AH, Heidtman K, Hotamisligil GS, Glimcher LH. Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion. Proc Natl Acad Sci U S A. 2011;108(21):8885–90.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Yong J, Itkin-Ansari P, Kaufman RJ. When less is better: ER stress and beta cell proliferation. Dev Cell. 2016;36(1):4–6.PubMedGoogle Scholar
  80. 80.
    Fonseca SG, Fukuma M, Lipson KL, Nguyen LX, Allen JR, Oka Y, et al. WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells. J Biol Chem. 2005;280(47):39609–15.PubMedGoogle Scholar
  81. 81.
    Moon JS, Karunakaran U, Elumalai S, Lee IK, Lee HW, Kim YW, et al. Metformin prevents glucotoxicity by alleviating oxidative and ER stress-induced CD36 expression in pancreatic beta cells. J Diabetes Complicat. 2017;31(1):21–30.PubMedGoogle Scholar
  82. 82.
    Kimple ME, Keller MP, Rabaglia MR, Pasker RL, Neuman JC, Truchan NA, et al. Prostaglandin E2 receptor, EP3, is induced in diabetic islets and negatively regulates glucose- and hormone-stimulated insulin secretion. Diabetes. 2013;62(6):1904–12.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Carboneau BA, Allan JA, Townsend SE, Kimple ME, Breyer RM, Gannon M. Opposing effects of prostaglandin E2 receptors EP3 and EP4 on mouse and human beta-cell survival and proliferation. Mol Metab. 2017;6(6):548–59.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Kimple ME, Moss JB, Brar HK, Rosa TC, Truchan NA, Pasker RL, et al. Deletion of GalphaZ protein protects against diet-induced glucose intolerance via expansion of beta-cell mass. J Biol Chem. 2012;287(24):20344–55.Google Scholar
  85. 85.
    Ceddia RP, Lee DK, Maulis MF, Carboneau BA, Threadgill DW, Poffenberger G, et al. The PGE2 EP3 receptor regulates diet-induced adiposity in male mice. Endocrinology. 2016;157(1):220–32.PubMedGoogle Scholar
  86. 86.
    Chan PC, Hsiao FC, Chang HM, Wabitsch M, Hsieh PS. Importance of adipocyte cyclooxygenase-2 and prostaglandin E2-prostaglandin E receptor 3 signaling in the development of obesity-induced adipose tissue inflammation and insulin resistance. FASEB J. 2016;30(6):2282–97.PubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Molecular Physiology and Biophysics, Vanderbilt UniversityNashvilleUSA
  2. 2.Department of MedicineVanderbilt University Medical CenterNashvilleUSA
  3. 3.Department of Veterans Affairs, Tennessee Valley Health AuthorityNashvilleUSA
  4. 4.Department of Cell & Developmental BiologyVanderbilt UniversityNashvilleUSA

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