Pancreatic Pericytes in Glucose Homeostasis and Diabetes

  • Limor LandsmanEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1122)


Glucose homeostasis relies on tightly regulated insulin secretion from pancreatic beta-cells, and its loss in diabetes is associated with the dysfunction of these cells. Beta-cells reside in the islets of Langerhans, which are highly vascularized by a dense capillary network comprised of endothelial cells and pericytes. While the requirement of the endothelium for the proper pancreatic function is well established, the role of pancreatic pericytes has only recently begun to unveil. Recent studies described multiple roles for pancreatic pericytes in glucose homeostasis, highlighting their function as both regulators of islet blood flow and as a source of critical signals that support proper beta-cell function and mass. Furthermore, recent findings point to the contribution of pericytic abnormalities to beta-cell dysfunction in type 2 diabetes, implicating the involvement of pancreatic pericytes in both the initiation and the progression of this disease. This newly gained data implicate pancreatic pericytes as critical components of the cellular network required for glucose regulation.


Pancreatic pericytes Islets of Langerhans Islet vasculature Islet pericytes Islet capillaries Beta-cells Beta-cell function Beta-cell dysfunction Beta-cell mass Glucose homeostasis Glucose-stimulated insulin secretion Type 2 diabetes 


  1. Almaça J, Weitz J, Rodriguez-Diaz R, Pereira E, Caicedo A (2018) The Pericyte of the pancreatic islet regulates capillary diameter and local blood flow. Cell Metab 27:630–644.e4. Scholar
  2. Apte M, Pirola RC, Wilson JS (2015) Pancreatic stellate cell: physiologic role, role in fibrosis and cancer. Curr Opin Gastroenterol 31:416–423. Scholar
  3. Armulik A, Genové G, Betsholtz C (2011) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21:193–215. Scholar
  4. Ashcroft FM, Rorsman P (2012) Diabetes mellitus and the β cell: the last ten years. Cell 148:1160–1171. Scholar
  5. Bonner-Weir S (1993) The microvasculature of the pancreas, with emphasis on that of the islets of Langerhans. In: Go VLW et al (eds) The pancreas: biology, pathobiology, and disease. Raven Press, New York, pp 759–768Google Scholar
  6. Bonner-Weir S, Aguayo-Mazzucato C (2016) Physiology: pancreatic [beta]-cell heterogeneity revisited. Nature 535:365–366. Scholar
  7. Bramswig NC, Kaestner KH (2014) Transcriptional and epigenetic regulation in human islets. Diabetologia 57:451–454. Scholar
  8. Brissova M, Aamodt K, Brahmachary P, Prasad N, Hong J-Y, Dai C, Mellati M, Shostak A, Poffenberger G, Aramandla R, Levy SE, Powers AC (2014) Islet microenvironment, modulated by vascular endothelial growth factor-a signaling, promotes β cell regeneration. Cell Metab 19:498–511. Scholar
  9. Cerasi E (2011) β-Cell dysfunction vs insulin resistance in type 2 diabetes: the eternal “chicken and egg” question. Medicographia 33:35–41Google Scholar
  10. Chen X, Zhang X, Chen F, Larson CS, Wang L-J, Kaufman DB (2009) Comparative study of regenerative potential of beta cells from young and aged donor mice using a novel islet transplantation model. Transplantation 88:496–503. Scholar
  11. Cinti F, Bouchi R, Kim-Muller JY, Ohmura Y, Sandoval PR, Masini M, Marselli L, Suleiman M, Ratner LE, Marchetti P, Accili D (2016) Evidence of β-cell dedifferentiation in human type 2 diabetes. J Clin Endocrinol Metab 101:1044–1054. Scholar
  12. Clevers H, Nusse R (2012) Wnt/β-catenin signaling and disease. Cell 149:1192–1205. Scholar
  13. Costes S, Langen R, Gurlo T, Butler PC (2013) β-Cell failure in type 2 diabetes: a case of asking too much of too few? Diabetes 62:327–335. Scholar
  14. Dai C, Brissova M, Reinert RB, Nyman L, Liu EH, Thompson C, Shostak A, Shiota M, Takahashi T, Powers AC (2013) Pancreatic islet vasculature adapts to insulin resistance through dilation and not angiogenesis. Diabetes 62:4144–4153. Scholar
  15. DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, Hu FB, Kahn CR, Raz I, Shulman GI, Simonson DC, Testa MA, Weiss R (2015) Type 2 diabetes mellitus. Nat Rev Dis Primers 1:15019. Scholar
  16. Diaferia GR, Jimenez-Caliani AJ, Ranjitkar P, Yang W, Hardiman G, Rhodes CJ, Crisa L, Cirulli V (2013) β1 integrin is a crucial regulator of pancreatic β-cell expansion. Development 140:3360–3372. Scholar
  17. Dor Y, Glaser B (2013) β-Cell dedifferentiation and type 2 diabetes. N Engl J Med 368:572–573. Scholar
  18. Dor Y, Brown J, Martinez O, Melton D (2004) Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429:41–46. Scholar
  19. Eberhard D, Lammert E (2009) The pancreatic beta-cell in the islet and organ community. Curr Opin Genet Dev 19:469–475. Scholar
  20. Epshtein A, Rachi E, Sakhneny L, Mizrachi S, Baer D, Landsman L (2017) Neonatal pancreatic pericytes support β-cell proliferation. Molecular Metabolism 6:1330–1338. Scholar
  21. Finegood DT, Scaglia L, Bonner-Weir S (1995) Dynamics of beta-cell mass in the growing rat pancreas. Estimation with a simple mathematical model. Diabetes 44:249–256CrossRefGoogle Scholar
  22. Fuchsberger C, Flannick J, Teslovich TM et al (2016) The genetic architecture of type 2 diabetes. Nature 536:41–47. Scholar
  23. Georgia S, Bhushan A (2004) Beta cell replication is the primary mechanism for maintaining postnatal beta cell mass. J Clin Investig 114:963–968. Scholar
  24. Gittes GK (2009) Developmental biology of the pancreas: a comprehensive review. Dev Biol 326:4–35. Scholar
  25. Goulley J, Dahl U, Baeza N, Mishina Y, Edlund H (2007) BMP4-BMPR1A signaling in beta cells is required for and augments glucose-stimulated insulin secretion. Cell Metab 5:207–219. Scholar
  26. Granot Z, Swisa A, Magenheim J, Stolovich-Rain M, Fujimoto W, Manduchi E, Miki T, Lennerz JK, Stoeckert CJ Jr, Meyuhas O, Seino S, Permutt MA, Piwnica-Worms H, Bardeesy N, Dor Y (2009) LKB1 regulates pancreatic β cell size, polarity, and function. Cell Metab 10:296–308. Scholar
  27. Grant SFA, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, Stefansson K (2006) Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 38:320–323. Scholar
  28. Gregg BE, Moore PC, Demozay D, Hall BA, Li M, Husain A, Wright AJ, Atkinson MA, Rhodes CJ (2012) Formation of a human β-cell population within pancreatic islets is set early in life. J Clin Endocrinol Metab 97:3197–3206. Scholar
  29. Hammes H-P (2017) Diabetic retinopathy: hyperglycaemia, oxidative stress and beyond. Diabetologia 61:1–10. Scholar
  30. Harari N, Sakhneny L, Khalifa-Malka L, Busch A, Hertel KJ, Hebrok M, Landsman L (2019) Pancreatic pericytes originate from the embryonic pancreatic mesenchyme. Developmental Biology In pressGoogle Scholar
  31. Hayden MR, Sowers JR (2007) Isletopathy in type 2 diabetes mellitus: implications of islet RAS, islet fibrosis, islet amyloid, remodeling, and oxidative stress. Antioxid Redox Signal 9:891–910. Scholar
  32. Hayden MR, Karuparthi PR, Habibi J, Wasekar C, Lastra G, Manrique C, Stas S, Sowers JR (2007) Ultrastructural islet study of early fibrosis in the Ren2 rat model of hypertension. Emerging role of the islet pancreatic pericyte-stellate cell. JOP 8:725–738PubMedGoogle Scholar
  33. Hayden MR, Yang Y, Habibi J, Bagree SV, Sowers JR (2010) Pericytopathy oxidative stress and impaired cellular longevity in the pancreas and skeletal muscle in metabolic syndrome and type 2 diabetes. Oxidative Med Cell Longev 3:290–303. Scholar
  34. Helgason A, Pálsson S, Thorleifsson G, Grant SFA, Emilsson V, Gunnarsdottir S, Adeyemo A, Chen Y, Chen G, Reynisdottir I, Benediktsson R, Hinney A, Hansen T, Andersen G, Borch-Johnsen K, Jørgensen T, Schäfer H, Faruque M, Doumatey A, Zhou J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Sigurdsson G, Hebebrand J, Pedersen O, Thorsteinsdottir U, Gulcher JR, Kong A, Rotimi C, Stefansson K (2007) Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. Nat Genet 39:218–225. Scholar
  35. Hogan MF, Hull RL (2017) The islet endothelial cell: a novel contributor to beta cell secretory dysfunction in diabetes. Diabetologia 60:952–959CrossRefGoogle Scholar
  36. Houtz J, Borden P, Ceasrine A, Minichiello L, Kuruvilla R (2016) Neurotrophin signaling is required for glucose-induced insulin secretion. Dev Cell 39:329–345. Scholar
  37. Kragl M, Lammert E (2010) Basement membrane in pancreatic islet function. Adv Exp Med Biol 654:217–234. Scholar
  38. Kragl M, Schubert R, Karsjens H, Otter S, Bartosinska B, Jeruschke K, Weiss J, Chen C, Alsteens D, Kuss O, Speier S, Eberhard D, Müller DJ, Lammert E (2016) The biomechanical properties of an epithelial tissue determine the location of its vasculature. Nat Commun 7:13560. Scholar
  39. Lammert E, Cleaver O, Melton D (2001) Induction of pancreatic differentiation by signals from blood vessels. Science 294:564–567. Scholar
  40. Longnecker DS, Gorelick F, Thompson ED (2018) Anatomy, histology, and fine structure of the pancreas, 2nd ed. Wiley-Blackwell, ChichesterGoogle Scholar
  41. Lyssenko V, Lupi R, Marchetti P, Del Guerra S, Orho-Melander M, Almgren P, Sjögren M, Ling C, Eriksson K-F, Lethagen A-L, Mancarella R, Berglund G, Tuomi T, Nilsson P, Del Prato S, Groop L (2007) Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Investig 117:2155–2163. Scholar
  42. Mastracci TL, Sussel L (2012) The endocrine pancreas: insights into development, differentiation, and diabetes. Wiley Interdiscip Rev Developmental Biology 1:609–628. Scholar
  43. Meier JJ, Butler AE, Saisho Y, Monchamp T, Galasso R, Bhushan A, Rizza RA, Butler PC (2008) Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans. Diabetes 57:1584–1594. Scholar
  44. Mandarino LJ, Finlayson J, Hassell JR (1994) High glucose downregulates glucose transport activity in retinal capillary pericytes but not endothelial cells. Invest Ophthalmol Vis Sci 35:964–972.Google Scholar
  45. Morikawa S, Baluk P, Kaidoh T, Haskell A, Jain RK, McDonald DM (2002) Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 160:985–1000. Scholar
  46. Nikolova G, Jabs N, Konstantinova I, Domogatskaya A, Tryggvason K, Sorokin L, Fässler R, Gu G, Gerber H-P, Ferrara N, Melton DA, Lammert E (2006) The vascular basement membrane: a niche for insulin gene expression and Beta cell proliferation. Dev Cell 10:397–405. Scholar
  47. Otonkoski T, Banerjee M, Korsgren O, Thornell L-E, Virtanen I (2008) Unique basement membrane structure of human pancreatic islets: implications for beta-cell growth and differentiation. Diabetes Obes Metab 10(Suppl 4):119–127. Scholar
  48. Ouaamari El A, Dirice E, Gedeon N, Hu J, Zhou J-Y, Shirakawa J, Hou L, Goodman J, Karampelias C, Qiang G, Boucher J, Martinez R, Gritsenko MA, De Jesus DF, Kahraman S, Bhatt S, Smith RD, Beer H-D, Jungtrakoon P, Gong Y, Goldfine AB, Liew CW, Doria A, Andersson O, Qian W-J, Remold-O’Donnell E, Kulkarni RN (2016) SerpinB1 promotes pancreatic β cell proliferation. Cell Metab 23:194–205. Scholar
  49. Prentki M, Matschinsky FM, Madiraju SRM (2013) Metabolic signaling in fuel-induced insulin secretion. Cell Metab 18:162–185. Scholar
  50. Reinert RB, Brissova M, Shostak A, Pan FC, Poffenberger G, Cai Q, Hundemer GL, Kantz J, Thompson CS, Dai C, McGuinness OP, Powers AC (2013) Vascular endothelial growth factor-a and islet vascularization are necessary in developing, but not adult, pancreatic islets. Diabetes 62:4154–4164. Scholar
  51. Richards OC, Raines SM, Attie AD (2010) The role of blood vessels, endothelial cells, and vascular pericytes in insulin secretion and peripheral insulin action. Endocr Rev 31:343–363. Scholar
  52. Riley KG, Pasek RC, Maulis MF, Dunn JC, Bolus WR, Kendall PL, Hasty AH, Gannon M (2015) Macrophages are essential for CTGF-mediated adult β-cell proliferation after injury. Mol Metab 4:584–591. Scholar
  53. Rorsman P, Braun M (2013) Regulation of insulin secretion in human pancreatic islets. Annu Rev Physiol 75:155–179. Scholar
  54. Sakhneny L, Rachi E, Epshtein A, Guez HC, Wald-Altman S, Lisnyansky M, Khalifa-Malka L, Hazan A, Baer D, Priel A, Weil M, Landsman L (2018) Pancreatic Pericytes support β-cell function in a Tcf7l2-dependent manner. Diabetes 67:437–447. Scholar
  55. Salpeter SJ, Klein AM, Huangfu D, Grimsby J, Dor Y (2010) Glucose and aging control the quiescence period that follows pancreatic beta cell replication. Development 137:3205–3213. Scholar
  56. Sasson A, Rachi E, Sakhneny L, Baer D, Lisnyansky M, Epshtein A, Landsman L (2016) Islet Pericytes are required for β-cell maturity. Diabetes 65:3008–3014. Scholar
  57. Schaeffer M, Hodson DJ, Lafont C, Mollard P (2011) Endocrine cells and blood vessels work in tandem to generate hormone pulses. J Mol Endocrinol 47:R59–R66. Scholar
  58. Stolovich-Rain M, Hija A, Grimsby J, Glaser B, Dor Y (2012) Pancreatic beta cells in very old mice retain capacity for compensatory proliferation. J Biol Chem 287:27407–27414. Scholar
  59. Stratman AN, Davis GE (2012) Endothelial cell-pericyte interactions stimulate basement membrane matrix assembly: influence on vascular tube remodeling, maturation, and stabilization. Microsc Microanal 18:68–80. Scholar
  60. Talchai C, Xuan S, Lin HV, Sussel L, Accili D (2012) Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell 150:1223–1234. Scholar
  61. Tang S-C, Chiu Y-C, Hsu C-T, Peng S-J, Fu Y-Y (2013) Plasticity of Schwann cells and pericytes in response to islet injury in mice. Diabetologia 56:2424–2434. Scholar
  62. Tarussio D, Metref S, Seyer P, Mounien L, Vallois D, Magnan C, Foretz M, Thorens B (2014) Nervous glucose sensing regulates postnatal β cell proliferation and glucose homeostasis. J Clin Investig 124:413–424. Scholar
  63. van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A, van der Horn K, Batlle E, Coudreuse D, Haramis AP, Tjon-Pon-Fong M, Moerer P, Van Den Born M, Soete G, Pals S, Eilers M, Medema R, Clevers H (2002) The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111:241–250CrossRefGoogle Scholar
  64. Wang P, Fiaschi-Taesch NM, Vasavada RC, Scott DK, García-Ocaña A, Stewart AF (2015) Diabetes mellitus--advances and challenges in human β-cell proliferation. Nat Rev Endocrinol 11:201–212. Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Cell and Developmental Biology, Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael

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