The Role of Human Herpesvirus 8 in Diabetes Mellitus Type 2: State of the Art and a Medical Hypothesis

  • Raffaello PompeiEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 901)


Diabetes is a common chronic disease due to an altered glucose metabolism, caused by the quantitative and/or qualitative dysfunction of the insulin hormone. Two types of diabetes are recognized: juvenile diabetes, or type 1, which has an autoimmune origin, and adult diabetes, or type 2 (DMT2), which covers 90–95 % of all diabetic patients.

The causes of DMT2 are not yet clear: heredity, life style, nutrition, and environment are considered the main risk factors. Several viral infections, namely cytomegalovirus, coxsackie and other enteroviruses, rubella and hepatitis C virus, have been claimed to be associated with some forms of diabetes. The direct role of viruses as a cause or as a risk of type 1 diabetes has been amply described in several recent reviews. Therefore, this review focuses attention on the role of a human herpes pathogenic virus in the onset of DMT2. By carrying out an analysis of recent literature, we describe the findings reported on an extremely deceitful virus, such as Human Herpes virus 8, and present a medical hypothesis on a possible relationship between this virus and DMT2.


Human Herpesvirus 8 Diabetes type 2 Latent virus infection Insulin resistance 



The authors appreciate the collaboration of Ms Sally Davies for manuscript preparation and correction. The grant for this work was funded by the Fondazione Banco di Sardegna 2014–2015.

Conflict of Interest

The author declares no conflict of interest.


  1. Ablashi DV, Chatlynne LG, Whitman GEJR, Cesarman E (2002) Spectrum of Karposi’s sarcoma-associated Herpesvirus, or Human Herpesvirus 8, diseases. Clin Microbiol Rev 15:439–464CrossRefPubMedPubMedCentralGoogle Scholar
  2. Angius F, Uda S, Piras E, Spolitu S, Ingianni A, Batetta B, Pompei R (2015) Neutral lipid alterations in human herpesvirus 8-infected HUVEC cells and their possible involvement in neo-angiogenesis. BMC Microbiology 15(1):74CrossRefPubMedPubMedCentralGoogle Scholar
  3. Bhatt AP, Jacobs SR, Freemerman AJ et al (2012) Dysregulation of fatty acid synthesis and glycolysis in non-Hodgkin lymphoma. Proc Natl Acad Sci U S A 109:11818–11823CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bottero V, Chakraborty S, Chandran B (2013) Reactive oxygen species are induced by Kaposi’s sarcoma-associated Herpesvirus early during primary infection of endothelial cells to promote virus entry. J Virol 87(3):1733–1749CrossRefPubMedPubMedCentralGoogle Scholar
  5. Cabana VG, Siegel JN, Sabesin SM (1989) Effects of the acute phase response on the concentration and density distribution of plasma lipids and apolipoproteins. J Lipid Res 30:39–49PubMedGoogle Scholar
  6. Campos SP, Baumann H (1992) Insulin is a prominent modulator of the cytokine-stimulated expression of acute-phase plasma protein genes. Mol Cell Biol 12:1789–1797CrossRefPubMedPubMedCentralGoogle Scholar
  7. Carroll PA, Kenerson HL, Yeung RS, Lagunoff M (2006) Latent Kaposi’s sarcoma-associated Herpesvirus infection of endothelial cells activate hypoxia-induced factors. J Virol 80:10802–10812CrossRefPubMedPubMedCentralGoogle Scholar
  8. Caselli E, Fiorentini S, Amici C, Di Luca D, Caruso A, Santoro MG (2007) Human Herpesvirus 8 acute infection of endothelial cells induces monocyte chemoattractant protein 1-dependent capillary-like structure formation: role of the IKK/NF-kB pathway. Blood 109:2718–2726PubMedGoogle Scholar
  9. Caselli E, Rizzo R, Ingianni A, Contini PP, Pompei R, Di Luca D (2014) High prevalence of HHV8 infection and specific killer cell immunoglobulin-like receptors allotypes in Sardinian patients with type 2 diabetes mellitus. J Med Virol 86(10):1745–1751CrossRefPubMedGoogle Scholar
  10. Corkey BE (2012) Banting lecture 2011, hyperinsulinemia: cause or consequence? Diabetes 61(1):4–13CrossRefPubMedGoogle Scholar
  11. Delgado T, Carroll PA, Punjani AS, Margineantu D, Hockenbery DM, Lagunoff M (2010) Induction of the Warburg effect by Kaposi’s sarcoma Herpesvirus is required for the maintenance of latently infected endothelial cells. Proc Natl Acad Sci 107(23):10696–10701CrossRefPubMedPubMedCentralGoogle Scholar
  12. Delgado T, Sanchez EL, Camarda R, Lagunoff M (2012) Global metabolic profiling of infection by an oncogenic virus: KSHV induces and requires lipogenesis for survival of latent infection. PLoS Pathog 8(8):e1002866CrossRefPubMedPubMedCentralGoogle Scholar
  13. Douglas JL, Gustin JK, Viswanathan K, Mansouri M, Moses AV, Fruh K (2010) The great escape: viral strategies to counter BST-2/tetherin. PLoS Pathog 6:1–12CrossRefGoogle Scholar
  14. Dourmishev LA, Dourmishev AL, Palmeri D, Schwartz RA, Lukac DA (2003) Molecular genetics of Kaposi’s sarcoma-associated Herpesvirus (Human Herpesvirus 8) epidemiology and pathogenesis. Microbiol Mol Biol Rev 67:175–212CrossRefPubMedPubMedCentralGoogle Scholar
  15. Diabete – EpiCentro (2015) – Istituto Superiore di Sanità –
  16. Fallahi P, Ferrari SM, Colaci M et al (2013) Hepatitis C virus infection and type 2 diabetes. Clin Ter 164(5):e393–404PubMedGoogle Scholar
  17. Ganem D (2010) KSHV and the pathogenesis of Kaposi sarcoma: listening to human biology and medicine. J Clin Invest 120:939–949CrossRefPubMedPubMedCentralGoogle Scholar
  18. Gregory SM, Wang L, West JA, Dittmer DP, Damania B (2012) Latent KSHV infection of monocytes downregulates expression of adaptive immunity response costimulatory receptors and proinflammatory cytokine expression. J Virol 86:3916–3923CrossRefPubMedPubMedCentralGoogle Scholar
  19. Guilluy C, Zhang Z, Bhende PM et al (2011) Latent KSHV infection increases the vascular permeability of human endothelial cells. Blood 118:5344–5354CrossRefPubMedPubMedCentralGoogle Scholar
  20. Hober D, Alidjinou EK (2013) Enteroviral pathogenesis of type 1 diabetes: queries and answers. Curr Opin Infect Dis 26(3):263–269CrossRefPubMedGoogle Scholar
  21. Ingianni A, Carta F, Reina A, Manai M, Desogus A, Pompei R (2007) Prevalence of Herpesvirus 8 infection in type 2 diabetes mellitus patients. Am J Infect Dis 3(3):123–127CrossRefGoogle Scholar
  22. Ingianni A, Piras E, Laconi S, Angius F, Batetta B, Pompei R (2013) Latent Herpesvirus 8 infection improves both insulin and glucose uptake in primary endothelial cells. New Microbiol 36:257–265PubMedGoogle Scholar
  23. Jaïdane H, Sauter P, Sane F, Goffard A, Gharbi J, Hober D (2010) Enteroviruses and type 1 diabetes: towards a better understanding of the relationship. Rev Med Virol 20(5):265–280CrossRefPubMedGoogle Scholar
  24. Mcallister SC, Moses AV (2007) Endothelial cell- and lymphocyte-based in vitro systems for understanding KSHV biology. Curr Top Microbiol Immunol 312:211–244PubMedGoogle Scholar
  25. Negro F, Alaei M (2009) Hepatitis C virus and type 2 diabetes. World J Gastroenterol 15(13):1537–1547CrossRefPubMedPubMedCentralGoogle Scholar
  26. Okumura Y, Kudo J, Ikuta T, Kurokawa S, Ishibashi H, Okubo H (1985) Influence of acute-phase proteins on the activity of natural killer cells. Inflammation 9:211–219CrossRefPubMedGoogle Scholar
  27. Ottensmeyer FP, Beniac DR, Luo RZ, Yip CC (2000) Mechanism of transmembrane signaling: insulin binding and the insulin receptor. Biochemistry 39:2103–2112CrossRefGoogle Scholar
  28. Ozcan U, Cao Q, Erkan Y et al (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306(5695):457–461CrossRefPubMedGoogle Scholar
  29. Parravicini C, Chandran B, Corbellino M et al (2000) Differential viral protein expression in Kaposi’s sarcoma-associated herpesvirus-infected diseases: Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. Am J Pathol 156:743–749CrossRefPubMedPubMedCentralGoogle Scholar
  30. Pattullo V, Heathcote J (2010) Hepatitis C and diabetes: one treatment for two diseases? Liver Int 30(3):356–364CrossRefPubMedGoogle Scholar
  31. Pickup JC, Crook MA (1998) Is type II diabetes mellitus a disease of the innate immune system? Diabetologia 41:1241–1248CrossRefPubMedGoogle Scholar
  32. Pickup JC, Day C, Bailey CJ et al (1995) Plasma sialic acid in animal models of diabetes mellitus: evidence for modulation of sialic acid concentrations by insulin deficiency. Life Sci 57:1383–1391CrossRefPubMedGoogle Scholar
  33. Pickup JC, Mattock MB, Chusney GD, Burt D (1997) NIDDM as a disease of the innate immune system: association of acute phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia 40:1286–1292CrossRefPubMedGoogle Scholar
  34. Piras E, Palmieri G, Madeddu MA, Contini PP, Pompei R, Ingianni A (2014) High prevalence of Herpesvirus 8 in Sardinia: its possible role in the development of Diabetes mellitus type 2. 42° National Congress of the Italian Society of Microbiology, Torino, October, p 102Google Scholar
  35. Raggo C, Ruhl R, Mcallister S et al (2005) Novel cellular genes essential for transformation of endothelial cells by Kaposi’s sarcoma-associated herpesvirus. Cancer Res 65:5084–5095CrossRefPubMedGoogle Scholar
  36. Rose PP, Carroll JM, Carroll PA et al (2007) The insulin receptor is essential for virus-induced tumorigenesis of Kaposi’s sarcoma. Oncogene 26:1995–2005CrossRefPubMedGoogle Scholar
  37. Seo J, Fortuno ES 3rd et al (2009) Atf4 regulates obesity, glucose homeostasis, and energy expenditure. Diabetes 58(11):2565–2573CrossRefPubMedPubMedCentralGoogle Scholar
  38. Sobngwi E, Choukem SP, Agbalika F et al (2008) Ketosis-prone type 2 diabetes mellitus and human Herpesvirus 8 infection in sub-Saharan Africans. JAMA 299(23):2770–2776CrossRefPubMedGoogle Scholar
  39. Spagnuolo I, Patti A, Sebastiani G, Nigi L, Dotta F (2013) The case for virus-induced type 1 diabetes. Curr Opin Endocrinol Diabetes Obes 20(4):292–298CrossRefPubMedGoogle Scholar
  40. Thompson D, Harrison SP, Evans SW, Whicher JT (1991) Insulin modulation of acute phase protein production in a human hepatoma cell line. Cytokine 3:619–626CrossRefPubMedGoogle Scholar
  41. van der Werf N, Kroese FG, Rozing J, Hillebrands JL (2007) Viral infections as potential triggers of type 1 diabetes. Diabetes Metab Res Rev 23(3):169–183CrossRefPubMedGoogle Scholar
  42. Wang L, Damania B (2008) Kaposi’s sarcoma-associated herpesvirus confers a survival advantage to endothelial cell. Cancer Res 68:4640–4648CrossRefPubMedPubMedCentralGoogle Scholar
  43. Wang HW, Trotter MW, Lagos D et al (2004) Kaposi sarcoma herpesvirus-induced cellular programming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma. Nat Genet 36:687–693CrossRefPubMedGoogle Scholar
  44. Watanabe T, Sugaya M, Atkins AM et al (2003) Kaposi’s sarcoma-associated herpesvirus latency-associated nuclear antigen prolongs the life span of primary umbilical vein endothelial cells. J Virol 77:6188–6196CrossRefPubMedPubMedCentralGoogle Scholar
  45. Wen KW, Damania B (2010) Kaposi sarcoma-associated herpesvirus (KSHV): molecular biology and oncogenesis. Cancer Lett 289:140–150CrossRefPubMedGoogle Scholar
  46. Wilson SJ, Tsao EH, Webb BLJ et al (2007) X box binding protein XBP-1s transactivates the Kaposi’s sarcoma-associated herpesvirus (KSHV) ORF50 promoter, linking plasma cell differentiation to KSHV reactivation from latency. J Virol 81(24):13578–13586CrossRefPubMedPubMedCentralGoogle Scholar
  47. Winter WE, Signorino MR (2002) Diabetes mellitus: pathophysiology, etiologies, complications, management, and laboratory evaluation: special topics in diagnostic testing. American Association for Clinical Chemistry (AACC) Press, Washington, DC, pp 1–137Google Scholar
  48. Yoshizawa T, Hinoi E, Dae YJ et al (2009) The transcription factor ATF4 regulates glucose metabolism in mice through its expression in osteoblasts. J Clin Invest 119(9):2807–2817CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of Biomedical SciencesUniversity of CagliariCagliariItaly

Personalised recommendations