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Diabetes mellitus and the skin

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Abstract

Diabetes is a debilitating, life-threatening disease accounting in 2015 for the death of 5 million people worldwide. According to new estimations, 415 million adults currently suffer from the disease, and this number is expected to rise to 642 million by 2040. High glucose blood levels also affect the skin among systemic organs, and skin disorders can often predict the onset of this metabolic disorder. In this review, we address the pathomechanistic effects of diabetes on the skin and give an overview on the most common skin diseases associated with diabetes.

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References

  1. Canivell S, Gomis R. Diagnosis and classification of autoimmune diabetes mellitus. Autoimmun Rev. 2014;13(4–5):403–7. doi:10.1016/j.autrev.2014.01.020.

    Article  CAS  PubMed  Google Scholar 

  2. 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. doi:10.2337/dc14-0396.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Meurer M, Stumvoll M, Szeimies RM. Skin changes in diabetes mellitus. Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete. 2004;55(5):428–35. doi:10.1007/s00105-004-0726-3.

    Article  CAS  PubMed  Google Scholar 

  4. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107(9):1058–70. doi:10.1161/CIRCRESAHA.110.223545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Park HY, Kim JH, Jung M, Chung CH, Hasham R, Park CS, et al. A long-standing hyperglycaemic condition impairs skin barrier by accelerating skin ageing process. Exp Dermatol. 2011;20(12):969–74. doi:10.1111/j.1600-0625.2011.01364.x.

    Article  CAS  PubMed  Google Scholar 

  6. Sakai S, Kikuchi K, Satoh J, Tagami H, Inoue S. Functional properties of the stratum corneum in patients with diabetes mellitus: similarities to senile xerosis. Br J Dermatol. 2005;153(2):319–23. doi:10.1111/j.1365-2133.2005.06756.x.

    Article  CAS  PubMed  Google Scholar 

  7. Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol: Off J Korean Physiol Soc Korean Soc Pharmacol. 2014;18(1):1–14. doi:10.4196/kjpp.2014.18.1.1.

    Article  CAS  Google Scholar 

  8. Paul RG, Bailey AJ. Glycation of collagen: the basis of its central role in the late complications of ageing and diabetes. Int J Biochem Cell Biol. 1996;28(12):1297–310.

    Article  CAS  PubMed  Google Scholar 

  9. Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, et al. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med (Berl). 2005;83(11):876–86. doi:10.1007/s00109-005-0688-7.

    Article  CAS  Google Scholar 

  10. Fleming TH, Humpert PM, Nawroth PP, Bierhaus A. Reactive metabolites and AGE/RAGE-mediated cellular dysfunction affect the aging process: a mini-review. Gerontology. 2011;57(5):435–43. doi:10.1159/000322087000322087.

    CAS  PubMed  Google Scholar 

  11. Gkogkolou P, Bohm M. Advanced glycation end products: key players in skin aging? Dermatoendocrinol. 2012;4(3):259–70. doi:10.4161/derm.220282012DE0431.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhu P, Yang C, Chen LH, Ren M, Lao GJ, Yan L. Impairment of human keratinocyte mobility and proliferation by advanced glycation end products-modified BSA. Arch Dermatol Res. 2011;303(5):339–50. doi:10.1007/s00403-010-1102-z.

    Article  CAS  PubMed  Google Scholar 

  13. Alikhani Z, Alikhani M, Boyd CM, Nagao K, Trackman PC, Graves DT. Advanced glycation end products enhance expression of pro-apoptotic genes and stimulate fibroblast apoptosis through cytoplasmic and mitochondrial pathways. J Biol Chem. 2005;280(13):12087–95. doi:10.1074/jbc.M406313200.

    Article  CAS  PubMed  Google Scholar 

  14. Berge U, Behrens J, Rattan SI. Sugar-induced premature aging and altered differentiation in human epidermal keratinocytes. Ann N Y Acad Sci. 2007;1100:524–9. doi:10.1196/annals.1395.058.

    Article  CAS  PubMed  Google Scholar 

  15. Ravelojaona V, Robert AM, Robert L. Expression of senescence-associated beta-galactosidase (SA-beta-Gal) by human skin fibroblasts, effect of advanced glycation end-products and fucose or rhamnose-rich polysaccharides. Arch Gerontol Geriatr. 2009;48(2):151–4. doi:10.1016/j.archger.2007.12.004S0167-4943(07)00245-2.

    Article  CAS  PubMed  Google Scholar 

  16. Sejersen H, Rattan SI. Dicarbonyl-induced accelerated aging in vitro in human skin fibroblasts. Biogerontology. 2009;10(2):203–11. doi:10.1007/s10522-008-9172-4.

    Article  CAS  PubMed  Google Scholar 

  17. Kueper T, Grune T, Muhr GM, Lenz H, Wittern KP, Wenck H, et al. Modification of vimentin: a general mechanism of nonenzymatic glycation in human skin. Ann N Y Acad Sci. 2008;1126:328–32. doi:10.1196/annals.1433.039.

    Article  CAS  PubMed  Google Scholar 

  18. Uchiki T, Weikel KA, Jiao W, Shang F, Caceres A, Pawlak D, et al. Glycation-altered proteolysis as a pathobiologic mechanism that links dietary glycemic index, aging, and age-related disease (in nondiabetics). Aging Cell. 2012;11(1):1–13. doi:10.1111/j.1474-9726.2011.00752.x.

    Article  CAS  PubMed  Google Scholar 

  19. Giardino I, Edelstein D, Brownlee M. Nonenzymatic glycosylation in vitro and in bovine endothelial cells alters basic fibroblast growth factor activity. A model for intracellular glycosylation in diabetes. J Clin Invest. 1994;94(1):110–7. doi:10.1172/JCI117296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ukeda H, Hasegawa Y, Ishi T, Sawamura M. Inactivation of Cu, Zn-superoxide dismutase by intermediates of Maillard reaction and glycolytic pathway and some sugars. Biosci Biotechnol Biochem. 1997;61(12):2039–42.

    Article  CAS  PubMed  Google Scholar 

  21. Baynes JW. The Maillard hypothesis on aging: time to focus on DNA. Ann N Y Acad Sci. 2002;959:360–7.

    Article  CAS  PubMed  Google Scholar 

  22. Dyer DG, Dunn JA, Thorpe SR, Bailie KE, Lyons TJ, McCance DR, et al. Accumulation of Maillard reaction products in skin collagen in diabetes and aging. J Clin Invest. 1993;91(6):2463–9. doi:10.1172/JCI116481.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jeanmaire C, Danoux L, Pauly G. Glycation during human dermal intrinsic and actinic ageing: an in vivo and in vitro model study. Br J Dermatol. 2001;145(1):10–8.

    Article  CAS  PubMed  Google Scholar 

  24. DeGroot J, Verzijl N, Wenting-Van Wijk MJ, Bank RA, Lafeber FP, Bijlsma JW, et al. Age-related decrease in susceptibility of human articular cartilage to matrix metalloproteinase-mediated degradation: the role of advanced glycation end products. Arthritis Rheum. 2001;44(11):2562–71.

    Article  CAS  PubMed  Google Scholar 

  25. Avery NC, Bailey AJ. The effects of the Maillard reaction on the physical properties and cell interactions of collagen. Pathol Biol (Paris). 2006;54(7):387–95. doi:10.1016/j.patbio.2006.07.005.

    Article  CAS  Google Scholar 

  26. Argyropoulos AJ, Robichaud P, Balimunkwe RM, Fisher GJ, Hammerberg C, Yan Y, et al. Alterations of dermal connective tissue collagen in diabetes: molecular basis of aged-appearing skin. PLoS One. 2016;11(4):e0153806. doi:10.1371/journal.pone.0153806.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Mizutari K, Ono T, Ikeda K, Kayashima K, Horiuchi S. Photo-enhanced modification of human skin elastin in actinic elastosis by N(epsilon)-(carboxymethyl)lysine, one of the glycoxidation products of the Maillard reaction. J Invest Dermatol. 1997;108(5):797–802.

    Article  CAS  PubMed  Google Scholar 

  28. Braverman IM. Elastic fiber and microvascular abnormalities in aging skin. Clin Geriatr Med. 1989;5(1):69–90.

    CAS  PubMed  Google Scholar 

  29. Petrofsky J, Lee H, Trivedi M, Hudlikar AN, Yang CH, Goraksh N, et al. The influence of aging and diabetes on heat transfer characteristics of the skin to a rapidly applied heat source. Diabetes Technol Ther. 2010;12(12):1003–10. doi:10.1089/dia.2010.0152.

    Article  PubMed  Google Scholar 

  30. Petrofsky JS, McLellan K, Bains GS, Prowse M, Ethiraju G, Lee S, et al. Skin heat dissipation: the influence of diabetes, skin thickness, and subcutaneous fat thickness. Diabetes Technol Ther. 2008;10(6):487–93. doi:10.1089/dia.2008.0009.

    Article  PubMed  Google Scholar 

  31. Fang M, Wang J, Li S, Guo Y. Advanced glycation end-products accelerate the cardiac aging process through the receptor for advanced glycation end-products/transforming growth factor-beta-Smad signaling pathway in cardiac fibroblasts. Geriatr Gerontol Int. 2015;28(10):12499.

    Google Scholar 

  32. Serban AI, Stanca L, Geicu OI, Munteanu MC, Dinischiotu A. RAGE and TGF-beta1 cross-talk regulate extracellular matrix turnover and cytokine synthesis in AGEs exposed fibroblast cells. PLoS One. 2016;11(3):e0152376. doi:10.1371/journal.pone.0152376.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Gowd V, Gurukar A, Chilkunda ND. Glycosaminoglycan remodeling during diabetes and the role of dietary factors in their modulation. World J Diabetes. 2016;7(4):67–73. doi:10.4239/wjd.v7.i4.67.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Cerami C, Founds H, Nicholl I, Mitsuhashi T, Giordano D, Vanpatten S, et al. Tobacco smoke is a source of toxic reactive glycation products. Proc Natl Acad Sci U S A. 1997;94(25):13915–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Monami M, Lamanna C, Gori F, Bartalucci F, Marchionni N, Mannucci E. Skin autofluorescence in type 2 diabetes: beyond blood glucose. Diabetes Res Clin Pract. 2008;79(1):56–60. doi:10.1016/j.diabres.2007.07.007.

    Article  CAS  PubMed  Google Scholar 

  36. Lutgers HL, Graaff R, Links TP, Ubink-Veltmaat LJ, Bilo HJ, Gans RO, et al. Skin autofluorescence as a noninvasive marker of vascular damage in patients with type 2 diabetes. Diabetes Care. 2006;29(12):2654–9. doi:10.2337/dc05-2173.

    Article  PubMed  Google Scholar 

  37. van Waateringe RP, Slagter SN, van der Klauw MM, van Vliet-Ostaptchouk JV, Graaff R, Paterson AD, et al. Lifestyle and clinical determinants of skin autofluorescence in a population-based cohort study. Eur J Clin Investig. 2016;46(5):481–90. doi:10.1111/eci.12627.

    Article  CAS  Google Scholar 

  38. Furst JR, Bandeira LC, Fan WW, Agarwal S, Nishiyama KK, McMahon DJ, Dworakowski E, Jiang H, Silverberg SJ, Rubin MR. Advanced glycation endproducts and bone material strength in type 2 diabetes. J Clin Endocrinol Metab. jc20161437. 2016. doi:10.1210/jc.2016-1437.

  39. Yamanaka M, Matsumura T, Ohno R, Fujiwara Y, Shinagawa M, Sugawa H, et al. Non-invasive measurement of skin autofluorescence to evaluate diabetic complications. J Clin Biochem Nutr. 2016;58(2):135–40. doi:10.3164/jcbn.15-132.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Hangai M, Takebe N, Honma H, Sasaki A, Chida A, Nakano R, et al. Association of advanced glycation end products with coronary artery calcification in Japanese subjects with type 2 diabetes as assessed by skin autofluorescence. J Atheroscler Thromb. 2016. doi:10.5551/jat.30155.

    PubMed  PubMed Central  Google Scholar 

  41. Romano G, Moretti G, Di Benedetto A, Giofre C, Di Cesare E, Russo G, et al. Skin lesions in diabetes mellitus: prevalence and clinical correlations. Diabetes Res Clin Pract. 1998;39(2):101–6.

    Article  CAS  PubMed  Google Scholar 

  42. Perez MI, Kohn SR. Cutaneous manifestations of diabetes mellitus. J Am Acad Dermatol. 1994;30(4):519–31. quiz 532–514.

    Article  CAS  PubMed  Google Scholar 

  43. Goncalves B, Ferreira C, Alves CT, Henriques M, Azeredo J, Silva S. Vulvovaginal candidiasis: epidemiology, microbiology and risk factors. Crit. Rev. Microbiol. 2015;1–23. doi:10.3109/1040841X.2015.1091805.

  44. Behm B, Schreml S, Landthaler M, Babilas P. Skin signs in diabetes mellitus. J Eur Acad Dermatol Venereol: JEADV. 2012;26(10):1203–11. doi:10.1111/j.1468-3083.2012.04475.x.

    Article  CAS  PubMed  Google Scholar 

  45. Shah BR, Hux JE. Quantifying the risk of infectious diseases for people with diabetes. Diabetes Care. 2003;26(2):510–3.

    Article  PubMed  Google Scholar 

  46. Stern Shavit S, Soudry E, Hamzany Y, Nageris B. Malignant external otitis: factors predicting patient outcomes. Am J Otolaryngol. 2016. doi:10.1016/j.amjoto.2016.04.005.

    PubMed  Google Scholar 

  47. Spichler A, Hurwitz BL, Armstrong DG, Lipsky BA. Microbiology of diabetic foot infections: from Louis Pasteur to ‘crime scene investigation’. BMC Med. 2015;13:2. doi:10.1186/s12916-014-0232-0.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Lipsky BA, Berendt AR, Cornia PB, Pile JC, Peters EJ, Armstrong DG, et al. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2012;54(12):e132–73. doi:10.1093/cid/cis346.

    Article  Google Scholar 

  49. Rhoads DD, Cox SB, Rees EJ, Sun Y, Wolcott RD. Clinical identification of bacteria in human chronic wound infections: culturing vs. 16S ribosomal DNA sequencing. BMC Infect Dis. 2012;12:321. doi:10.1186/1471-2334-12-321.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Gallacher SJ, Thomson G, Fraser WD, Fisher BM, Gemmell CG, MacCuish AC. Neutrophil bactericidal function in diabetes mellitus: evidence for association with blood glucose control. Diabet Med: J Br Diabet Assoc. 1995;12(10):916–20.

    Article  CAS  Google Scholar 

  51. Rajagopalan S. Serious infections in elderly patients with diabetes mellitus. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2005;40(7):990–6. doi:10.1086/427690.

    Article  Google Scholar 

  52. Alavi A, Sibbald RG, Mayer D, Goodman L, Botros M, Armstrong DG, et al. Diabetic foot ulcers: part I. Pathophysiology and prevention. J Am Acad Dermatol. 2014;70(1):1 e1–18. doi:10.1016/j.jaad.2013.06.055. quiz 19–20.

    Article  Google Scholar 

  53. Quattrini C, Jeziorska M, Malik RA. Small fiber neuropathy in diabetes: clinical consequence and assessment. Int J Low Extrem Wounds. 2004;3(1):16–21. doi:10.1177/1534734603262483.

    Article  CAS  PubMed  Google Scholar 

  54. Rasi A, Soltani-Arabshahi R, Shahbazi N. Skin tag as a cutaneous marker for impaired carbohydrate metabolism: a case-control study. Int J Dermatol. 2007;46(11):1155–9. doi:10.1111/j.1365-4632.2007.03287.x.

    Article  PubMed  Google Scholar 

  55. Sudy E, Urbina F, Maliqueo M, Sir T. Screening of glucose/insulin metabolic alterations in men with multiple skin tags on the neck. J der Deutschen Dermatologischen Gesellschaft = J Ger Soc Dermatol: JDDG. 2008;6(10):852–6. doi:10.1111/j.1610-0387.2008.06720.x.

    Google Scholar 

  56. Hollister DS, Brodell RT. Finger ‘pebbles’. a dermatologic sign of diabetes mellitus. Postgrad Med. 2000;107(3):209–10.

    Article  CAS  PubMed  Google Scholar 

  57. Solak B, Kara RO, Acikgoz SB. Kosem M (2015) First and only symptom of undiagnosed diabetes mellitus: eruptive xanthoma. BMJ Case Rep. 2015. doi:10.1136/bcr-2015-212160.

    Google Scholar 

  58. Baykal L, Arica DA, Yayli S, Orem A, Bahadir S, Altun E, et al. Prevalence of metabolic syndrome in patients with mucosal lichen planus: a case-control study. Am J Clin Dermatol. 2015;16(5):439–45. doi:10.1007/s40257-015-0142-8.

    Article  PubMed  Google Scholar 

  59. Seyhan M, Ozcan H, Sahin I, Bayram N, Karincaoglu Y. High prevalence of glucose metabolism disturbance in patients with lichen planus. Diabetes Res Clin Pract. 2007;77(2):198–202. doi:10.1016/j.diabres.2006.12.016.

    Article  CAS  PubMed  Google Scholar 

  60. Jockenhofer F, Kroger K, Klode J, Renner R, Erfurt-Berge C, Dissemond J. Cofactors and comorbidities of necrobiosis lipoidica: analysis of the German DRG data from 2012. J der Deutschen Dermatologischen Gesellschaft = J German Soc Dermatol: JDDG. 2016;14(3):277–84. doi:10.1111/ddg.12749.

    Google Scholar 

  61. Nebesio CL, Lewis C, Chuang TY. Lack of an association between granuloma annulare and type 2 diabetes mellitus. Br J Dermatol. 2002;146(1):122–4.

    Article  CAS  PubMed  Google Scholar 

  62. Lee H, Lee MH, Lee DY, Kang HY, Kim KH, Choi GS, et al. Prevalence of vitiligo and associated comorbidities in Korea. Yonsei Med J. 2015;56(3):719–25. doi:10.3349/ymj.2015.56.3.719.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Maitra SK, Rowland Payne CM. The obesity syndrome and acanthosis nigricans. Acanthosis nigricans is a common cosmetic problem providing epidemiological clues to the obesity syndrome, the insulin-resistance syndrome, the thrifty metabolism, dyslipidaemia, hypertension and diabetes mellitus type II. J Cosmet Dermatol. 2004;3(4):202–10. doi:10.1111/j.1473-2130.2004.00078.x.

    Article  CAS  PubMed  Google Scholar 

  64. Yamaoka H, Sasaki H, Yamasaki H, Ogawa K, Ohta T, Furuta H, et al. Truncal pruritus of unknown origin may be a symptom of diabetic polyneuropathy. Diabetes Care. 2010;33(1):150–5. doi:10.2337/dc09-0632.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Makrantonaki E, Steinhagen-Thiessen E, Nieczaj R, Zouboulis CC, Eckardt R. Prevalence of skin diseases in hospitalised geriatric patients—association with gender, duration of hospitalisation and geriatric assessment. Z Gerontol Geriatr. 2016.

  66. Ghosh SK, Bandyopadhyay D, Chatterjee G. Bullosis diabeticorum: a distinctive blistering eruption in diabetes mellitus. Int J Diabetes Dev Countries. 2009;29(1):41–2. doi:10.4103/0973-3930.50714.

    Article  Google Scholar 

  67. Gupta V, Gulati N, Bahl J, Bajwa J, Dhawan N. Bullosis diabeticorum: rare presentation in a common disease. Case Rep Endocrinol. 2014;2014:862912. doi:10.1155/2014/862912.

    PubMed  PubMed Central  Google Scholar 

  68. Vinik AI, Freeman R, Erbas T. Diabetic autonomic neuropathy. Semin Neurol. 2003;23(4):365–72. doi:10.1055/s-2004-817720.

    Article  PubMed  Google Scholar 

  69. Saray Y, Seckin D, Bilezikci B. Acquired perforating dermatosis: clinicopathological features in twenty-two cases. J Eur Acad Dermatol Venereol: JEADV. 2006;20(6):679–88. doi:10.1111/j.1468-3083.2006.01571.x.

    Article  CAS  PubMed  Google Scholar 

  70. Karagiannidis I, Nikolakis G, Zouboulis CC. Endocrinologic Aspects of hidradenitis suppurativa. Dermatol Clin. 2016;34(1):45–9. doi:10.1016/j.det.2015.08.005.

    Article  CAS  PubMed  Google Scholar 

  71. Gelfand JM. Psoriasis, type 2 diabetes mellitus, and obesity: weighing the evidence. JAMA Dermatol. 2016. doi:10.1001/jamadermatol.2016.0670.

    Google Scholar 

  72. Kiziltan ME, Benbir G. Clinical and nerve conduction studies in female patients with diabetic dermopathy. Acta Diabetol. 2008;45(2):97–105. doi:10.1007/s00592-008-0031-1.

    Article  CAS  PubMed  Google Scholar 

  73. Wicks K, Torbica T, Mace KA. Myeloid cell dysfunction and the pathogenesis of the diabetic chronic wound. Semin Immunol. 2014;26(4):341–53. doi:10.1016/j.smim.2014.04.006.

    Article  CAS  PubMed  Google Scholar 

  74. Arsanjani Shirazi A, Nasiri M, Yazdanpanah L. Dermatological and musculoskeletal assessment of diabetic foot: a narrative review. Diabetes Metab Syndr. 2016. doi:10.1016/j.dsx.2016.03.004.

    PubMed  Google Scholar 

  75. Maruyama K, Asai J, Ii M, Thorne T, Losordo DW, D'Amore PA. Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing. Am J Pathol. 2007;170(4):1178–91. doi:10.2353/ajpath.2007.060018.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Brancato SK, Albina JE. Wound macrophages as key regulators of repair: origin, phenotype, and function. Am J Pathol. 2011;178(1):19–25. doi:10.1016/j.ajpath.2010.08.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Yan C, Gao N, Sun H, Yin J, Lee P, Zhou L, et al. Targeting imbalance between IL-1beta and IL-1 receptor antagonist ameliorates delayed epithelium wound healing in diabetic mouse corneas. Am J Pathol. 2016. doi:10.1016/j.ajpath.2016.01.019.

    Google Scholar 

  78. Okizaki SI, Ito Y, Hosono K, Oba K, Ohkubo H, Kojo K, et al. Vascular endothelial growth factor receptor type 1 signaling prevents delayed wound healing in diabetes by attenuating the production of IL-1beta by recruited macrophages. Am J Pathol. 2016. doi:10.1016/j.ajpath.2016.02.014.

    PubMed  Google Scholar 

  79. Thandavarayan RA, Garikipati VN, Joladarashi D, Suresh Babu S, Jeyabal P, Verma SK, et al. Sirtuin-6 deficiency exacerbates diabetes-induced impairment of wound healing. Exp Dermatol. 2015;24(10):773–8. doi:10.1111/exd.12762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Shaw T, Martin P. Epigenetic reprogramming during wound healing: loss of polycomb-mediated silencing may enable upregulation of repair genes. EMBO Rep. 2009;10(8):881–6. doi:10.1038/embor.2009.102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wonders J, Eekhoff EM, Heine R, Bruynzeel DP, Rustemeyer T. Insulin allergy: background, diagnosis and treatment. Ned Tijdschr Geneeskd. 2005;149(50):2783–8.

  82. Ullman HR, Dasgupta A, Recht M, Cash JM. CT of dystrophic calcification in subcutaneous soft tissues secondary to chronic insulin injection. J Comput Assist Tomogr. 2005;19(4):657–9.

  83. Clerx V, Van Den Keybus C, Kochuyt A, Goossens A. Drug intolerance reaction to insulin therapy caused by metacresol. Contact Dermatitis. 2003;48(3):162–3.

    Article  CAS  PubMed  Google Scholar 

  84. Beltrand J, Guilmin-Crepon S, Castanet M, Peuchmaur M, Czernichow P, Levy-Marchal C. Insulin allergy and extensive lipoatrophy in child with type 1 diabetes. Horm Res. 2006;65(5):253–60. doi:10.1159/000092515.

    CAS  PubMed  Google Scholar 

  85. Bernardez C, Scharer L, Molina-Ruiz AM, Requena L. Nodular amyloidosis at the sites of insulin injections. J Cutan Pathol. 2015;42(7):496–502. doi:10.1111/cup.12501.

    Article  PubMed  Google Scholar 

  86. Aouidad I, Fite C, Marinho E, Deschamps L, Crickx B, Descamps V. A case report of bullous pemphigoid induced by dipeptidyl peptidase-4 inhibitors. JAMA Dermatol. 2013;149(2):243–5. doi:10.1001/jamadermatol.2013.1073.

    Article  PubMed  Google Scholar 

  87. Attaway A, Mersfelder TL, Vaishnav S, Baker JK. Bullous pemphigoid associated with dipeptidyl peptidase IV inhibitors. A case report and review of literature. J Dermatol Case Rep. 2014;8(1):24–8. doi:10.3315/jdcr.2014.1166.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Byrd JB, Touzin K, Sile S, Gainer JV, Yu C, Nadeau J, et al. Dipeptidyl peptidase IV in angiotensin-converting enzyme inhibitor associated angioedema. Hypertension. 2008;51(1):141–7. doi:10.1161/HYPERTENSIONAHA.107.096552.

    Article  CAS  PubMed  Google Scholar 

  89. Desai S, Brinker A, Swann J, Iyasu S. Sitagliptin-associated drug allergy: review of spontaneous adverse event reports. Arch Intern Med. 2010;170(13):1169–71. doi:10.1001/archinternmed.2010.188.

    Article  PubMed  Google Scholar 

  90. Pasmatzi E, Monastirli A, Habeos J, Georgiou S, Tsambaos D. Dipeptidyl peptidase-4 inhibitors cause bullous pemphigoid in diabetic patients: report of two cases. Diabetes Care. 2011;34(8):e133. doi:10.2337/dc11-0804.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Skandalis K, Spirova M, Gaitanis G, Tsartsarakis A, Bassukas ID. Drug-induced bullous pemphigoid in diabetes mellitus patients receiving dipeptidyl peptidase-IV inhibitors plus metformin. J Eur Acad Dermatol Venereol: JEADV. 2012;26(2):249–53. doi:10.1111/j.1468-3083.2011.04062.x.

    Article  CAS  PubMed  Google Scholar 

  92. Arakaki RF. Sodium-glucose cotransporter-2 inhibitors and genital and urinary tract infections in type 2 diabetes. Postgrad Med. 2016;128(4):409–17. doi:10.1080/00325481.2016.1167570.

    Article  PubMed  Google Scholar 

  93. Goldberg I, Sasson A, Gat A, Srebrnik A, Brenner S. Pemphigus vulgaris triggered by glibenclamide and cilazapril. Acta Dermatovenerol Croat: ADC. 2005;13(3):153–5.

    PubMed  Google Scholar 

  94. Ozuguz P, Kacar SD, Ozuguz U, Karaca S, Tokyol C. Erythroderma secondary to gliclazide: a case report. Cutan Ocul Toxicol. 2014;33(4):342–4. doi:10.3109/15569527.2013.870188.

    Article  PubMed  Google Scholar 

  95. Selvaag E, Thune P. Phototoxicity to sulphonamide-derived oral antidiabetics and diuretics: investigations in hairless mice. Photodermatol Photoimmunol Photomed. 1997;13(1–2):4–8.

    Article  CAS  PubMed  Google Scholar 

  96. Noakes R. Lichenoid drug eruption as a result of the recently released sulfonylurea glimepiride. Australas J Dermatol. 2003;44(4):302–3.

  97. Goh CL. Psoriasiform drug eruption due to glibenclamide. Australas J Dermatol. 1987;28(1):30–2.

    Article  CAS  PubMed  Google Scholar 

  98. Koca R, Altinyazar HC, Yenidunya S, Tekin NS. Psoriasiform drug eruption associated with metformin hydrochloride: a case report. Dermatol Online J. 2003;9(3):11.

  99. Ben Salem C, Hmouda H, Slim R, Denguezli M, Belajouza C, Bouraoui K. Rare case of metformin-induced leukocytoclastic vasculitis. Ann Pharmacother. 2006;40(9):1685–7. doi:10.1345/aph.1H155.

    Article  PubMed  Google Scholar 

  100. Burger DE, Goyal S. Erythema multiforme from metformin. Ann Pharmacother. 2004;38(9):1537. doi:10.1345/aph.1E074.

  101. Andres-Ramos I, Blanco-Barrios S, Fernandez-Lopez E, Santos-Briz A. Exenatide-induced eosinophil-rich granulomatous panniculitis: a novel case showing injected microspheres. Am J Dermatopathol. 2015;37(10):801–2. doi:10.1097/DAD.0000000000000243.

    Article  PubMed  Google Scholar 

  102. Shan SJ, Guo Y. Exenatide-induced eosinophilic sclerosing lipogranuloma at the injection site. Am J Dermatopathol. 2014;36(6):510–2. doi:10.1097/DAD.0000000000000036.

    Article  PubMed  Google Scholar 

  103. Boysen NC, Stone MS. Eosinophil-rich granulomatous panniculitis caused by exenatide injection. J Cutan Pathol. 2014;41(1):63–5. doi:10.1111/cup.12246.

  104. Kono T, Hayami M, Kobayashi H, Ishii M, Taniguchi S. Acarbose-induced generalised erythema multiforme. Lancet. 1999;354(9176):396–7. doi:10.1016/S0140-6736(99)02135-2.

    Article  CAS  PubMed  Google Scholar 

  105. Wu CS, Chang WY, Lan CC, Chen GS, Chiu HH. Acute generalized exanthematous pustulosis possibly induced by acarbose. Int J Dermatol. 2008;47(12):1313–5. doi:10.1111/j.1365-4632.2008.03668.x.

    Article  PubMed  Google Scholar 

  106. Slama G, Eschwege E, Bernard MH, Grimaldi A, Oppert JM, Pouchain D, et al. One-year follow-up in real clinical practice conditions of type 2 diabetic patients treated with rosiglitazone: the Avantage study. Ann Endocrinol. 2008;69(1):36–46. doi:10.1016/j.ando.2007.10.024.

    Article  CAS  Google Scholar 

  107. Young RJ, Hannan WJ, Frier BM, Steel JM, Duncan LJ. Diabetic lipohypertrophy delays insulin absorption. Diabetes Care. 1984;7(5):479–80.

    Article  CAS  PubMed  Google Scholar 

  108. Binder E, Lange O, Edlinger M, Meraner D, Abt D, Moser C, et al. Frequency of dermatological side effects of continuous subcutaneous insulin infusion in children and adolescents with type 1 diabetes. Exp Clin Endocrinol Diabetes: Off J, German Soc Endocrinol German Diabetes Assoc. 2015;123(4):260–4. doi:10.1055/s-0034-1394381.

    Article  CAS  Google Scholar 

  109. Ligueros-Saylan M, Foley JE, Schweizer A, Couturier A, Kothny W. An assessment of adverse effects of vildagliptin versus comparators on the liver, the pancreas, the immune system, the skin and in patients with impaired renal function from a large pooled database of phase II and III clinical trials. Diabetes Obes Metab. 2010;12(6):495–509. doi:10.1111/j.1463-1326.2010.01214.x.

    Article  CAS  PubMed  Google Scholar 

  110. Ansorge S, Nordhoff K, Bank U, Heimburg A, Julius H, Breyer D, et al. Novel aspects of cellular action of dipeptidyl peptidase IV/CD26. Biol Chem. 2011;392(3):153–68. doi:10.1515/BC.2011.008.

    Article  CAS  PubMed  Google Scholar 

  111. Brown NJ, Byiers S, Carr D, Maldonado M, Warner BA. Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angioedema. Hypertension. 2009;54(3):516–23. doi:10.1161/HYPERTENSIONAHA.109.134197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, et al. PPARgamma signaling and metabolism: the good, the bad and the future. Nat Med. 2013;19(5):557–66. doi:10.1038/nm.3159.

    Article  CAS  PubMed  Google Scholar 

  113. Cerqueira MT, Pirraco RP, Marques AP. Stem cells in skin wound healing: are we there yet? Adv Wound Care. 2016;5(4):164–75. doi:10.1089/wound.2014.0607.

    Article  Google Scholar 

  114. Otero-Vinas M, Falanga V. Mesenchymal stem cells in chronic wounds: the spectrum from basic to advanced therapy. Adv Wound Care. 2016;5(4):149–63. doi:10.1089/wound.2015.0627.

    Article  Google Scholar 

  115. Jiang D and Scharffetter-Kochanek K (2015) Chapter 14: Mesenchymal stem cells in wound repair, tissue homeostasis and aging. In Geiger H, Heinrich J, Florian MC (Eds.), Stem cell aging: mechanisms, consequences, rejuvenation. Springer. ISBN 978-3-7091-1231-1.

  116. Dash SN, Dash NR, Guru B, Mohapatra PC. Towards reaching the target: clinical application of mesenchymal stem cells for diabetic foot ulcers. Rejuvenation Res. 2014;17(1):40–53. doi:10.1089/rej.2013.1467.

    Article  PubMed  Google Scholar 

  117. Qi Y, Jiang D, Sindrilaru A, Stegemann A, Schatz S, Treiber N, et al. TSG-6 released from intradermally injected mesenchymal stem cells accelerates wound healing and reduces tissue fibrosis in murine full-thickness skin wounds. J Investig Dermatol. 2014;134(2):526–37. doi:10.1038/jid.2013.328.

    Article  CAS  PubMed  Google Scholar 

  118. Kim CH, Lee JH, Won JH, Cho MK. Mesenchymal stem cells improve wound healing in vivo via early activation of matrix metalloproteinase-9 and vascular endothelial growth factor. J Korean Med Sci. 2011;26(6):726–33. doi:10.3346/jkms.2011.26.6.726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Kuo YR, Wang CT, Cheng JT, Wang FS, Chiang YC, Wang CJ. Bone marrow-derived mesenchymal stem cells enhanced diabetic wound healing through recruitment of tissue regeneration in a rat model of streptozotocin-induced diabetes. Plast Reconstr Surg. 2011;128(4):872–80. doi:10.1097/PRS.0b013e3182174329.

    Article  CAS  PubMed  Google Scholar 

  120. Wan J, Xia L, Liang W, Liu Y, Cai Q. Transplantation of bone marrow-derived mesenchymal stem cells promotes delayed wound healing in diabetic rats. J Diabetes Res. 2013;2013:647107. doi:10.1155/2013/647107.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Dash NR, Dash SN, Routray P, Mohapatra S, Mohapatra PC. Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells. Rejuvenation Res. 2009;12(5):359–66. doi:10.1089/rej.2009.0872.

    Article  CAS  PubMed  Google Scholar 

  122. Si Y, Zhao Y, Hao H, Liu J, Guo Y, Mu Y, et al. Infusion of mesenchymal stem cells ameliorates hyperglycemia in type 2 diabetic rats: identification of a novel role in improving insulin sensitivity. Diabetes. 2012;61(6):1616–25. doi:10.2337/db11-1141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Yang RH, Qi SH, Shu B, Ruan SB, Lin ZP, Lin Y, et al. Epidermal stem cells (ESCs) accelerate diabetic wound healing via the Notch signaling pathway. Biosci Rep. 2016. doi:10.1042/BSR20160034.

    Google Scholar 

  124. Rezania A, Bruin JE, Arora P, Rubin A, Batushansky I, Asadi A, O'Dwyer S, Quiskamp N, Mojibian M, Albrecht T, Yang YH, Johnson JD, Kieffer TJ. Reversal of diabetes with insulinproducing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol 2014;32(11):1121–33. doi:10.1038/nbt.3033.

  125. Yamanaka S. Induction of pluripotent stem cells from mouse fibroblasts by four transcription factors. Cell Prolif. 2008;41 Suppl 1:51–6. doi:10.1111/j.1365-2184.2008.00493.x.

    PubMed  Google Scholar 

  126. Maherali N, Hochedlinger K. Induced pluripotency of mouse and human somatic cells. Cold Spring Harb Symp Quant Biol. 2008;73:157–62. doi:10.1101/sqb.2008.73.017.

    Article  CAS  PubMed  Google Scholar 

  127. Alipio Z, Liao W, Roemer EJ, Waner M, Fink LM, Ward DC, et al. Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic beta-like cells. Proc Natl Acad Sci U S A. 2010;107(30):13426–31. doi:10.1073/pnas.1007884107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Tateishi K, He J, Taranova O, Liang G, D'Alessio AC, Zhang Y. Generation of insulin-secreting islet-like clusters from human skin fibroblasts. J Biol Chem. 2008;283(46):31601–7. doi:10.1074/jbc.M806597200.

    Article  CAS  PubMed  Google Scholar 

  129. Zhang D, Jiang W, Liu M, Sui X, Yin X, Chen S, et al. Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells. Cell Res. 2009;19(4):429–38. doi:10.1038/cr.2009.28.

    Article  CAS  PubMed  Google Scholar 

  130. Maehr R. iPS cells in type 1 diabetes research and treatment. Clin Pharmacol Ther. 2011;89(5):750–3. doi:10.1038/clpt.2011.1.

    Article  CAS  PubMed  Google Scholar 

  131. Maehr R, Chen S, Snitow M, Ludwig T, Yagasaki L, Goland R, et al. Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci U S A. 2009;106(37):15768–73. doi:10.1073/pnas.0906894106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Prigione A, Hossini AM, Lichtner B, Serin A, Fauler B, Megges M, et al. Mitochondrial-associated cell death mechanisms are reset to an embryonic-like state in aged donor-derived iPS cells harboring chromosomal aberrations. PLoS One. 2011;6(11):e27352. doi:10.1371/journal.pone.0027352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Wei R, Hong T. Lineage reprogramming: a promising road for pancreatic β cell regeneration. Trends Endocrinol Metab 2016;27(3):163–76. doi:10.1016/j.tem.2016.01.002.

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Acknowledgments

E.M. is grateful for being a recipient of the Hertha-Nathorff Program and D.J. is supported by the Baustein Program provided by the Medical Faculty of the University Ulm.

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Authors and Affiliations

  1. Department of Dermatology and Allergic Diseases, Universitätsklinikum Ulm, Life Science Building N27, James-Franck Ring/Meyerhofstrasse 11c, 89081, Ulm, Germany

    E. Makrantonaki, D. Jiang, M. Wlaschek & K. Scharffetter-Kochanek

  2. Department of Dermatology, Venereology, Allergology and Immunology, Städtisches Klinikum Dessau, Dessau, Germany

    E. Makrantonaki, A. M. Hossini, G. Nikolakis & C. C. Zouboulis

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  1. E. Makrantonaki
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Makrantonaki, E., Jiang, D., Hossini, A.M. et al. Diabetes mellitus and the skin. Rev Endocr Metab Disord 17, 269–282 (2016). https://doi.org/10.1007/s11154-016-9373-0

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