Reviews

Skin manifestations of diabetes

Cleveland Clinic Journal of Medicine. 2008 November;75(11):772, 774, 776-777, 780-787

References

Landau J, Davis E. The small blood-vessels of the conjunctiva and nail bed in diabetes mellitus. Lancet 1960; 2:731
Huntley A. Diabetes mellitus: review. Dermatology Online Journal 1995; vol 1(2). http://dermatology.cdlib.org/DOJvol1num2/diabetes/dmreview.html. Accessed July 30, 2008.
Ahmed I, Goldstein B. Diabetes mellitus. Clin Dermatol 2006; 24:237–246.
Petzelbauer P, Wolff K, Tappeiner G. Necrobiosis lipoidica: treatment with systemic corticoids. Br J Dermatol 1992; 126:542.
Sibbald RG, Schachter RK. The skin and diabetes mellitus. Int J Dermatol 1984; 23:567–584.
Ferringer T, Miller F. Cutaneous manifestations of diabetes mellitus. Dermatol Clin 2002; 20:483–492.
Cohen O, Yaniv R, Karasik A, Trau H. Necrobiosis lipoidica and diabetic control revisited. Med Hypotheses 1996; 46:348–350.
Nguyen K, Washenik K, Shupak J. Necrobiosis lipoidica diabeticorum treated with chloroquine. J Am Acad Dermatol 2002; 46 suppl 2:34–36.
Stanway A, Rademaker M, Newman P. Healing of severe ulcerative necrobiosis lipoidica with cyclosporine. Australas J Dermatol 2004; 45:119–122.
Dittmar M, Kahaly GJ. Polyglandular autoimmune syndromes: immunogenetics and long-term follow-up. J Clin Endocrinol Metab 2003; 88:2983–2992.
Forschner T, Buchholtz S, Stockfleth E. Current state of vitiligo therapy-evidence-based analysis of the literature. J Dtsch Dermatol Ges 2007; 5:467–475.
Petrou-Amerikanou C, Markopoulos AK, Belazi M, Karamitsos D, Papanayotou P. Prevalence of oral lichen planus in diabetes mellitus according to the type of diabetes. Oral Dis 1998; 4:37–40.
Mobini N, Toussaint S, Kamino H. Noninfectious, erythematous, papular, and squamous diseases. In:Elder DE, editor. Lever’s Histopathology of the Skin. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2005:179–214.
Nikoleishvili LR, Kurashvili RB, Virsaladze DK. Characteristic changes of skin and its accessories in type 2 diabetes mellitus. Georgian Med News 2006; 131:43–46.
Lithner F, Hietala S-O. Skeletal lesions of the feet in diabetics and their relationship to cutaneous erythema with or without necrosis of the feet. Acta Med Scand 1976; 200:155–161.
Collier A, Matthews DM, Kellett HA, Clarke BF, Hunter JA. Change in skin thickness associated with cheiroarthropathy in insulin dependent diabetes mellitus. Br Med J (Clin Res Ed) 1986; 292:936.
Perez MI, Kohn SR. Cutaneous manifestations of diabetes mellitus. J Am Acad Dermatol 1994; 30:519–530.
Libecco JF. Finger pebbles and diabetes: a case with broad involvement of the dorsal fingers and hands. Arch Dermatol 2001; 137:510–511.
Brik R, Berant M, Vardi P. The scleroderma-like syndrome of insulin-dependent diabetes mellitus. Diabetes Metab Rev 1991; 7:121–128.
Jelinek JE. Cutaneous manifestations of diabetes mellitus. Int J Dermatol 1994; 33:605–617.
Huntley AC. The cutaneous manifestations of diabetes mellitus. J Am Acad Dermatol 1989; 7:427–455.
Jennings AM, Milner PC, Ward JD. Hand abnormalities are associated with the complications of diabetes in type 2 diabetes. Diabet Med 1989; 6:43–47.
Cole GW, Headley J, Skowsky R. Scleredema diabeticorum: a common and distinct cutaneous manifestation of diabetes mellitus. Diabetes Care 1983; 6:189–192.
Kahana M, Grossman E, Feinstein A, Ronnen M, Cohen M, Millet MS. Skin tags: a cutaneous marker for diabetes mellitus. Acta Derm Venereol 1987; 67:175–177.
Margolis J, Margolis LS. Skin tags—a frequent sign of diabetes mellitus [letter]. N Engl J Med 1976; 294:1184.
Garcia Hidalgo L. Dermatological complications of obesity. Am J Clin Dermatol 2002; 3:497–506.
Scheinfeld NS. Obesity and dermatology. Clin Dermatol 2004; 22:303–309.
Crook MA. Skin tags and the atherogenic lipid profile. J Clin Pathol 2000; 53:873–874.
Tompkins RR. Skin tags and diabetes. Arch Dermatol 1977; 113:1463.
Sibbald RG, Landolt SJ, Toth D. Skin and diabetes. Endocrinol Metab Clin North Am 1996; 25:463–472.
Hermanns-Le T, Scheen A, Pierard GE. Acanthosis nigricans associated with insulin resistance: pathophysiology and management. Am J Clin Dermatol 2004; 5:199–203.
Katz RA. Treatment of acanthosis nigricans with oral isotretinoin. Arch Dermatol 1980; 116:110.
Morton CA, Henderson IS, Jones MC, Lowe JG. Acquired perforating dermatosis in a British dialysis population. Br J Dermatol 1996; 135:671–677.
Saray Y, Seçkin D, Bilezikçi B. Acquired perforating dermatosis: clinicopathological features in twenty-two cases. J Eur Acad Dermatol Venereol 2006; 20:679–688.
Wilmer WA, Magro CM. Calciphylaxis:emerging concepts in prevention, diagnosis, and treatment. Dialysis 2002; 15:172–186.
Muller SA. Dermatologic disorders associated with diabetes mellitus. Mayo Clin Proc 1966; 41:689.
Meurer M, Stumvoll M, Szeimies RM. Hautveränderungen bei Diabetes mellitus. Hautartz 2004; 55:428–435.
Grammer L. Insulin allergy. Clin Rev Allergy 1986; 4:189–200.
Richardson T, Kerr D. Skin-related complications of insulin therapy: epidemiology and emerging management strategies. Am J Clin Dermatol 2003; 4:661–667.
Murao S, Hirata K, Ishida T, Takahara J. Lipoatrophy induced by recombinant human insulin injection. Intern Med 1998; 37:1031–1033.
Barranco R, Herrero T, Tornero P, et al. Systemic allergic reaction by a human insulin analog. Allergy 2003; 58:536–537.
Burge MR, Carey JD. Vitiligo associated with subcutaneous insulin lispro infusion in type 1 diabetes. Diabetes Care 2004; 27:275–276.
Durand-Gonzalez KN, Guillausseau N, Pecquet C, Gayno JP. Glargine insulin is not an alternative in insulin allergy. Diabetes Care 2003; 26:2216.
Blumer IR. Severe injection site reaction to insulin detemir. Diabetes Care 2006; 29:946.
Darmon P, Castera V, Koeppel MC, Petitjean C, Dutour A. Type III allergy to insulin detemir. Diabetes Care 2005; 28:2980.
Deerochanawong C, Chandraprasert S. Glimepiride in type 2 diabetes mellitus Thai patients. J Med Assoc Thai 2001; 84:1221–1228.
Noakes R. Lichenoid drug eruption as a result of the recently released sulfonylurea glimepiride. Australas J Dermatol 2003; 44:302–303.
Koca R, Altinyazar HC, Yenidünya S, Tekin NS. Psoriasiform [sic] drug eruption associated with metformin hydrochloride: a case report. Dermatol Online J 2003; 9:11. http://dermatology.cdlib.org/93/case_reports/metformin/koca.html. Accessed July 30, 2008.
Burger DE, Goyal S. Erythema multiforme from metformin. Ann Pharmacother 2004; 38:1537.
Klapholz L, Leitersdorf E, Weinrauch L. Leucocytoclastic vasculitis and pneumonitis induced by metformin. BMJ (Clin Res Ed) 1986; 293:483.
Ben Salem C, Hmouda H, Slim R, Denguezli M, Belajouza C, Bouraoui K. Rare case of metformin-induced leucocytoclastic vasculitis. Ann Pharmacother 2006; 40:1685–1687.
Litt JZ. Litt’s Drug Eruption Reference Manual. London: Taylor and Francis, 2001.
Balfour JA, McTavish D. Acarbose: an update of its pharmacology and therapeutic use in diabetes mellitus. Drugs 1993; 46:1024–1054. Erratum in: Drugs 1994; 48:929.
Kono T, Hayami M, Kobayashi H, Ishii M, Taniguchi S. Acarbose-induced generalized erythema multiforme. Lancet 1999; 354:396–397.
Ahr HJ, Boberg M, Krause HP, et al. Pharmacokinetics of acarbose. Part 1: Absorption, concentration in plasma, metabolism, and excretion after single administration of 14C acarbose to rats, dogs and man. Arzneimittelforschung 1989; 39:1254–1260.
Poszepczynska-Guigné E, Viguier M, Assier H, Pinquier L, Hochedez P, Dubertret L. Acute generalized exanthematous pustulosis induced by drugs with low-digestive absorption: acarbose and nystatin. Ann Dermatol Venereol 2003; 130:439–442.

SKIN MANIFESTATIONS ASSOCIATED WITH TYPE 2 DIABETES

Yellow nails

Elderly type 2 diabetic patients tend to have yellow nails. A prevalence of 40% to 50% in patients with type 2 diabetes has been reported,¹⁴ but occasionally yellow nails are also found in normal elderly people and in patients with onychomycosis. The yellow discoloration in diabetes is most evident on the distal end of the hallux nail. It probably represents end-products of glycosylation, similar to the yellow color in diabetic skin, although this has not yet been confirmed.¹⁵

Diabetic thick skin

Diabetes mellitus is generally associated with a thickening of the skin,² measurable via ultrasonography,¹⁶ and this thickening may increase with age in all diabetic patients, unlike normally aging skin.

Diabetic thick skin occurs in three forms. First is the general asymptomatic but measurable thickening. Second is a clinically apparent thickening of the skin involving the fingers and hands. Third is diabetic scleredema, an infrequent syndrome in which the dermis of the upper back becomes markedly thickened.^2,6

Thickening of the skin on the dorsum of the hands occurs in 20% to 30% of all diabetic patients, regardless of the type of diabetes.¹⁷ Manifestations range from pebbled knuckles to diabetic hand syndrome.² Pebbled knuckles (or Huntley papules) are multiple minute papules, grouped on the extensor side of the fingers, on the knuckles, or on the periungual surface.¹⁸ The prevalence of diabetic hand syndrome varies from 8% to 50%.¹⁹ It begins with stiffness of the metacarpophalangeal and proximal interphalangeal joints and progresses to limit joint mobility.^20,21 Dupuytren contracture (or palmar fascial thickening) may further complicate diabetic hand syndrome.^5,22

Scleredema diabeticorum is characterized by remarkable thickening of the skin of the posterior neck and upper back, occasionally extending to the deltoid and lumbar regions. A peau d’orange appearance of the skin can occur, often with decreased sensitivity to pain and touch.

Scleredema occurs in 2.5% to 14% of people with diabetes⁶ and is sometimes confused with scleredema of Buschke, a rare disorder in which areas of dermal thickening occur, mostly on the face, arms, and hands, often after an upper respiratory infection. It clears spontaneously in months or years. Women are affected more often than men. These characteristics differentiate scleredema of Buschke from scleredema diabeticorum, which almost exclusively occurs in long-standing diabetes, is usually permanent, is not related to previous infection, and is limited to the posterior neck and upper back. No effective treatment is known for scleredema diabeticorum.²³

Skin tags or acrochordons

Skin tags are small, pedunculated, soft, often pigmented lesions occurring on the eyelids, the neck, and the axillae. A few studies have reported an association between multiple skin tags and diabetes, and between skin tags and insulin resistance.^24–27 Crook²⁸ found that skin tags were associated with the typical atherogenic lipid profile seen in insulin-resistant states: elevated triglycerides and low levels of high-density-lipoprotein cholesterol. In a large study of patients with skin tags,²⁴ over 25% had diabetes and 8% had impaired glucose tolerance.²⁴

Treatment is not necessary, but skin tags can be removed with grade 1 scissors, cryotherapy, or electrodessication.²⁸ Skin tags may be regarded as a sign of impaired glucose tolerance, diabetes, and increased cardiovascular risk.^28,29

Diabetic dermopathy

Diabetic dermopathy (ie, shin spots and pigmented pretibial papules) affects 7% to 70% of all diabetic patients. It is not specific for diabetes: 20% of nondiabetic people show similar lesions. Men are affected more often than women, and the mean age is 50 years.

Shin spots present as multiple, bilateral, asymmetrical, annular or irregular red papules or plaques on the extensor surface of the lower legs and may precede abnormal glucose metabolism. The clinician usually sees only the end result: atrophic, scarred, hyperpigmented, finely scaled macules. Lesions may also be found on the forearms, thighs, and lateral malleoli. Several studies found severe microvascular complications in patients with diabetic dermopathy, indicating a close association with a high risk of accelerated diabetes complications.

Treatment is not very effective; however, some lesions resolve spontaneously.^6,30

Acanthosis nigricans

Figure 3. The velvety, hyperpigmented plaques of acanthosis nigricans occur usually in body folds and are thought to be related to high levels of circulating insulin.

Acanthosis nigricans (Figure 3) presents as hyperpigmented, velvety plaques in body folds. The dark color is due to thickening of keratin-containing superficial epithelium.³¹ It is traditionally classified as benign in insulin-resistant states. However, it can occur as a sign of paraneoplasm (particularly in stomach cancer), as an adverse effect of certain drugs (eg, nicotinic acid, corticosteroids), and in various endocrinopathies (eg, acromegaly, Cushing syndrome, leprechaunism). Even in the insulin-resistant diabetic patient, an underlying pathologic condition should be excluded.

The pathogenesis is most likely related to high levels of circulating insulin, which binds to insulin-like growth factor receptors to stimulate the growth of keratinocytes and dermal fibroblasts.

Although the lesions are generally asymptomatic, they can be painful, malodorous, or macerated.3 The most effective treatment is lifestyle alteration. Weight reduction and exercise can reduce insulin resistance. Acanthosis nigricans is reversible with weight reduction if it is seen as a complication of obesity. If the lesions are asymptomatic, they need no treatment. Ointments containing salicylic or retinoic acid can be used to reduce thicker lesions in areas of maceration in order to decrease odor and promote comfort. Systemic isotretinoin (Accutane) improves acanthosis nigricans, but it recurs when the drug is discontinued.^3,5,6,32

Acquired perforating dermatosis

Acquired perforating dermatosis is seen in patients with kidney failure, type 2 diabetes, or type 1 diabetes. A prevalence of up to 10% has been reported in dialysis patients.^33,34

The characteristic lesions are 2- to 10-mm, pruritic, dome-shaped papules and nodules with a hyperkeratotic plug. They occur mainly on the limbs, the trunk, and the dorsal surface of the hands, and to a lesser extent on the face. The Koebner phenomenon (also called isomorphic effect) may also occur.

Histologic study shows a hyperplastic epidermis with marked spongiosis directly over the plug. The contents of the plug itself are collagen, elastic fibers, nuclear debris, and polymorphonuclear leukocytes. These leukocytes have been implicated in the pathogenesis of acquired perforating dermatosis.^6,17

The lesions are chronic but may heal after months if trauma and scratching are avoided. Further treatments include topical keratolytics, psoralen-ultraviolet A light, ultraviolet B light, topical and systemic retinoids, topical and intralesional steroids, oral antihistamines, and cryotherapy.⁶

References

Landau J, Davis E. The small blood-vessels of the conjunctiva and nail bed in diabetes mellitus. Lancet 1960; 2:731
Huntley A. Diabetes mellitus: review. Dermatology Online Journal 1995; vol 1(2). http://dermatology.cdlib.org/DOJvol1num2/diabetes/dmreview.html. Accessed July 30, 2008.
Ahmed I, Goldstein B. Diabetes mellitus. Clin Dermatol 2006; 24:237–246.
Petzelbauer P, Wolff K, Tappeiner G. Necrobiosis lipoidica: treatment with systemic corticoids. Br J Dermatol 1992; 126:542.
Sibbald RG, Schachter RK. The skin and diabetes mellitus. Int J Dermatol 1984; 23:567–584.
Ferringer T, Miller F. Cutaneous manifestations of diabetes mellitus. Dermatol Clin 2002; 20:483–492.
Cohen O, Yaniv R, Karasik A, Trau H. Necrobiosis lipoidica and diabetic control revisited. Med Hypotheses 1996; 46:348–350.
Nguyen K, Washenik K, Shupak J. Necrobiosis lipoidica diabeticorum treated with chloroquine. J Am Acad Dermatol 2002; 46 suppl 2:34–36.
Stanway A, Rademaker M, Newman P. Healing of severe ulcerative necrobiosis lipoidica with cyclosporine. Australas J Dermatol 2004; 45:119–122.
Dittmar M, Kahaly GJ. Polyglandular autoimmune syndromes: immunogenetics and long-term follow-up. J Clin Endocrinol Metab 2003; 88:2983–2992.
Forschner T, Buchholtz S, Stockfleth E. Current state of vitiligo therapy-evidence-based analysis of the literature. J Dtsch Dermatol Ges 2007; 5:467–475.
Petrou-Amerikanou C, Markopoulos AK, Belazi M, Karamitsos D, Papanayotou P. Prevalence of oral lichen planus in diabetes mellitus according to the type of diabetes. Oral Dis 1998; 4:37–40.
Mobini N, Toussaint S, Kamino H. Noninfectious, erythematous, papular, and squamous diseases. In:Elder DE, editor. Lever’s Histopathology of the Skin. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2005:179–214.
Nikoleishvili LR, Kurashvili RB, Virsaladze DK. Characteristic changes of skin and its accessories in type 2 diabetes mellitus. Georgian Med News 2006; 131:43–46.
Lithner F, Hietala S-O. Skeletal lesions of the feet in diabetics and their relationship to cutaneous erythema with or without necrosis of the feet. Acta Med Scand 1976; 200:155–161.
Collier A, Matthews DM, Kellett HA, Clarke BF, Hunter JA. Change in skin thickness associated with cheiroarthropathy in insulin dependent diabetes mellitus. Br Med J (Clin Res Ed) 1986; 292:936.
Perez MI, Kohn SR. Cutaneous manifestations of diabetes mellitus. J Am Acad Dermatol 1994; 30:519–530.
Libecco JF. Finger pebbles and diabetes: a case with broad involvement of the dorsal fingers and hands. Arch Dermatol 2001; 137:510–511.
Brik R, Berant M, Vardi P. The scleroderma-like syndrome of insulin-dependent diabetes mellitus. Diabetes Metab Rev 1991; 7:121–128.
Jelinek JE. Cutaneous manifestations of diabetes mellitus. Int J Dermatol 1994; 33:605–617.
Huntley AC. The cutaneous manifestations of diabetes mellitus. J Am Acad Dermatol 1989; 7:427–455.
Jennings AM, Milner PC, Ward JD. Hand abnormalities are associated with the complications of diabetes in type 2 diabetes. Diabet Med 1989; 6:43–47.
Cole GW, Headley J, Skowsky R. Scleredema diabeticorum: a common and distinct cutaneous manifestation of diabetes mellitus. Diabetes Care 1983; 6:189–192.
Kahana M, Grossman E, Feinstein A, Ronnen M, Cohen M, Millet MS. Skin tags: a cutaneous marker for diabetes mellitus. Acta Derm Venereol 1987; 67:175–177.
Margolis J, Margolis LS. Skin tags—a frequent sign of diabetes mellitus [letter]. N Engl J Med 1976; 294:1184.
Garcia Hidalgo L. Dermatological complications of obesity. Am J Clin Dermatol 2002; 3:497–506.
Scheinfeld NS. Obesity and dermatology. Clin Dermatol 2004; 22:303–309.
Crook MA. Skin tags and the atherogenic lipid profile. J Clin Pathol 2000; 53:873–874.
Tompkins RR. Skin tags and diabetes. Arch Dermatol 1977; 113:1463.
Sibbald RG, Landolt SJ, Toth D. Skin and diabetes. Endocrinol Metab Clin North Am 1996; 25:463–472.
Hermanns-Le T, Scheen A, Pierard GE. Acanthosis nigricans associated with insulin resistance: pathophysiology and management. Am J Clin Dermatol 2004; 5:199–203.
Katz RA. Treatment of acanthosis nigricans with oral isotretinoin. Arch Dermatol 1980; 116:110.
Morton CA, Henderson IS, Jones MC, Lowe JG. Acquired perforating dermatosis in a British dialysis population. Br J Dermatol 1996; 135:671–677.
Saray Y, Seçkin D, Bilezikçi B. Acquired perforating dermatosis: clinicopathological features in twenty-two cases. J Eur Acad Dermatol Venereol 2006; 20:679–688.
Wilmer WA, Magro CM. Calciphylaxis:emerging concepts in prevention, diagnosis, and treatment. Dialysis 2002; 15:172–186.
Muller SA. Dermatologic disorders associated with diabetes mellitus. Mayo Clin Proc 1966; 41:689.
Meurer M, Stumvoll M, Szeimies RM. Hautveränderungen bei Diabetes mellitus. Hautartz 2004; 55:428–435.
Grammer L. Insulin allergy. Clin Rev Allergy 1986; 4:189–200.
Richardson T, Kerr D. Skin-related complications of insulin therapy: epidemiology and emerging management strategies. Am J Clin Dermatol 2003; 4:661–667.
Murao S, Hirata K, Ishida T, Takahara J. Lipoatrophy induced by recombinant human insulin injection. Intern Med 1998; 37:1031–1033.
Barranco R, Herrero T, Tornero P, et al. Systemic allergic reaction by a human insulin analog. Allergy 2003; 58:536–537.
Burge MR, Carey JD. Vitiligo associated with subcutaneous insulin lispro infusion in type 1 diabetes. Diabetes Care 2004; 27:275–276.
Durand-Gonzalez KN, Guillausseau N, Pecquet C, Gayno JP. Glargine insulin is not an alternative in insulin allergy. Diabetes Care 2003; 26:2216.
Blumer IR. Severe injection site reaction to insulin detemir. Diabetes Care 2006; 29:946.
Darmon P, Castera V, Koeppel MC, Petitjean C, Dutour A. Type III allergy to insulin detemir. Diabetes Care 2005; 28:2980.
Deerochanawong C, Chandraprasert S. Glimepiride in type 2 diabetes mellitus Thai patients. J Med Assoc Thai 2001; 84:1221–1228.
Noakes R. Lichenoid drug eruption as a result of the recently released sulfonylurea glimepiride. Australas J Dermatol 2003; 44:302–303.
Koca R, Altinyazar HC, Yenidünya S, Tekin NS. Psoriasiform [sic] drug eruption associated with metformin hydrochloride: a case report. Dermatol Online J 2003; 9:11. http://dermatology.cdlib.org/93/case_reports/metformin/koca.html. Accessed July 30, 2008.
Burger DE, Goyal S. Erythema multiforme from metformin. Ann Pharmacother 2004; 38:1537.
Klapholz L, Leitersdorf E, Weinrauch L. Leucocytoclastic vasculitis and pneumonitis induced by metformin. BMJ (Clin Res Ed) 1986; 293:483.
Ben Salem C, Hmouda H, Slim R, Denguezli M, Belajouza C, Bouraoui K. Rare case of metformin-induced leucocytoclastic vasculitis. Ann Pharmacother 2006; 40:1685–1687.
Litt JZ. Litt’s Drug Eruption Reference Manual. London: Taylor and Francis, 2001.
Balfour JA, McTavish D. Acarbose: an update of its pharmacology and therapeutic use in diabetes mellitus. Drugs 1993; 46:1024–1054. Erratum in: Drugs 1994; 48:929.
Kono T, Hayami M, Kobayashi H, Ishii M, Taniguchi S. Acarbose-induced generalized erythema multiforme. Lancet 1999; 354:396–397.
Ahr HJ, Boberg M, Krause HP, et al. Pharmacokinetics of acarbose. Part 1: Absorption, concentration in plasma, metabolism, and excretion after single administration of 14C acarbose to rats, dogs and man. Arzneimittelforschung 1989; 39:1254–1260.
Poszepczynska-Guigné E, Viguier M, Assier H, Pinquier L, Hochedez P, Dubertret L. Acute generalized exanthematous pustulosis induced by drugs with low-digestive absorption: acarbose and nystatin. Ann Dermatol Venereol 2003; 130:439–442.

Skin manifestations of diabetes

References

Yellow nails

Diabetic thick skin

Skin tags or acrochordons

Diabetic dermopathy

Acanthosis nigricans

Acquired perforating dermatosis

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