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 EFFECTS OF ORAL HYPOGLYCEMIC AGENTS

First-generation sulfonylureas

Figure 4. (Left) Erythema exsudativum multiforme and (above) erythema nodosum in diabetic patients taking a first-generation sulfonylurea.

Most cutaneous reactions to oral hypoglycemic drugs have been reported with first-generation sulfonylureas (eg, chlorpropamide, tolbutamide [Orinase]). Between 1% and 5% of patients taking first-generation sulfonylureas develop cutaneous reactions within the first 2 months of treatment. Maculopapular eruptions are the most common reaction and often disappear with discontinuation of the medication. Other cutaneous reactions are generalized erythema, urticaria, lichenoid eruptions, erythema exsudativum multiforme (Figure 4), exfoliative dermatitis, erythema nodosum (Figure 4), and photosensitivity reactions. Even if a photo-patch test is negative in a patient with a photosensitivity reaction, the oral glucose-lowering drug should be switched.

In 10% to 30% of patients using chlorpropamide, an alcohol flush is induced, consisting of redness and warmth, headache, tachycardia, and occasionally dyspnea, starting about 15 minutes after alcohol consumption. Usually, the symptoms disappear after an hour. This reaction pattern seems to be inherited in an autosomal-dominant pattern.^6,37

Second-generation sulfonylureas

Second-generation sulfonylureas such as glipizide (Glucotrol) and glimepiride (Amaryl) have also been associated with cutaneous reactions. The most frequent reactions associated with glipizide are photosensitivity, rash, urticaria, and pruritus. These are reported less often with glimepiride. Deerochanawong⁴⁶ reported patients with skin rash after the use of glimepiride. A case of lichenoid drug eruption was described by Noakes.⁴⁷

Other oral hypoglycemic drugs

Metformin (Glucophage), a biguanide-derivative antihyperglycemic drug, is the first-choice oral drug in type 2 diabetic patients. Dermal side effects reported include psoriatiform drug eruption,⁴⁸ erythema exsudativum multiforme,⁴⁹ and leukocytoclastic vasculitis.^50,51Litt’s Drug Eruption Manual gives the risk of photosensitivity reaction to metformin as 1% to 10%⁵² but cites no reference for this statement. Erythema, exanthema, pruritus, and urticaria have also been reported as side effects of metformin.⁵²

Acarbose (Precose) is minimally absorbed from the gut: only about 1% of a dose reaches the bloodstream,53 and thus it seldom causes adverse effects. Kono et al⁵⁴ reported a case of acarbose-induced generalized erythema multiforme confirmed by a challenge test. The drug-induced lymphocyte stimulation test and patch test for acarbose were negative. Ahr et al⁵⁵ reported that acarbose labeled with carbon 14 was poorly absorbed when given orally, but that up to 35% of this formulation of acarbose was absorbed after degradation by digestive enzymes, intestinal microorganisms, or both. Because the drug-induced lymphocyte stimulation test and the patch test were negative in the patient described by Kono et al,⁵⁴ it is possible that the degradation products of acarbose induced the allergic reaction after absorption. Poszepczynska-Guigné et al⁵⁶ described the first case of acute generalized exanthematous pustulosis induced after administration of acarbose.

Thiazolidinediones. Edema has been reported as an adverse cutaneous effect of rosiglitazone (Avandia) and pioglitazone (Actos).⁵²

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

First-generation sulfonylureas

Second-generation sulfonylureas

Other oral hypoglycemic drugs

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