Diabetes mellitus skin changesE10-E14 + Hauterkrankung

Diabetes mellitus is the most common metabolic disease in humans; 5 million people in Germany suffer from this disease. About 1/3 of diabetics develop skin diseases. These occur both in manifest diabetes and in the pre-diabetic stage. However, they can also be superimposed by diabetogenically induced organ diseases (nephropathy, neuropathy, retinopathy, macro- and microangiopathy).

The diabetic skin changes are sometimes associated with a significantly increased morbidity and mortality.

4 types of diabetes are distinguished:

• Type 1 diabetes (special form LADA diabetes)
• Type 2 diabetes (>90%)
• Type 3 diabetes = other specific forms of diabetes (e.g. drugs such as glucocorticoids, genetic defects in beta cell function(MODY1-14), rare immunological diseases; genetic forms)
• Type 4 diabetes = gestational diabetes (GDM).

• Skin changes occur both in manifest diabetes and in the pre-diabetic stage. The percentages listed refer to several publications with larger collectives.
• Skin changes in diabetes mellitus can be classified into 5 disease groups:
  1. Skin infections
  2. Skin diseases with overfrequent association to diabetes mellitus
  3. Skin diseases due to diabetic complications
  4. Skin diseases due to diabetogenic organ diseases and their secondary effects on the skin (e.g. effects of a diabetic nephropathy)
  5. Reactions to antidiabetic therapy (ADR).

Skin infections:

• Bacterial infections:
  • Folliculitis
  • Furunculosis
  • Abscess, phlegmon
  • Neck carbuncle
  • Erythrasma
  • Otitis externa (also caused by Pseudomonas aeruginosa).
• Yeast infections (gastrointestinal candidiasis as reservoir; also the dentures; cave: plastic indwelling catheters - here also non-C-albicans pathogens such as C. glabrata and C. tropicalis):
  • Candidiasis (14% of diabetics)
  • Candidiasis, chronic mucocutaneous
  • Balanitis, vulvovaginitis
  • Paronychia
  • Perlèche.
• Other infections:
  • Tinea (one hand two feet syndrome)
  • Scabies norvegica
  • Mucormycosis.

Skin diseases with hyper association to diabetes mellitus:

• Granulomatous changes:
  • Granuloma anulare disseminatum (0,2%)
  • Necrobiosis lipoidica.
• Metabolic disorders:
  • glucagonoma syndrome (erythema necrolyticum migrans)
  • Hyperlipoproteinemia (eruptive xanthomas: in 0,6% of diabetics)
  • Porphyria cutanea tarda
• Insulin resistance syndromes:
  • Filiform fibromas of the axillae/groin regions (in 26% of diabetics)
  • Acanthosis nigricans (in 5% of diabetics)
  • Congenital lipodystrophy.
• Diseases of the connective tissue:
  • Diabetic dermopathy
  • Werner syndrome (progeria adultorum)
  • Bullosis diabeticorum
  • Epidermolysis bullosa acquisita.
  • Dupuytren's contracture
  • Induratio penis plastica
  • Scleroedema adultorum
  • Limited joint mobility syndrome.
• Other diseases:
  • Lipid deposition diseases, systematized
  • Kyrle's disease (hyperkeratosis follicularis et parafollicularis in cutem penetrans)
  • Reactive, perforating collagenosis
  • Lichen planus (with oral mucosal involvement)
  • Black hair tongue
  • Kaposi's sarcoma
  • Pseudoscleroderma
  • Bullosis diabeticorum (0.4%)
  • Hirsutism (diabeticorum)
  • Along with Addison's disease, Hashimoto's thyroiditis in autoimmunologic polyendocrinologic syndrome.
  • Deposits, discoloration:
    • Eruptive xanthomas (hyperlipidemic xanthomas: 0,6%)
    • Vitiligo
    • Rubeosis diabeticorum
    • Erythema palmare et plantare symptomaticum
    • Erythromelalgia
    • pseudoacanthosis nigricans
    • pretibial pigment spots.

Skin diseases due to diabetic complications:

• Angiopathies:
  • Atrophy blanche
  • leg ulcer
  • Thrombophlebitis
  • Arteriosclerosis with pAVK
  • Purpura
  • Other chronic wounds.
• Polyneuropathy (see Diabetic Polyneuropathy):
  • Common pressure calluses, with incorrect pressure on the soles of the feet
  • Burning-feet syndrome
  • Malum perforans
  • Diabetic foot syndrome
  • Diabetic pruritus (In 27.5% of patients with type 2 diabetes - Ko MJ et al 2013).
• Diabetic nephropathy with dermatological complications of potentially occurring superimposed chronic kidney disease (especially in end-stage renal failure).

Skin disorders due to antidiabetic therapy:

• Oral antidiabetics:
  • Allergic reactions
  • Photosensitivity reactions
  • Alcohol-induced flushing phenomena under sulfonylureas.
• Insulin:
  • Allergic reactions (5-10%)
  • Insulin-induced lipatrophy (14%)
  • Lipomatoses ( lipomatosis, benign symmetric)
  • "Insulin tumors" (at insulin injection sites).

Prevalence of diabetes mellitus: 6% of the population. About one third of all diabetics develop skin symptoms during the course of the disease.

It has been proven that diabetes mellitus on the one hand directly damages increased pathological glucose concentrations, on the other hand indirectly, by forming "advanced glycation end-products(AGEs)". AGEs are formed in a non-enzymatic reaction (glycation) of glucose and proteins, lipids and nucleic acid AGEs. They induce negative effects on almost all cell systems. Pathological glucose concentrations inhibit the proliferation, migration and protein biosynthesis of keratinocytes and fibroblasts. In endothelial cells they induce apoptosis and inhibit nitric oxide synthase (NOS) and thus NO synthesis. This leads to a reduced vasodilation in vivo. Pathological glucose concentrations suppress chemotaxis and phagocytosis of cell types of the innate immune defence.

AGEs interact with a number of intracellular and extracellular proteins, e.g. collagen type I, superoxide dismutase 1 or epidermal growth factor receptor and weaken their biological function. Furthermore, AGEs bind to RAGE (Receptor for AGEs). This leads to activation of the NF-κB signalling pathway with induction of proinflammatory cytokines, and both pathological glucose concentrations and AGEs lead to increased formation of intracellular oxidative stress (formation of reactive oxygen species - ROS). This is caused by a depletion of antioxidative protective enzymes such as glutathione or mitochondrial superoxide dismutase. On the other hand, ROS-generating enzymes such as nicotinamide adenine dinucleotide phosphate oxidase are induced.

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2. Guardiano RA et al (2003) Generalized granuloma annulare in a patient with adult onset diabetes mellitus. J Drugs Dermatol 2: 666-668
3. Ko MJ et al (2013) Postprandial blood glucose is associated with generalized pruritus in patients with type 2 diabetes. Eur J Dermatol 23:688-693.
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