Expert opinion: Cutaneous problems in insulin therapy

Skin problems are common in patients who inject insulin. By Pat Miles, Dr David Kerr and Dr Tristan Richardson

The incidence and prevalence of all types of diabetes is increasing at an alarming rate. Modern therapy often uses intensive insulin regimens to achieve tight control of blood glucose levels and reduce the long-term risk of complications associated with the condition. Unfortunately, insulin therapy can be associated with important cutaneous side-effects.

The treatment of diabetes with subcutaneous injections of insulin is generally well tolerated, with most patients experiencing no serious problems with their injection sites. However, a small number of patients do experience problems, such as allergy and lipodystrophy (see box 1).

BOX 1: SKIN COMPLICATIONS
Diabetes mellitus
  • Necrobiosis lipoidica diabeticorum
  • Diabetic dermopathy
  • Diabetic thick skin
  • Diabetic bullae
  • Acanthosis nigricans
  • Yellow skin
  • Pigmented purpuric dermatoses
Insulin therapy
  • Lipohypertrophy
  • Lipoatrophy
  • Abscess
  • Insulin oedema
  • Idiosyncratic injection site pigmentation
  • Insulin allergy
  • Zinc/protamine allergy
  • Skin pigmentation

Although these are rare, healthcare professionals need to be aware of cutaneous insulin reactions, their potential treatment options and their impact on glycaemic control.

Bruising or bleeding
The most common skin complaint in those who inject insulin is bruising or bleeding, with the majority reporting occasional problems. Advice to press down over the site with clean gauze or tissue as the needle is removed may help to prevent this.

If the problem persists, changing to a smaller gauge or shorter needle and ensuring a fresh needle is used for each injection may be beneficial. Patients often need reassurance that occasional bleeding is normal.

Lipohypertrophy
Lipohypertrophy is the formation of raised, soft, fatty lumps at the injection site, affecting about 30 per cent of patients with type-1 diabetes and 5 per cent of those with type-2 diabetes.1 The lipogenic effect of insulin results in subcutaneous fat deposition as a result of repeated insulin inoculation. These areas have poor blood supply, which may not absorb insulin predictably and can lead to erratic blood glucose control.

These fatty areas have fewer nerve endings, with less discomfort associated with each insulin injection, so the site continues to be used, exacerbating the problem. Areas of lipohypertrophy can vary in size between a few centimetres to large areas, commonly of the anterior abdominal wall.

Prevention is the best remedy and advice to rotate and use different sites needs to be reinforced from the moment a patient starts on insulin. Once these fatty lumps have formed, changing to a different site will improve absorption and needs to be accompanied by advice to reduce the insulin dose to prevent hypoglycaemia. Treatment is to rotate injection sites, in the hope that regression will occur, but changing to short-acting rapidly absorbed insulin may be a useful adjunct.2

Novel approaches include switching to pump therapy where overall insulin requirements are reduced, lessening the lipogenic stimulus. In some patients, areas of lipohypertrophy will reabsorb over a period of months, but in others they remain, and a cosmetic improvement may be gained from liposuction.3

Lipoatrophy
This insulin-induced loss of subcutaneous fat at the injection site may involve an immune-mediated inflammatory process with the release of lysosomal enzymes.4 It used to affect up to half of patients injecting insulin, but with the introduction of highly purified insulins, this has dropped to fewer than 10 per cent.5 As with lipohypertrophy, the advice is to avoid the affected site, but spontaneous resolution is rare. There has been some success with repeatedly injecting highly purified porcine or human insulin into the area, or using an analogue insulin injected into the edge of the atrophic area to promote regeneration of fat cells.6

If this fails, adding dexamethasone to the insulin injection at 4µg per unit may be effective.7 Inhaled insulin has been approved by NICE for use in patients with severe or persisent problems with injection sites, including lipodystrophy.

Skin pigmentation
Pigmentation can occur at injection sites (figure 1), sometimes leading to plaque formation resembling acanthosis nigricans.8 Rarely, keloids develop. Localised amyloidosis has also been described and can be mistaken for lipohypertrophy.9 Lesions are firmer and more solid than lipohypertrophy, and unlikely to regress after injection site rotation. As with lipohypertrophy, insulin absorption may be affected and treatment by excision may be appropriate. Diagnosis at excision or biopsy is by usual histological methodology and staining.

Fig 1: Skin pigmentation associated with insulin injection

Insulin allergies
Twenty years ago, allergic reactions to insulin were said to occur in up to 55 per cent of patients.10 They are less common now, but most patients still have some immunological reaction to insulin. The development of low titres of insulin-binding antibodies is frequent,11 but very few patients treated with purified human insulins (<3 per cent) develop local reactions10 and only 0.01 per cent experience systemic allergic reactions.12

Local allergic reactions to insulin are usually erythematous, pruritic and indurated. Many skin reactions are short-lived and resolve spontaneously within a few weeks, despite continuation of insulin therapy. The allergic reaction is mediated through immunogenic responses to a number of components, including the insulin molecule itself, pro-insulin, or the zinc/protamine additives contained in the longer-acting formulations.

Antihistamines are useful in symptom control and can block the wheal-and-flare response. If the skin reactions persist for longer than two to four weeks, changing to a less allogenic insulin type – for example, the newer analogue insulins – may be beneficial.13 If this does not resolve the allergic reaction, other options can be considered (see box 2). The use of insulin pump therapy in managing cutaneous complications of insulin therapy is increasing, but this method carries its own small risk of abscess formation and scarring. Fortunately, with improved education for patients, these are relatively uncommon.

BOX 2: TREATMENT OPTIONS
For insulin allergy
  • If skin reactions persist for more than two to four weeks, swap insulin to a less allogenic type, such as the newer analogue insulins
  • If this does not resolve the allergic reaction, consider:
    – Dividing the insulin dose and varying the delivery site
    – Adding dexamethasone 4 microgram to each unit of insulin per injection
    – Oral antihistamines (or corticosteroids)
    – Inhaled insulin
    – Continuous insulin infusion (pump) therapy
    – Insulin desensitisation

A range of desensitisation schedules has been proposed,14,15 some of which have achieved good success rates. A novel approach to insulin allergy that is unresponsive to initial methods is the use of inhaled insulin, although this too is associated with the development of insulin antibodies, but no clinically significant reduction in lung function.16

Systemic allergy with urticaria, generalised rash, pruritus or paresthesia is very rare. However, angioneurotic oedema and circulatory collapse have also been described in association with insulin use.17 Treatment is similar to anaphylaxis of any cause.

The rise in the use of analogue insulins has resulted in a reduction in the use of both human and NPH insulin, with a likely reduction in allergic responses, although case reports of allergy continue to appear.18

Skin abscesses
Skin abscesses from insulin injection per se are vanishingly rare. However, skin abscesses or cellulitis in relation to continuous insulin infusion are one of the most common causes listed for discontinuation of pump therapy.19

Infusion sets need be changed every two to three days. In most cases, simple washing of the skin is all that is necessary before inserting infusion sets. Nevertheless, skin infections, including abscess formation, can occur.20 Most cases are bacterial, usually staphylococcal or streptococcal species.

Conclusion
Cutaneous complications from insulin are under-recognised by patients and healthcare professionals. They may be cosmetic, irritating or even life-threatening. Lipodystrophy and insulin allergy also influence diabetes control and predispose to hypoglycaemia or so-called ‘brittle diabetes’.

A thorough examination of patients’ injection sites may enable improved glycaemic control, by facilitating a change in insulin type or mode of delivery, and potentially minimising the risk of acute and long-term complications.

- Pat Miles is a diabetes nurse specialist at Bournemouth Diabetes & Endocrine Centre (BEDC), Royal Bournemouth Hospital; Dr David Kerr is consultant physician and visiting professor at BEDC and the centre of postgraduate medical research and education, Bournemouth University; Dr Tristan Richardson is consultant physician at BEDC, Royal Bournemouth Hospital

References
1. Hauner H, Stockamp B, Haastert B. Prevalence of lipohypertrophy in insulin-treated diabetic patients and predisposing factors. Exp Clin Endocrinol Diabetes 1996; 104: 106-10.
2. Roper NA, Bilous RW. Resolution of lipohypertrophy following change of short-acting insulin to insulin lispro (Humalog). Diabet Med 1998; 15: 1063-4.
3. Samdal F, Amland PF, Sandsmark M, Birkeland KI. Diabetic lipohypertrophy treated with suction-assisted lipectomy. J Intern Med 1993; 234: 489-92.
4. Edidin DV. Cutaneous manifestations of diabetes mellitus in children. Pediatr Dermatol 1985; 2: 161-79.
5. Wilson RM, Douglas CA, Tattershall RB, Reeves WG. Immunogenicity of highly purified bovine insulin: a comparison with conventional bovine and highly purified human insulins. Diabetologia 1985; 28: 667-70.
6. Valenta LJ, Elias AN. Insulin-induced lipodystrophy in diabetic patients resolved by treatment with human insulin. Ann Intern Med 1985; 102: 790-1.
7. Kumar D, Miller L, Mehtalia S. Use of dexamethasone in treatment of insulin lipoatrophy. Diabetes 1977; 26: 296-9.
8. Anderson JA, Adkinson NF. Allergic reactions to drugs and biologic agents. JAMA 1987; 258: 2891-9.
9. Swift B, Hawkins PN, Richards C, Gregory R. Examination of insulin injection sites: an unexpected finding of localized amyloidosis. Diabet Med 2002; 19: 881-2.
10. Galloway JA, Fireman P, Fineberg SE. Complications of insulin therapy: a brief review of four years experience with human insulin (rDNA). In: Church J (ed). Diabetes mellitus: achievements and scepticism: proceedings of a symposium. Royal Society of Medicine, London, 1984.
11. Grammer L. Insulin allergy. Clin Rev Allergy 1986; 4: 189-200.
12. Granic M, Pavlic Renar I, Metelko Z, Skrabalo Z. Insulin allergy. Diabetes Care 1986; 9: 99-100.
13. Yasuda H, Nagata M, Moriyama H et al. Human insulin analog insulin aspart does not cause insulin allergy. Diabetes Care 2001; 24: 2008-9.
14. Galloway JA, Bressler R. Insulin treatment in diabetes. Med Clin North Am 1978; 62: 663-80.
15. Grammer LC, Chen PY, Patterson R. Evaluation and management of insulin allergy. J Allergy Clin Immunol 1983; 71: 250-4.
16. Stoever JA, Palmer JP. Inhaled insulin and insulin antibodies: a new twist to an old debate. Diabetes Technol Ther 2002; 4: 157-61.
17. Menoscal A, Lavarello A, Garcia de los Rios M. Anaphylactic shock due to highly purified porcine insulin. Rev Med Chil 1986; 114: 969-72.
18. Takata H, Kumon Y, Osaki F et al. The human insulin analogue aspart is not the almighty solution for insulin allergy. Diabetes Care 2003; 26: 253-4.
19. Guinn TS, Bailey GJ, Mecklenburg RS. Factors related to discontinuation of continuous subcutaneous insulin-infusion therapy. Diabetes Care 1988; 11: 46-51.
20. Mecklenburg RS, Benson EA, Benson JW et al. Acute complications associated with insulin infusion pump therapy. Report of experience with 161 patients. JAMA 1984; 252: 3265-9.


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