Insulin-induced Lipoatrophy in a Patient on Insulin Analogue Therapy: a Case Report

Insulin-induced lipoatrophy is a rare skin complication in patients with diabetes mellitus. It is characterized primarily by localized subcutaneous atrophy of the fatty tissue at the site of frequent insulin injection. We report a clinical case of a 38-year-old woman with lipoatrophy, developed during treatment with insulin analogues. Lipoatrophic zone formation began 3 months after the treatment was initiated. A lipoatrophic defect developed on the thighs and the upper outer arms, resulting from repeated insulin injections at the same site. Regarding lipoatrophic areas, treatment with topical administration of corticosteroids was attempted but without a significant clinical effect. The best prevention from lipoatrophy development is education of patients regarding rotation of insulin injection sites and more frequent needle change.


INTRODUCTION
Insulin therapy is one of the iatrogenic causes of localized acquired lipoatrophy. In addition, acquired lipoatrophy may be a complication of local action due to other injectable agents such as corticosteroids, antibiotics, heparin, vaccines, and growth hormone. It may also occur as a result of an abscess, recurrent trauma (lipoatrophy semicircularis), localized scleroderma (morphea), cutaneous systemic lupus erythematosus, dermatomyositis, etc. Insulin-induced lipoatrophy is a rare skin complication in patients with diabetes mellitus. [1][2][3] In past years, when bovine and porcine insulin was used, its incidence used to be significantly higher, between 10-55%. 4 However, in the era of human insulin and insulin analogues, lipoatrophy occurred in approximately 3.6% of treated patients. 3,5,6 It is most common in young women with type 1 diabetes mellitus. 4,7 The reason for its occurrence may be: the use of the same insulin injection site over a long period of time, irregularly changing needles of injection devices, applying different analogue insulin to the same patient. 1

sulin. Six months later the therapy was switched to one with a short-acting insulin analogue (aspart) and long-acting insulin analogue (detemir).
In the endocrinology consulting room, the patient presented in July 2015 with severe hypoglycemia, with registered blood sugar level of 1.9 mmol/L. Based on medical history and physical examination, it became clear that the type of diabetes had not been classified correctly. The patient reported that she had gained 30 kg in two years and used to be having frequent episodes of hypoglycemia, including ones with loss of consciousness. The patient had never been educated on insulin dose titration, therefore she was using the constant dose prescribed by the endocrinologist as a definitive and fixed one. In addition, the patient had another endocrine di-sease -autoimmune thyroiditis in a hypothyroid phase. At the time of examination, she was being treated with 75 μg of levothyroxine once daily for substitution. She reported a family history of thyroid disease and diabetes mellitus. There was no evidence for diabetic complications.
Data from physical examination included: Obesity class I (BMI=34 kg/m 2 ), and four areas of lipoatrophy with a diameter of about 10 cm each, located on thighs and upper outer arms (Figs 1, 2). Lipoatrophic zone formation began 3 months after initiation of treatment with insulin analogues. The patient had not been instructed to rotate the injection sites and continuously administered insulin in the same area until lipoatrophy occurred, the zone then deepened and enlarged. It was not until then when she changed the location.  Following the examination, several laboratory tests were recommended and performed (Table 1).

DISCUSSION
Insulin-induced lipoatrophy is considered an immunological side effect during the course of insulin therapy. 1,5,7 The pathogenesis is still not clear enough. It is characterized by the local formation of complexes between the injected agent and circulating antibodies, activation of the complement system and infiltration of inflammatory cells. 4 The local accumulation of immune complexes is followed by vascular changes. Overproduction of cytokines and TNF-α by mast cells inhibit adipocyte differentiation. Besides, the presence of anti-insulin antibodies is also associated with cutaneous atrophy. 1,2,6 The lipoatrophic areas of the skin appear in a period of time that varies between 4 weeks and 2 years after initiation of insulin therapy. It is crucial to recognize and treat this condition as early as possible. Insulin absorption at these sites is unpredictable, which creates the prerequisites for hyperglycemia or hypoglycemia. [1][2][3][4][5][6]8,9 A key element in prevention of this complication is the education of patients with diabetes. They should be instructed to alternate the injection sites, to observe the skin, and not to use the same needle for a long period of time (up to 12 times). 9,10 In case of lipoatrophy, attempts to treat the affected areas include topical corticosteroid injections. A positive reversal is recorded in some of the treated patients. 11

CONCLUSION
The present case report is intended to draw attention to one of the rare complications of diabetes mellitus, in particular one related with insulin therapy. Even treatment with insulin analogues may cause skin changes. Patient's education is very important in regard of titration of insulin doses depending on blood glucose values, as well as on the diet and the physical activity. Patients on insulin therapy should be advised on rotation of insulin injection sites and the need for more frequent needle change. This will minimize the occurrence of local skin reactions as an insulin treatment complication.