Discussion
A review of the literature revealed 18 reported cases of acanthosis nigricans at sites of repeated insulin injection (Table).5-20 Acanthosis nigricans at the site of insulin injection afflicts patients of any age, with cases observed in patients aged 14 to 75 years. Sixteen (84%) of 19 cases were male. Fourteen cases (73%) had T2DM; the rest of the patients had T1DM. The duration of insulin injection therapy prior to onset ranged from immediate to 13 years (median 4 years). Fourteen cases (73%) were reported on the abdomen; however, other sites, such as thighs and upper arm, also were reported. Lesions size varied from 12 to 360 cm2. Two cases had associated amyloidosis. The average HbA1c reported at presentation was 10%. Following insulin injection-site rotation, most of the cases reported improvement of both glycemic control and acanthosis nigricans appearance.
In the case described by Kudo and colleagues, a 59-year-old male patient with T2DM had been injecting insulin into the same spot on his abdomen for 10 years. He developed acanthosis nigricans and an amyloidoma so large and firm that it bent the needle when he injected insulin.11
Most of the cases we found in the literature were after 2005 and associated with the use of human or analog insulin. These cases may be related to a bias, as cases may be easier to find in digital archives in the later years, when human or analog insulins have been in common use. Also noteworthy, in cases that reported dosage, most were not very high, and the highest daily dose was 240 IU/d. Ten reports of injection-site acanthosis nigricans were in dermatology journals; only 5 reports were in endocrinology journals and 3 in general medical journals, indicating possible less awareness of this phenomenon in other HCPs who care for patients with DM.
Complications of Same-Site Injections
Acanthosis nigricans. Commonly found in the armpits, neck folds, and groin, acanthosis nigricans is known as one of the calling cards for insulin resistance, obesity, and hyperinsulinemia.21 Acanthosis nigricans can be seen in people with or without DM and is not limited to those on insulin therapy. However, same-site insulin injections for 4 to 6 years also may result in injection-site acanthosis nigricans–like lesions because of factors such as insulin exposure at the local tissue level.16
Acanthosis nigricans development is characterized by hyperpigmented, hyperkeratotic, velvety, and sometimes verrucous plaques.6 Acanthosis nigricans surrounding repeated injection sites is hypothesized to develop as a result of localized hyperinsulinemia secondary to insulin resistance, which increases the stimulation of IGF, thereby causing epidermal hypertrophy.5-20 If insulin injection therapy continues to be administered through the acanthosis nigricans lesion, it results in decreased insulin absorption, leading to poor glycemic control.13
Acanthosis nigricans associated with insulin injection is reversible. After rotation of injection sites, lesions either decrease in size or severity of appearance.5-8,11 Also, by avoiding injection into the hyperkeratotic plaques and using normal subcutaneous tissue for injection, patients’ response to insulin improves, as measured by HbA1c and by decreased daily insulin requirement.6-8,10,12,18-20
Lipohypertrophy. This is characterized by an increase in localized adipose tissue and is the most common cutaneous complication of insulin therapy.2 Lipohypertrophy presents as a firm, rubbery mass in the location of same-site insulin injections.22 Development of lipohypertrophy is suspected to be the result of either (1) anabolic effect of insulin on local adipocytes, promoting fat and protein synthesis; (2) an autoimmune response by immunoglobulin (Ig) G or IgE antibodies to insulin, immune response to insulin of different species, or to insulin injection techniques; or (3) repeated trauma to the injection site from repeated needle usage.4,23