In a study assessing the prevalence of lipohypertrophy and its relation to insulin technique, 49.1% of participants with lipohypertrophy had glycemic variability compared with 6.5% of participants without lipohypertrophy.3 Johansson and colleagues described an impairment of insulin absorption in lipohypertrophic tissues, causing a 25% lower plasma insulin concentration compared with that of normal tissues.4 These findings suggest a significant effect of lipohypertrophy on insulin absorption—unnecessarily increasing insulin consumption and worsening glycemic control.
Primary prevention measures include injection site inspection and patient education about rotation and abstaining from needle reuse.22 If a patient already has signs of lipohypertrophy, data supports education and insulin injection technique practice as simple and effective means to reduce insulin action variability and increase glycemic control.24
Lipoatrophy. Lipoatrophy is described as a local loss of subcutaneous adipose tissue often in the face, buttocks, legs and arm regions and can be rooted in genetic, immune, or drug-associated etiologies.25 Insulin-induced lipoatrophy is suspected to be the result of tumor necrosis factor-α hyperproduction in reaction to insulin crystal presence at the injection site.26,27 Overall, lipoatrophy development has decreased since the use of recombinant human insulin and analog insulin therapy.28 The decrease is hypothesized to be due to increased subcutaneous tissue absorption rate of human insulin and its analog, decreasing overall adipocyte exposure to localized high insulin concentration.27 Treatments for same-site insulin-derived lipoatrophy include changing injection sites and preparation of insulin.26 When injection into the lipoatrophic site was avoided, glycemic control and lipoatrophy appearance improved.26
Amyloidosis. Amyloidosis indicates the presence of an extracellular bundle of insoluble polymeric protein fibrils in tissues and organs.29 Insulin-induced amyloidosis presents as a hard mass or ball near the injection site.29 Insulin is one of many hormones that can form amyloid fibrils, and there have been several dozen cases reported of amyloid formation at the site of insulin injection.29-31 Although insulin-derived amyloidosis is rare, it may be misdiagnosed as lipohypertrophy due to a lack of histopathologic testing or general awareness of the complication.29
In a case series of 7 patients with amyloidosis, all patients had a mean HbA1c of 9.3% (range, 8.5-10.2%) and averaged 1 IU/kg bodyweight before intervention.30 After the discovery of the mass, participants were instructed to avoid injection into the amyloidoma, and average insulin requirements decreased to 0.48 IU/kg body weight (P = .40).30 Patients with amyloidosis who rotated their injection sites experienced better glycemic control and decreased insulin requirements.30
Pathophysiology of Localized Insulin Resistance
Insulin regulates glucose homeostasis in skeletal muscle and adipose tissue, increases hepatic and adipocyte lipid synthesis, and decreases adipocyte fatty acid release.32 Generalized insulin resistance occurs when target tissues have decreased glucose uptake in response to circulating insulin.32 Insulin resistance increases the amount of free insulin in surrounding tissues. At high concentrations, insulin fosters tissue growth by binding to IGF-1 receptors, stimulating hypertrophy and reproduction of keratinocytes and fibroblasts.33 This pathophysiology helps explain the origin of localized acanthosis nigricans at same-site insulin injections.