Insulin-Related Lipohypertrophy: Lipogenic Action or Tissue Trauma?

Abstract

Lipohypertrophy has been suggested as an outcome of lipogenic action of insulin and/or injection-related tissue trauma. In a cross-sectional study, we evaluated the predictors of lipohypertrophy in 372 type 1 diabetes patients (mean age 17.1 years) receiving subcutaneous insulin with pen and/or syringes for ≥3 months. On examining injection sites with inspection and palpation technique, 62.1% patients demonstrated lipohypertrophy. Univariate analysis showed that gender, BMI, HbA1c, injection device, rotation, injection area, needle length, insulin regimen, and total daily dose of insulin were associated with lipohypertrophy (p < 0.05). Notably, the mean needle reuse was comparable in patients with or without lipohypertrophy (8.1 vs. 7.2, p = 0.534). In multivariate logistic regression, gender, HbA1c, TDD, injection devices, and needle length lost its significance. Further, injections over smaller area (≤8.5 × 5.5 cm) and non-rotation of sites were found to be strongest independent predictor of lipohypertrophy (p < 0.0005 for both) with increased odds of 23.2 (95% CI 9.1–59.2) and 6.3 (95% CI 3.4–11.9) times, respectively. Being underweight was also a significant independent predictor (odds ratio [OR] 13.0 [95% CI 2.2–75.2], p = 0.004). Compared to rapid plus long-acting analogs, regular insulin plus long-acting analogs and conventional premixed insulin users had 3.2 (95% CI 1.5–6.8, p = 0.003) and 4.6 (95% CI 1.4–15.7, p = 0.014) fold higher risk of lipohypertrophy (mean injection frequency 4.01 vs. 4.01 vs. 2.09, respectively). Sub-group analysis showed that lipohypertrophy was 79% less likely in patients with multiple daily injections (≥4) than twice-daily regimen (OR 0.21, p < 0.0005). Moreover, lipohypertrophy was reduced to half with bolus doses of rapid-acting insulin analogs than regular insulin (p = 0.003), even though mean injection frequency was comparable (4.01 vs. 3.93, p = 0.229). This difference was statistically insignificant for basal doses with NPH or long-acting analogs (p = 0.069). Therefore, injection area, rotation, BMI, and insulin regimen are the best predictors of lipohypertrophy and together could correctly identify lipohypertrophy status in 84.4% patients with excellent discrimination capability (AUC = 0.906, p < 0.0005). In conclusion, findings of our study suggest that delivering rapidly absorbed insulin analogs over large injection area along with greater split of total daily doses reduce insulin-induced lipogenesis and outplay tissue trauma added through frequent injections and needle reuse.

Insulin-Induced Skin Lipohypertrophy in Type 2 Diabetes: a Multicenter Regional Survey in Southern Italy

“…Also, as our patients only used insulin analogs, we could not compare LH rates associated with them to those associated with human regular, NPH, or premixed insulin preparations, which often were used instead, in studies published by other investigators. However, many studies found no significant differences among the types of insulin concerning the association with LHs [43][44][45][46][47][48].…”

Extent of lipohypertrophy in diabetic patients—Sometimes much more than meets the eye

“…Insulin therapy may cause LH due to lipogenic action and/or injection‐related tissue trauma with repeated administration in the same site . The prevalence of LH is reported at 37% .…”

The clinical relevance of lipohypertrophy

“…A recent audit from India [3] reported a much lower prevalence at 12.5% of all insulin users although this was a retrospective collection of cases based only on clinical examination and could be an underestimate while another survey [4] on injection technique found that based on a physical examination by nurses, one in five diabetic patients on insulin had LH. Two recent studies [5,6] from India reported that more than 60% of the patients developed LH. Lipohypertrophy was found to be more prevalent in obese patients and those with hypoglycemia and higher HbA1C [7].…”

“…LH which appears as a rubbery swelling in the subcutaneous (SC) tissue at injecting sites is believed to develop secondary to the lipogenic action of insulin or to the trauma related to injections [5]. Various factors reported to be associated with a greater risk of LH in diabetic patients include longer duration of insulin use, failure to injection site rotation, needle reuse [4], longer needles, longer duration of diabetes [7,8], low BMI, total daily dose of insulin, twice daily insulin regimen, the use of conventional insulins compared with analogues [5], and poor glycemic control [8,9]. It has been shown that the risk of LH with insulin reuse is substantially higher than those who do not reuse.…”

“…In children with LH who received specific instructions from diabetic nurses to rotate injection sites and not to reuse needles, it was shown that in 3 months, 90% of LH lesions had resolved and glycemic control had significantly improved [4]. However, other workers reported no effect of avoiding reuse of needles [5]. Injection technique (IT) education, particularly with respect to use of shorter needles, has been shown to effectively prevent LH in prospective randomized controlled trials [12].…”