Leveraging Mechanical Forces to Target Insulin Injection–Induced Lipohypertrophy and Fibrosis

As of 2017, more than 30 million Americans—nearly 10% of the population—have diabetes (1). More than 1.5 million new cases of diabetes were diagnosed in 2015 (1). The prevalence of both type 1 and type 2 diabetes is rapidly increasing, and by 2050, diabetes is expected to affect more than one in five adults in the United States (2–5). The economic burden of diabetes is enormous and growing; in 2017, it was estimated to be $327 billion, including $237 billion in direct medical costs (6), a nearly twofold increase from 2007 (3).

The 1.25 million American adults living with type 1 diabetes comprise 5.6% of all U.S. adults with a diabetes diagnosis (7). Because these patients are unable to produce sufficient endogenous insulin, they are reliant on exogenous insulin injections for their entire lives. In addition to individuals with type 1 diabetes, roughly 30% of patients with type 2 diabetes also require insulin therapy, typically in the setting of A1C levels that are uncontrolled with oral hypoglycemic agents (8–11).

Recently, exorbitant insulin prices have dominated news headlines across the United States. In just 5 years, from 2012 to 2017, the cost of insulin increased by 110% (6). Insulin costs totaled more than $14 billion in 2017, not including required supplies and equipment, which were responsible for an additional $5 billion in costs (6).

Long-term Sequelae of Insulin Use

Beyond the sizeable economic burden of insulin use, long-term insulin administration can also cause a host of problems for patients. In particular, repeated insulin injections and insulin pump use often result in complications and changes in the skin at injection or pump sites (Figure 1) (12). The two most common injection site complications are:

1. Fibrosis, the accumulation of stiff, dense scar tissue at the injection site (Figure 1A, middle left). The formation of fibrotic tissue is a chronic process resulting from repeated minor tissue trauma (i.e., injections or pump insertions) and a resulting inflammatory response in the local area (13–17).

2. Lipohypertrophy, a local accumulation of fatty tissue at the injection site (Figure 1A, middle right). This process is thought to result from local stimulation of adipocytes (fat cells) by insulin, which is an important hormone in the regulation of lipid metabolism (18). Over time, this stimulation leads to both excessive growth of individual adipocytes (hypertrophy) and excessive proliferation of adipocytes (hyperproliferation/hyperplasia) (17,19).

FIGURE 1.

Modulating the skin mechanical environment to mitigate insulin injection site complications. A) Repeated insulin injections over time (top) can lead to two main skin sequelae: skin fibrosis, resulting from chronic injection-induced inflammation (middle row, left) and lipohypertrophy, resulting from adipocyte stimulation by insulin (middle row, right). Both of these complications contribute to impaired and inconsistent insulin uptake (bottom). B) Reduction of mechanical tension at the injection site (top), via a tension-offloading skin dressing applied to the site, could prevent injection-related skin complications. Tension offloading is known to reduce skin fibrosis after injury (middle row, left), and compressive force may reduce lipohypertrophy by preventing adipocyte expansion (middle row, right). Reduced lipohypertrophy and fibrosis would improve insulin absorption (bottom).

These processes are interrelated, and patients often experience both complications concurrently. For example, lipohypertrophy frequently exhibits fibrotic features with regions of fibrotic/scar tissue (17). Injection site complications are incredibly common; lipohypertrophy has an estimated prevalence of between 14.5 and 88% of insulin-dependent people with diabetes (20). These sequelae occur regardless of the injection/insertion site, method of insulin administration (injection or insulin pump), or type of insulin used (21).

Fibrosis and lipohypertrophy can have direct consequences for patients resulting from visible or palpable changes to the affected tissue. These changes are associated with reduced treatment satisfaction and increased depression (22). Furthermore, injection site complications can have detrimental effects on diabetes management, as these pathological skin changes affect the absorption and bioavailability of insulin administered at affected sites. This transformation has two serious consequences:

1. Insulin therapy is less effective. Fibrosis and lipohypertrophy cause significantly reduced insulin absorption and effect (23,24). This reduction leads to substantial waste in diabetes treatment. One study found that total daily insulin doses for patients with lipohypertrophy were, on average, 36% higher than for those without lipohypertrophy (absolute difference of 15 IU/day) (25). Even using the most conservative estimate of the proportion of insulin users who have lipohypertrophy, this increase in insulin requirement would equate to well over $1 billion per year in the United States in unnecessary insulin costs. Essentially, fibrosis and lipohypertrophy result in increased costs of treatment without any increased benefit.

2. Insulin response is more unpredictable. For insulin-dependent people with diabetes, achieving appropriate insulin levels throughout the day can be, quite literally, a matter of life or death. Irregular or unpredictable insulin responses can result in dangerous outcomes, including over- or underdosing. Fibrosis and lipohypertrophy have been found to increase intra-patient variability in insulin absorption, insulin effect, and blood glucose levels (23,25). Such variability has serious consequences for patients; studies have found evidence of a 2.7 times increased risk of hypoglycemia (26), as well as increased risks of hyperglycemia (23) and diabetic ketoacidosis (27) in patients with lipohypertrophy.

Clearly, the prevention of injection site fibrosis and lipohypertrophy could result in not only significant cost savings for both patients and health care systems, but also meaningful and substantial health benefits for people with diabetes who are dependent on exogenous insulin.

Tackling the Problem

No treatments currently exist to prevent or reduce the burden of injection-induced fibrosis and lipohypertrophy. The only advice patients can be offered is to rotate their injection sites. However, there are a limited number of available and convenient injection sites; this issue is particularly problematic for children diagnosed with insulin-dependent diabetes, who will require lifelong insulin injections. Furthermore, patients frequently have poor injection technique or fail to rotate injection sites correctly, which are risk factors for skin complications (26–29). In addition, advising site rotation does not address the issue of variable insulin absorption that can result from changing injection sites (30).

A treatment or device with the potential to reduce injection site complications could have enormous impact for the millions of patients who depend on insulin therapy. Such a product could be used directly at the injection site to prevent fibrosis and lipohypertrophy from developing. Ideally, it would include design elements that could target the two primary pathological mechanisms underlying these skin changes: deposition of fibrotic scar tissue and expansion of adipose tissue.

Modulation of mechanical forces at injury sites, either via reduction of physical tension or inhibition of cells’ ability to sense/signal mechanical cues, has proven to be a promising approach for preventing fibrosis or scarring in the setting of skin wound healing after injury. Clinically, tension offloading of wounds (through the use of dressings that compress the skin to reduce stretching forces across the wound, as shown in Figure 1) has been shown in multiple studies to reliably and significantly reduce scarring following injury (31,32). However, the strategy of targeting tissue mechanics has not been applied previously to skin fibrosis in the context of repeated insulin injections. Although the specific mechanism of injury differs, fundamental molecular and cellular elements of the scarring response to tissue damage are known to be conserved between different injury types (e.g., incisions vs. injections). Although clinical studies are needed to determine whether a mechanics-focused approach could similarly prevent fibrosis resulting from repeated injections, both in vitro and in vivo evidence support the potential of a tension-offloading approach to prevent both fibrosis and lipohypertrophy in the setting of insulin injection (Figure 1B).

Mechanical Influences on Fibrosis and Fat

The role of mechanical forces in modulating fibrosis has been well established (33). Increased tension on the skin is known to increase fibrosis and scarring; conversely, scarring can be reduced by either reducing mechanical stress or blocking cells’ ability to detect and respond to tension at the molecular level (31,32,34–36). Fibroblasts, the cells that produce fibrotic tissue throughout the body, are highly sensitive to mechanical forces. In the setting of increased tension, these cells are stimulated to produce extracellular matrix (37–39); excess production of pathological extracellular matrix is a hallmark of fibrosis. Thus, given the key role of mechanical tension in driving fibrosis and the efficacy of tension offloading for diminishing skin scarring, tension reduction may also be a promising strategy to reduce fibrotic tissue deposition in the setting of insulin injections (Figure 1B, middle left).

Adipocytes, like fibroblasts, are capable of sensing and responding to mechanical forces (40). Intriguingly, compressive force (i.e., the opposite of tension) has been found to inhibit the production and differentiation of adipocytes in vitro, through a mechanism that involves down-regulating the expression of genes that are critical to adipogenesis (41). These in vitro findings suggest that application of compressive force may be sufficient to reduce adipogenesis and therefore prevent or reduce hyperproliferation of adipose cells—a key underlying cellular process in lipohypertrophy—in patients (Figure 1B, middle right).

Theoretical Approach for Improving Insulin Administration

Although clinical studies have not yet been performed to determine whether tension offloading could reduce insulin injection–induced skin fibrosis (similar to its ability to reduce wound-induced skin fibrosis [i.e., scarring]), a mechanically targeting approach offers several potential benefits in this context. First, the in vitro and in vivo evidence discussed above suggests that this may be a promising approach for reducing both scarring and lipohypertrophy from repeated insulin injections. Second, given the large body of evidence supporting modulation of skin tension for reducing skin scarring, if such an approach were found to be effective in reducing insulin-related skin changes, existing infrastructure would make it easy to rapidly implement this preventive strategy in a large number of patients.

An ideal therapy would be a product that is currently available over the counter (to avoid the significant delay, often 10 years or longer, associated with new drug/device development [42]), affordable for patients, and low in risk (but potentially high in reward). We postulate that an existing skin dressing meets these criteria and could have the potential to benefit a large number of patients. The embrace device (Neodyne Biosciences, Newark, CA) is a tension-offloading dressing initially developed for scar prevention. This device has been shown in two separate randomized controlled trials to significantly reduce scarring and fibrosis after surgical incisions (31,32). The therapy functions by having a backing that allows the elastomeric sheet to be pre-stretched before application. After the dressing is adhered to the skin, the backing is removed. This process results in the dressing applying an overall tension-reducing/compressive force across the skin and the underlying tissue at full-thickness skin depths (34). Based on evidence that compressive forces reduce skin fibrosis (scarring) in vivo and inhibit adipogenesis in vitro, this dressing could have promise to reduce both fibrosis and lipohypertrophy resulting from repeated insulin injections.

Although both preclinical and clinical studies support the theory that tension offloading at insulin injection sites could reduce both lipohypertrophy and fibrosis, and clinical trials have robustly shown that tension-offloading dressings reduce skin fibrosis in the setting of wound healing (31,32,34), it will be crucial to validate this approach for the theoretical application discussed. Specifically, clinical trials would need to be performed to determine whether tension offloading at insulin injection sites in patients with diabetes is effective in preventing insulin injection site complications. Secondarily, such studies should explore whether tension-offloading dressings could also improve consistency of insulin uptake, as discussed above.

However, given the paucity of existing therapies to prevent these complications, the in vitro and in vivo evidence supporting the utility of tension offloading for reducing fibrosis and adipogenesis, and the exorbitant economic and human health costs associated with inefficient insulin use, we posit that this approach could be a low-cost, low-risk, and potentially extremely high-reward option. The potential impact of a therapeutic approach that could reduce injection site lipohypertrophy and fibrosis, in terms of not only saved resources, but also physical and mental benefit to patients who are dependent on lifelong insulin injections, is enormous. We hope that this article will inspire readers—whether patients, practitioners, or researchers—to consider how a mechanically targeted approach, potentially leveraging existing and readily available technology, could be explored further to benefit the millions of insulin-dependent patients in the United States and worldwide.