2023 Volume 143 Issue 10 Pages 865-870
Insulin therapy is one of the central treatments for diabetes mellitus. Insulin-derived localized amyloidosis (IDLA) is a known skin-related complication of insulin injection. This is one of the causes of poor glycemic control in diabetic patients on insulin therapy. The aim of this study was to review and update the findings on the extent and mechanism of reduced insulin absorption in IDLA. A literature search was conducted on decreased insulin absorption and its mechanisms, and nine references were selected, with seven of these on decreased insulin absorption and four on mechanisms. Insulin absorption at IDLA sites was reported to be 27–94% lower compared with normal sites. In addition, a comparison between nonpalpable and palpable IDLA sites revealed a significant decrease in insulin absorption at the palpable IDLA site. The mechanism of insulin malabsorption was found to be a reduction in insulin absorption at the palpable IDLA sites. Four mechanisms of decreased insulin absorption were identified: decreased subcutaneous blood flow, adsorption of administered insulin onto insulin amyloid fibers, impaired diffusion of insulin subcutaneously, and physical factors such as shaking of the insulin preparation. These mechanisms should be investigated in vivo in the future.
Insulin therapy is one of the central treatments for diabetes. A skin-related complication of insulin therapy is insulin-derived localized amyloidosis (IDLA), in which subcutaneously injected insulin deposits as amyloid protein at the injection site and forms a large ball-shaped subcutaneous mass.1–3) Amyloidosis is a disease in which insoluble amyloid fibrils with fibrous structures are deposited in tissues and cells throughout the body and is classified into systemic amyloidosis and focal amyloidosis based on the relationship between site of production of the fibril precursor protein and its deposition as fibrils.4) It has been shown that insulin absorption is decreased at the site of IDLA, resulting in poor glycemic control and increased insulin dosage.2,5) Therefore, IDLA is one of the causes of poor glycemic control in diabetic patients on insulin therapy that clinicians and healthcare providers frequently encounter in clinical practice. By contrast, administration of an increased insulin dose outside of the IDLA site can cause a sudden drop in blood glucose levels,5–7) and because IDLA can be palpable or nonpalpable,8) there is the possibility that unintentional administration of insulin outside of the IDLA site can cause severe hypoglycemic symptoms. That is, insulin therapy for diabetic patients depends on the patient actually administering the insulin and acquiring knowledge of insulin administration techniques.
Regarding the first IDLA report, in 1983, Strökel et al.9) found focal cutaneous amyloidosis at the site of porcine insulin injection in rats and humans, and suggested that insulin causes the formation of amyloid fibrils. Subsequently, in 1988, Dische et al.3) reported that porcine insulin-derived protein was present in amyloid protein extracted from local cutaneous amyloid deposits at porcine insulin injection sites in diabetic patients. Therefore, it was initially suggested that IDLA was caused by injecting animal-derived insulin into humans. However, in 2007, IDLA in diabetic patients injected with human insulin products was identified in the report of Albert et al.,10) and in 2009, Nagase et al.5) first referred to IDLA at the site of human insulin preparation injection in diabetic patient as insulin balls. To date, there have been few reports on IDLA, particularly on insulin balls, both, in Japan and internationally. Therefore, it is highly likely that both healthcare providers involved in teaching insulin therapy to diabetic patients and diabetic patients receiving insulin therapy are poorly aware of IDLA. Consequently, it is important to increase the knowledge of healthcare providers about IDLA and to utilize their knowledge in teaching insulin therapy to diabetic patients. Therefore, the purpose of this study was to review studies on the extent and mechanism of decreased insulin absorption by IDLA and to update these findings.
The research design of this study was a literature review with a scoping review.
2. Literature SearchIn this study, PubMed, ScienceDirect, Google Scholar, and Japan Medical Abstracts Society were used as literature databases. In addition, relevant literature was searched by hand-search. Key search terms such as “amyloidosis,” “insulin,” “absorption,” and “diabetes” were combined in the search formula.
3. Selection CriteriaThe selection criteria applied were participant, concept, context (PCC), with participant defined as diabetes; concept as IDLA or insulin-derived amyloidosis; and context as subcutaneous absorption. Of the papers that met the above selection criteria, literature published between 2004 and 2021 and written in English or Japanese was included. Exclusion criteria were literature without access to abstracts or full text and literature that did not include a general discussion or refer to IDLA or insulin absorption. A flow diagram of the literature selection process is presented in Fig. 1. Initially, all relevant studies were obtained through four databases and 13 duplicates were removed using Rayyan. Subsequently, the titles and abstracts of 925 studies were independently screened by two authors according to the selection criteria. The authors then read the full text of 44 relevant articles to determine eligibility. Finally, nine studies were eligible for the present study. Any discrepancies regarding eligibility were resolved through discussion among the authors.
Nine articles were selected for review, of which seven reported on insulin absorption (two original papers and five case reports)6–8,11–14) as shown in Table 1 and four described the mechanism of insulin absorption (two case reports and two animal or in vitro experiments)6,13,15,16) as shown in Table 2. The nine references were published between 2012 and 2020, and all were domestic references with Japanese authors.
| Author (Year) | Country | Research design | Target group | IDLA region | Insulintype | Serum insulin concentration | Insulin dosage |
|---|---|---|---|---|---|---|---|
| Yoshizaki et al.11) (2012) | Japan | Case report | A patient with type 2 DM (age 91) | Abdomen | Insulin analog | IDLA sites are 94% less than normal sites | |
| Nagase8) (2014) | Japan | Case report | 7 patients with type 1 or type 2 DM (32–82 years old) | Abdomen | Insulin analogs, human insulin | 53% reduction after changing injection site from IDLA site to normal site | |
| Type 1 DM patients: 4 | Insulin analog | IDLA sites reduced by 65% compared with normal sites | |||||
| Kusuki et al.12) (2015) | Japan | Original work | 10 cases of type 1 or type 2 DM (67–91 years old) | Abdomen | Insulin analogs, human insulin | IDLA sites decreased by 66% compared with normal sites. Collagen hyperplasia sites decreased by 53% | |
| IDLA: 4 cases | |||||||
| Collagen fibrosis: 6 cases | |||||||
| Kikuchi et al.13) (2017) | Japan | Case report | 22 DM patients | Abdomen | None stated | 42% less for the tactile type compared with the nonpalpable-type | |
| Palpable: 13 cases | |||||||
| Nonpalpable: 9 cases | |||||||
| Kanamaru et al.7) (2018) | Japan | Original work | Type 1 DM | Insulin analog | 53% reduction after changing injection site from IDLA site to normal site | ||
| Kikuchi6) (2019) | Japan | Case report | 6 cases of type 1 or type 2 DM (43–82 years old) | Abdomen | Insulin analog | IDLA sites were 27% less than normal sites | |
| Nagase14) (2020) | Japan | Case report | Type 2 DM Non-palpable: 2 cases | Abdomen | Insulin analog | IDLA sites reduced by 60% compared with normal sites | 42–48% reduction after changing injection site from IDLA site to normal site |
DM: Diabetes mellitus.
| Author (Year) | Country | Research design | Target group | Method | Results |
|---|---|---|---|---|---|
| Kikuchi et al.13) (2017) | Japan | Case report | 22 DM patients Palpable: 13 cases Nonpalpable: 9 cases | Subcutaneous blood flow was examined by contrast-enhanced ultrasound to study blood flow in the IDLA area (1) Comparison of sound intensity between IDLA and normal areas (2) Comparison of sound intensity of tactile and non-tactile types among IDLA sections | (1) The sound intensity in the IDLA area was significantly lower than that in the normal area, suggesting reduced blood flow in the IDLA. (2) Significantly lower sound intensity in the palpable type compared with the nonpalpable type, suggesting decreased blood flow in the palpable type. |
| Nakamura et al.15) (2018) | Japan | Animal experiments, in vitro experiments | Insulin tolerance studies were performed by creating IDLA in mouse skin and repeatedly injecting high concentrations of insulin amyloid fibers. | We have shown that IDLA inhibits insulin absorption. Simultaneous administration of insulin and insulin amyloid fibers revealed that this effect was due to the amyloid fibers themselves without a granulation tissue response. There was strongly adhesion to native human insulin and various insulin analogs. | |
| Ohno et al.16) (2019) | Japan | In vitro experiments | Humin® R was used as a model formulation for multiple daily injections and Novolapid® as a model formulation for continuous subcutaneous insulin infusion devices. Precipitate formation was evaluated by turbidimetry and amyloid formation was evaluated using thioflavin T. The effects of insulin concentration, presence of m-cresol, and pH changes on precipitate and amyloid formation in the formulation were studied. | Amyloid was formed at near-neutral pH. By contrast, when the pH was lowered to near the isoelectric point, while a precipitate was formed, this was not amyloid. When the pH was further lowered, amyloid was formed, suggesting that insulin tends to form amyloid in both positively and negatively charged states. The formulation additive m-cresol inhibited amyloid formation. When the additive in the formulation was removed, gels containing amyloid formed at the material interface. | |
| Kikuchi et al.6) (2019) | Japan | Case report | 6 cases of type 1 or type 2 DM (43–82 years old) | Ultrasound images of the affected and normal areas were obtained before and immediately after insulin administration, and the diffusion range of the insulin injection was determined by comparing both images. | It was suggested that insulin had not diffused in the affected subcutaneous tissue as in the normal area. This may be due to tissue stiffness in the affected area. |
DM: Diabetes mellitus.
The study subjects were type 1 or type 2 diabetics with an age range of 30–90 years, thus from adulthood to old age. The insulin injection sites in the subjects of all the studies were in the abdomen, and insulin absorption at IDLA sites occurring in the abdomen was studied. The types of insulin used were human insulin preparations (such as Humulin R Injection and Novolin R Injection) and insulin analogs (such as Novolapid Injection, Humalog Injection, and Lantus Injection).
In all seven reviewed articles on insulin absorption, decreased insulin absorption occurred at IDLA sites compared with normal sites. Serum insulin concentrations6,8,11–14) or insulin doses7,8,14) were used as outcome measures of decreased insulin absorption. Serum insulin concentrations were assessed 1–4 h after insulin injection, and a 27–94% decrease in insulin absorption at the IDLA site compared with the normal site was reported.6,8,11,12,14) When the insulin injection site was changed from the IDLA site to a normal site, insulin doses were reduced by 24–53%．7,8,14)
Kikuchi et al.13) compared insulin absorption by classifying IDLA into palpable and nonpalpable types by ultrasonography. The results showed that insulin absorption was reduced by 42% in the palpable IDLA area compared with the nonpalpable IDLA area.
3. Summary of the Papers Covering the Mechanism of Reduced Insulin AbsorptionFour different mechanisms of decreased insulin absorption were reported in the four papers, as shown in Table 2.
3-1. Decreased subcutaneous blood flowKikuchi et al.13) performed contrast-enhanced ultrasonography to examine blood flow in the IDLA region of the abdomen in 22 diabetic patients, comparing acoustic intensities of the IDLA region with normal areas, and of the IDLA regions which were classified as palpable or nonpalpable by ultrasound examination. The results showed that the acoustic intensity of the IDLA region was significantly lower than that of the normal area, suggesting decreased blood flow in the IDLA. The palpable type had a significantly lower acoustic intensity than the nonpalpable type, suggesting an even greater decreased blood flow in the palpable type.
3-2. Adsorption of insulin to insulin fibersNakamura et al.15) performed an insulin tolerance test by creating IDLA in mouse skin and repeatedly injecting high insulin amyloid fiber concentrations. The results showed that IDLA inhibited insulin absorption. Simultaneous administration of insulin and insulin amyloid fibers revealed that this effect was due to the amyloid fibers themselves, without a granulation tissue response. Furthermore, in vitro studies have shown that insulin amyloid fibrils have extremely strong adhesion to native human insulin and various insulin analogs.
3-3. Physical factorsOhno et al.16) used an in vitro experimental system to study the effects of insulin concentration, presence of m-cresol, pH changes, and shaking intensity on precipitate and amyloid formation in insulin preparations. Novolapid® (Novo Nordisk Pharma, Tokyo) was used as a model formulation for either multiple daily injections or in continuous subcutaneous insulin injectors. Sedimentation was evaluated by measuring turbidity, and amyloid formation was evaluated using thioflavin T. Thioflavin was detected using thioflavin T solution, an amyloid detection solution that fluoresces in the presence of amyloid; samples were added to the thioflavin T solution and fluorescence was measured in a spectrophotometer. The loss of m-cresol, a formulation additive (preservative), inhibited amyloid formation. Amyloid was formed at near-neutral pH and was accelerated when the pH was lowered further. Sudden and strong shaking of the insulin formulation accelerated amyloid formation.
3-4. Diffusion disorderKikuchi et al.6) obtained ultrasound images of six patients with type I or type II diabetes before and immediately after insulin administration in the affected and normal areas, and compared both images to determine the extent of insulin injection diffusion. The results showed reduced insulin diffusion in the subcutaneous tissue of the affected area compared with the normal area. The authors reported that this may be due to tissue sclerosis in the affected area.
This is the first study to apply a scoping review to determine the extent of insulin malabsorption and the mechanism thereof at the site of what was recently defined as “IDLA” in subcutaneous lesions in diabetic patients, and which is considered to be a clinical problem.
The results of this study showed that papers on reduced insulin absorption at IDLA sites were published from 2012, whereas those on the mechanism of reduced insulin absorption at such sites were published from 2017. Therefore, findings regarding decreased insulin absorption at IDLA sites and the details of the mechanism were only published in recent years, which indicates that issues associated with insulin administration and glycemic control at IDLA sites have become of increasing interest over the past decade. In addition, all the authors of the articles reviewed in this study were Japanese. This is because IDLA was named “insulin ball” and was first reported by Dr. Nagase in 2009.5) It is possible that Japan is the global leader in IDLA research.
Insulin absorption at IDLA sites was reported to be 27–94% lower than at normal sites, with large differences between papers. This may be due to the different timing of the serum insulin level evaluation after insulin administration and the different types of insulin preparations used in each paper. In addition, most of the reviewed papers were only case reports. In the future, studies with a higher level of evidence are needed, taking into consideration the conditions under which insulin absorption is examined and ensuring uniformity in the timing of evaluation, sample size, and study design.
The results of the present study revealed that there are two types of IDLA that cause decreased insulin absorption: nonpalpable and palpable, and even in the nonpalpable type, insulin absorption was decreased compared with normal sites. In addition, it was reported that the palpable type of IDLA decreased insulin absorption compared with the nonpalpable type of IDLA.13) Moreover, the results of this study revealed the occurrence of “nonpalpable” IDLA, which is not detectable by physical examination, but histologically produces subcutaneous tissue changes similar to those of IDLA. The results also indicated that nonpalpable IDLA is also at risk for decreased insulin absorption. In the future, healthcare providers working with diabetic patients on insulin therapy should be aware that there are cases in which physical examination reveals no mass or induration, whereas histological examination reveals changes in IDLA, which may result in altered insulin absorption and glycemic control. In addition, Kikuchi et al.13) in observing subcutaneous lesions by ultrasound imaging, identified nonpalpable forms. These results enable us to confirm the occurrence of nonpalpable IDLA, which has been difficult to detect in clinical practice. We believe that it is necessary to establish an evaluation method for IDLA that will replace physical observation in the future. Kikuchi et al.13) also compared ultrasound images of the palpable IDLA type with the nonpalpable IDLA type and proposed that the palpable type evolves from the nonpalpable type of low echogenicity, low distribution of contrast medium, high hardness, and with a strong insulin dose reduction effect. However, there is no direction of follow-up from induration to mass formation, and future prospective studies are needed to prove this hypothesis. Moreover, further studies are needed to clarify the mechanism of nonpalpable and palpable IDLA development and their effect on insulin absorption.
The results of the present study revealed that the mechanisms of decreased insulin absorption at the IDLA site include 1) decreased subcutaneous blood flow, 2) adsorption to amyloid fibers, 3) physical factors (shaking, additive changes due to storage time), and 4) impaired insulin diffusion. Subcutaneously administered insulin temporarily lodges at the site of administration, from where it diffuses into the tissues and enters the capillaries and capillary lymph vessels, where it is absorbed into the blood.
In the study of Nakamura et al.,15) an IDLA mouse model was established, and this showed that the mechanism of reduced insulin absorption at the IDLA site resulted from diminished insulin transference into the blood due to strong adsorption between the administered insulin and amyloid fibers. In addition, Kikuchi et al.13) showed from ultrasound images of insulin administered at the IDLA site that subcutaneously administered insulin does not diffuse at the IDLA site as it does at normal sites. These results suggested that tissue stiffness due to amyloid fibers inhibits insulin diffusion and leads to decreased insulin absorption. The detailed mechanism of how amyloid fibrils develop into induration remains to be investigated in the future.
Furthermore, Kikuchi et al.6) evaluated subcutaneous blood flow at the IDLA site by contrast-enhanced ultrasonography and found that the blood flow may be reduced at the IDLA site compared with the normal site. The results also suggested that the degree of blood flow reduction may be greater in the palpable type compared with the nonpalpable type. These results indicated that subcutaneous amyloid deposition may cause abnormalities in the vascular network of subcutaneous tissues, thus further detailed investigation is needed.
In an in vitro study, Ohno et al.16) reported that rapid and strong shaking of insulin preparations promotes amyloid formation, that the loss of the preservative cresol promotes increased amyloid formation regardless of the intensity of shaking, and that amyloid formation is enhanced at near-neutral pH. These results indicated that insulin preparations themselves can be a factor in amyloid formation due to rapid shaking of insulin preparations by medical personnel, storage period control, and handling of insulin preparations by mixing them into intravenous infusions. These findings need to be investigated in vivo.
In this study, we conducted a scoping review on the mechanisms of reduced insulin absorption at IDLA sites. The results revealed that the degree of insulin malabsorption varied in each paper. In addition, the mechanism of decreased insulin absorption was only reported as a phenomenon, and the underlying mechanism was often unknown. Further research on the details and mechanisms of decreased insulin absorption is needed to implement appropriate insulin therapy for diabetic patients in the future.
The authors thank the following board members of collaborative projects between the Japan Academy of Nursing Science and the Japanese Pharmacological Society who were involved in the development of the projects: Dr. Natsuko Seto, Dr. Kimie Takehara, Dr. Makoto Oe, Dr. Emi Kanno, Dr.Kanae Mukai, Dr.Hiromasa Tanno, Dr. Keisuke Nakanishi, Dr. Fumiya Hisano, Dr. Sayuri Nakamura, Dr. Yuko Matsui, Dr. Tomomi Horiguchi, Dr. Terumi Ueda, and Ms. Naoko Kageura.
The authors declare no conflict of interest.
