Localized Amyloidosis at the Site of Repeated Insulin Injection in a Diabetic Patient

Shikama, Yasuyoshi; Kitazawa, Junichi; Yagihashi, Norito; Uehara, Osamu; Murata, Yuuji; Yajima, Nobuhisa; Wada, Ryuichi; Yagihashi, Soroku

doi:10.2169/internalmedicine.49.2633

Cited by 133 publications

(114 citation statements)

References 9 publications

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“…However, another ligand of RAGE is the amylin polypeptide, which is co-produced with insulin by the pancreatic beta cells in response to elevation of plasma glucose [46]. Moreover, there is speculation that insulin may also bind to RAGE, since there is evidence of amyloidosis composed of iatrogenic A-Ins type amyloid [47]. Indeed, other investigators have suggested that proinflammatory RAGE and HLA II DRB1 polymorphisms may synergise to activate the immune response in diabetes complications [48].…”

Section: Discussionmentioning

confidence: 99%

Receptor for advanced glycation end-products (RAGE) provides a link between genetic susceptibility and environmental factors in type 1 diabetes

et al. 2011

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Aims/hypothesis This group of studies examines human genetic susceptibility conferred by the receptor for advanced glycation end-products (RAGE) in type 1 diabetes and investigates how this may interact with a western environment. Methods We analysed the AGER gene, using 13 tag SNPs, in 3,624 Finnish individuals from the FinnDiane study, Kuopio, Finland Diabetologia (2011) 54:1032-1042 DOI 10.1007/s00125-011-2058 followed by AGER associations with a high risk HLA genotype (DR3)-DQA1*05-DQB1*02/DRB1*0401-DQB1*0302 (n=546; HLA-DR3/DR4), matched in healthy newborn infants from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study (n=373) using allelic analysis. We also studied islets and circulating RAGE in NODLt mice. Results The rs2070600 and rs17493811 polymorphisms predicted increased risk of type 1 diabetes, whereas the rs9469089 SNP was related to decreased risk, on a high risk HLA background. Children from the DIPP study also showed a decline in circulating soluble RAGE levels, at seroconversion to positivity for type 1 diabetes-associated autoantibodies. Islet RAGE and circulating soluble RAGE levels in prediabetic NODLt mice decreased over time and were prevented by the AGE lowering therapy alagebrium chloride. Alagebrium chloride also decreased the incidence of autoimmune diabetes and restored islet RAGE levels. Conclusions/interpretation These studies suggest that inherited AGER gene polymorphisms may confer susceptibility to environmental insults. Declining circulating levels of soluble RAGE, before the development of overt diabetes, may also be predictive of clinical disease in children with high to medium risk HLA II backgrounds and this possibility warrants further investigation in a larger cohort.

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Section: Discussionmentioning

confidence: 99%

Receptor for advanced glycation end-products (RAGE) provides a link between genetic susceptibility and environmental factors in type 1 diabetes

et al. 2011

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“…Patients with AIns may present to the clinician as a direct result of noticing the nodular deposits or symptoms thereof. They may also have associated brittle diabetes as a result of unpredictable release of insulin from these nodules [16,17]. Additionally, inhaled insulin has also been shown to result in amyloid fibril formation in mice lungs with resultant pulmonary toxicity [18].…”

Section: Discussionmentioning

confidence: 99%

Pharmaceutical amyloidosis associated with subcutaneous insulin and enfuvirtide administration

D’Souza

Theis²,

Vrana³

et al. 2014

Amyloid

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Protein and peptide drugs administered subcutaneously, such as insulin can be amyloidogenic and result in localized amyloid deposits at the sites of medication injections. These iatrogenic amyloidoses typically present as a localized subcutaneous nodule or skin reaction at the site of administration, and often pose diagnostic challenges. We have analyzed the amyloid proteome in 52 cases of insulin and enfuvirtide associated amyloidosis using laser microdissection/tandem mass spectrometry. We show that the deposits are composed of the drug, as well as other amyloid precursor proteins such as apolipoproteins A-I, A-IV, E and serum amyloid protein. Mass spectrometry-based amyloid sub-typing allows for accurate amyloid diagnosis with resultant therapeutic and prognostic implications. This insight into the amyloid proteome in drug-induced amyloidosis may help further understand pathogenesis of amyloid fibril formation.

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“…The pathogenic deposition of insulin aggregate at the injection site is a notorious complication for the intravenous insulin injection and subcutaneous infusion (Dische et al 1988;Shikama et al 2009). Accordingly, insights into this deposition process can provide useful information, showing propensity of different insulin variants for the pathogenic aggregation.…”

Section: Comparing Aggregation Propensity Of Acetylated and Non-acetymentioning

confidence: 99%

Aspirin-mediated acetylation induces structural alteration and aggregation of bovine pancreatic insulin

Yousefi

Taheri

Alavi

et al. 2015

Journal of Biomolecular Structure and Dynamics

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The simple aggregation of insulin under various chemical and physical stresses is still an important challenge for both pharmaceutical production and clinical formulation. In the storage form, this protein is subjected to various chemical modifications which alter its physicochemical and aggregation properties. Aspirin (acetylsalicylic acid) which is the most widely used medicine worldwide has been indicated to acetylate a large number of proteins both in vitro and in vivo. In this study, as insulin treated with aspirin at 37°C, a significant level of acetylation was observed by flourescamine and o-phthalaldehyde assay. Also, different spectroscopic techniques, gel electrophoresis, and microscopic assessment were applied to compare the structural variation and aggregation/fibrillation propensity among acetylated and non-acetylated insulin samples. The results of spectroscopic assessments elucidate that acetylation induces insulin unfolding which is accompanied with the exposure of protein hydrophobic patches, a transition from alpha-helix to beta-sheet and increased propensity of the protein for aggregation. The kinetic studies propose that acetylation increases aggregation rate of insulin under both thermal and chemical stresses. Also, gel electrophoresis and dynamic light scattering experiments suggest that acetylation induces insulin oligomerization. Additionally, the results of Thioflavin T fluorescence study, Congo red absorption assessment, and microscopic analysis suggest that acetylation with aspirin enhances the process of insulin fibrillation. Overall, the increased susceptibility of acetylated insulin for aggregation may reflect the fact that this type of modification has significant structural destabilizing effect which finally makes the protein more vulnerable for pathogenic aggregation/fibrillation.

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Localized Amyloidosis at the Site of Repeated Insulin Injection in a Diabetic Patient

Abstract: Abstract

Cited by 133 publications

References 9 publications

Receptor for advanced glycation end-products (RAGE) provides a link between genetic susceptibility and environmental factors in type 1 diabetes

Receptor for advanced glycation end-products (RAGE) provides a link between genetic susceptibility and environmental factors in type 1 diabetes

Pharmaceutical amyloidosis associated with subcutaneous insulin and enfuvirtide administration

Aspirin-mediated acetylation induces structural alteration and aggregation of bovine pancreatic insulin

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