Title:
The association between injected insulin and diffused cutaneous amyloidosis
Abstract:
1. Objective:
Cutaneous amyloidosis had a prevalence around 7.87 per 10,000 persons in our
Taiwan1. No significant gender difference was noted in the prevalence of primary
cutaneous amyloidosis. Cutaneous amyloidosis had several types. Lichen (or papular)
amyloidosis, macular amyloidosis and nodular amyloidosis are 3 major form of
cutaneous amyloidosis. We reported a case of a patient with insulin glargine injection
for 11 months suffered cutaneous amyloidosis.
2. Methods:
A 53 years old female had been visiting our outpatient clinic since 2000 for the
treatment of her type 2 diabetes mellitus. She refused atopic dermatitis history. The
patient was initially treated with oral anti-diabetic agent but started insulin glargine
31u injection therapy every night since September , 2009. In August, 2010, she
suffered large sheet brownish ripple pattern papule formation over whole back,
abdominal wall and mild over her chest wall, and scratching nodules over bilateral
knee joint, lower limbs and upper limbs. After biopsy of her skin lesion, the pathology
revealed an unexpected diagnosis of cutaneous amyloidosis.
3. Result and Discussion
Amyloidosis could be primary or secondary, localized or systemic. Amyloidosis might
develop from several precursor protein and not a single distinct chemically substance2.
The histologic characteristic of amyloidosis are a fibrillary structure under EM and
green birefringence in polarized light.
The mechanism of Type 2 diabetes Mellitus is well known about insulin resistance,
defective insulin secretion, loss of β-cell mass with increased β-cell apoptosis and
islet amyloid3,4. β-cells expressed and secreted insulin and islet amyloid together,
which is derived from islet amyloid polypeptide (IAPP, amylin).
In the literature, a higher comorbidity of hyperlipidaemia and diabetes mellitus had
beed reported in the groups of patients with primary cutaneous amyloidosis. Besides
hyperlipidaemia and diabetes mellitus, it was also found high prevalence of ectopic
dermatitis when patients with primary cutaneous amyloidosis1. Why dose the patients
with primary cutaneous amyloidosis had a higher comorbidity of diabetes mellitus?
We had known the patient had repeated subcutaneous insulin injections had high
incidence with extrapancreatic local cutaneous amyloidosis in the literature3. The
insulin medication included porcine insulin, human recombinant insulin, Insulin
Aspart, Insulindetemir and Insulin Glargin5. Previous reports described the patient’s
cutaneuos amyloidosis was local mass like a insulin ball6. Injection amyloidosis
suspected related to insulin β-chain with sequence LVEALYL. The LVEALYL
segments are attacked into pairs of tightly interdigitated β-sheet, each pair displaying
the dry steric zipper interface typical of amyloid-like fibrils7.
However, the skin lesion of cutaneous amyloidosis in our patient was diffused and
over whole back, abdominal wall, chest wall and four limbs. We suspected local
insulin glargine which had the typical amyloid-like fibrils, LVEALYL segment, not
only induced local inflammation but diffused cutaneous amyloidosis.
4. Conclusion:
We had known that the patient received injection amyoidosis had high cormobidity
with primary cutaneous amyloidosis due to insulin β-chain with sequence LVEALYL.
We also found the patient with injection insulin had not only local insulin ball but also
diffuse cutaneous amyloidosis over whole back, four limbs but especially abdominal
wall and bilateral femoral area where was the injection site. We suspected the
amyloid-like fibrils not only induced local protein deposition but also diffuse
cytotoxic interaction. We suggested further study for the prevalence and mechanism
of insulin, included human recombinant insulin and insulin analogue, induced the
cutaneous amyloidosis in whole body skin.
5. Reference:
1. Lee DD, Huang CK, KO PC, Chang YT, Sun WZ, Oyang YJ. Association of primary
cutaneous amyloidosis with atopic dermatitis: a nationwide population-based study
in Taiwan. British J Dermatology 2010;164:148-153
2. Lonsdale-Eccles AA, Gonda P, Gilbertson JA, Haworth AE. Localized cutaneous
amyloid at an insulin injection site. Clin Exp Dermatol 2009, 34: e1027-e1028
3. Cooper GJS, Aitken JF, Zhang S, Is type 2 diabetes an amyloidosis and does it
really matter (to patients)? Diabetologia 2010;53:1011-1016
4. Haataja L, Gurlo T, Huang CJ, Butler PC Islet amyloid in type 2 diabetes, and the
toxic oligomer hypothesis. Endocr Rev 2008;29(3),303-16
5. Yumlu S, Barany R, Eriksson M, Rocken C. Localized insulin-derived amyloidosis in
patients with diabetes mellitus: a case report. Hum Pathol 2009;40: 1655-1660
6. Nagase T, Katsura Y, Iwaki Y, Nemoto K, Sekine H, Miwa K, Oh-i T, Kou K, Iwaya K,
Noritake M, Matsuoka T. The insulin ball . Lancet 2009; 373:184
7. Ivanova M, Sievers S, Sawaya M, Wall J, Eisenberg D. Molecular basis for insulin
fibril assembly. Proc Natl Acad Sci USA 2009;106:18990-18995
FigureA
Figure B
Figure C (H&E 200X)
Amorphus deposites within papillary dermis, and accompanies by melanin
incontinance at superfical dermis.
Figure D
The material is positive for pancytokeratin (AE1/AE3)