Persistent Cutaneous Insulin Allergy Resulting From High-Molecular-Weight Insulin Aggregates

Abstract

Cutaneous insulin allergy remains a clinical problem despite the use of highly purified human insulins. We used in vitro lymphocyte-transformation studies to examine the reactivity of various insulin formulations in diabetic patients with (n = 4) and without (n = 8) cutaneous allergies. Nonspecific response to concanavalin A demonstrated a greater than 40-fold response in both groups. Control patients did not respond to the addition of commercial insulin preparations (stimulation index [SI] less than 4), whereas allergic patients had an 11-fold response to beef (P less than 0.01), a 10-fold response to pork (P less than 0.01), and a 6-fold response to human (P less than 0.01) insulins. This response was limited to a single insulin manufacturer's preparations and was uniform in all three species tested. Efforts to identify the offending agent revealed no lymphoblast transformation when crystalline insulin was used or when commercial preparations were purified to a single peak by high-performance liquid chromatography (HPLC). Pure crystalline insulin dimers of beef, pork, and human species were tested; control subjects responded with mean SIs of 1.9, 1.9, and 1.8, respectively, whereas allergic patients showed greater reactivity to beef (SI 7.3) and pork (SI 14.8). The lymphoblast-transformation response to crystalline human dimer was dose dependent with mean SIs of 0.9 at low concentration (2.8 ng/ml) and 19.2 at a higher concentration (20.4 ng/ml). The commercial insulin preparations were run on size-exclusion HPLC to determine high-molecular-weight aggregate content. Independent of species, a single manufacturer had products demonstrating aggregate levels 3- to 6-fold higher than those found in other manufacturers' preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

Generalized allergy due to zinc in insulin treated with zinc-free insulin

“…Since our patient had an atopic background, allergic reactions should be more common to occur. Associations of insulin allergy with other allergies have been formerly discussed [5]. At first, the patient received human recombinant insulin (HRI) for that allergy is encountered in less than 1% of patients [2].…”

Allergic reactions to human insulin: a review of current knowledge and treatment options

“…However, several case reports regarding development of local and generalized insulin allergy on insulin analogue treatment have been published [24,27,[35][36][37]. On the other hand, it has been shown that persistent cutaneous insulin allergy resulted from high-molecular-weight insulin aggregates [38]. Rapid-acting insulin analogues revealed with an immediate dissociation of hexamer structure to monomers, so that they might be less antigenic [38,39].…”

“…On the other hand, it has been shown that persistent cutaneous insulin allergy resulted from high-molecular-weight insulin aggregates [38]. Rapid-acting insulin analogues revealed with an immediate dissociation of hexamer structure to monomers, so that they might be less antigenic [38,39]. Successful treatment of local and systemic insulin allergy has been reported with switching of insulin treatment to a rapidacting insulin analogue, namely insulin lispro [40][41][42][43], aspart [44,45] or glulisine [46].…”

Lability Landscape and Protease Resistance of Human Insulin Amyloid: A New Insight into Its Molecular Properties

“…[40][41][42][43][44] Regular injections of insulin can also cause long-term effects, such as depositions of insulin amyloid, which have been observed in diabetic patients after repeated injections. [45][46][47] In our studies, we produced insulin amyloids in the absence of Zn 2+ ions and under low pH conditions where the protein exists in the destabilized monomeric state. Moreover, we conducted the studies in the low protein concentration regime, which disfavors hexamer formation, especially in the absence of Zn 2+ ions.…”