Insulin allergy, injection site fat atrophy and fat necrosis are relatively rare complications of insulin therapy. With the purification of insulin and the advent of recombinant human insulin and human insulin analogs, the incidence of all these complications has decreased.
Insulin allergy
1. Causes of allergic reactions to insulin.
(1) The patient is allergic.
(2) Allergy to disinfectants: such as iodophor, alcohol, etc.
(3) Allergy to the ingredients in insulin preparations: such as fish essence protein, etc.
(4) Allergy to animal insulin: the amino acid composition of animal insulin is different from that of human insulin, and the patient’s body will produce insulin-specific antibodies after the injection of animal insulin thus causing an allergic reaction. In addition, animal insulin is impure and contains more impurity proteins, which can produce IgE antibodies after being injected into human body, thus causing allergic reactions.
(5) Allergy to genetically recombinant human insulin: The structure of genetically recombinant human insulin is identical to that of endogenous insulin, and theoretically no allergic reaction will occur, but there are still reports of allergic reactions in the course of clinical use. It is currently believed that the mechanism is, on the one hand, the high concentration of insulin in commercial preparations can form a multimeric form, thus causing changes in its three-dimensional spatial configuration, resulting in antigenicity in vivo, and on the other hand, allergy to the excipients or impurity proteins in the drug.
(6) Allergy to insulin analogues: insulin analogues theoretically lead to enhanced antigenicity because of the change in the order or type of amino acids, but many insulin-allergic patients in clinical applications have their symptoms reduced or even relieved after changing to insulin analogues, and the mechanism may be that they enter the body in monomeric form and remain in the subcutaneous for a shorter period of time, thus leading to their weakened antigenicity.
2. Clinical manifestations and types of insulin allergic reactions.
Insulin allergic reactions include local reactions and systemic reactions, among which local reactions are more common. Insulin allergic reactions can occur both in the first time insulin users and in those who use insulin again. Local reactions usually occur within 2 weeks after treatment, with rash, burning sensation, itching, blistering and hard nodules at the insulin injection site. Systemic allergic reactions often occur in patients who have interrupted insulin therapy and then restarted it, or in patients who are using it for the first time. Clinical manifestations include facial and oral mucous membrane edema, generalized rash, urticaria, vomiting, abdominal pain, diarrhea, and in severe cases, there may be difficulty in breathing, asthma, decrease in blood pressure, and even shock and death. Both case 1 and case 2 showed local and systemic allergic reactions. Insulin allergic reaction can be divided into type I, type III and type IV. Type I allergic reaction is an IgE-mediated rapid allergic reaction. After insulin injection, specific IgE antibodies are produced, and IgE binds to mast cells or basophils. When the body is exposed to the antigen again, mast cells and basophils degranulate and release a large amount of inflammatory transmitters, causing type I allergic reactions. It is mainly a local allergic reaction that occurs immediately after insulin injection, with edema, erythema and itching at the injection site. These reactions are generally self-limiting and can resolve on their own; a few cases can be seen to develop into systemic allergic reactions with different manifestations. Type III insulin allergic reactions are characterized by local Arthus reactions, mainly insulin-insulin antibody complexes causing basophil degeneration, local histamine and other inflammatory substances release, involving complement binding, leukocyte chemotaxis and inflammatory reactions caused by the formation of antigen-antibody complexes. Type III insulin allergic reaction caused by human insulin is mainly manifested as soft, tender nodules under the skin at the injection site 4-8 h after insulin injection and lasts for 48 h. Type IV allergic reaction is rare and is a T cell-mediated delayed allergic reaction, which usually occurs 8-12 h after insulin injection and lasts for 4-7 days. Subcutaneous nodules usually occur at 24h or later, and pathological examination shows mononuclear cell infiltration.
3. Treatment of insulin allergic reaction.
(1) Discontinuation of insulin: milder allergic reactions local to the injection will resolve on their own after stopping insulin use.
(2) change oral hypoglycemic drugs: insulin is not used in large doses, and if the patient’s condition allows, consider stopping insulin and changing to oral hypoglycemic drugs to control blood sugar.
(3) Use of anti-allergy drugs: Patients who cannot stop insulin can add antihistamines, and most patients can have their symptoms relieved. A few scholars add glucocorticoids while using insulin, and also use prednisone 50-60mg/d, but most people do not advocate the use of it because of the characteristics of large side effects and easy relapse after stopping the drug.
(4) Change the type of insulin preparation: Patients with allergic reactions caused by using animal insulin can switch to genetically recombinant human insulin or human insulin analogues with higher purity; patients who are allergic to genetically recombinant human insulin can switch to insulin analogues. It has been reported that patients who are allergic to animal and recombinant human insulin tend to have no allergic reaction to lysergic insulin and can have good glycemic control without adverse reactions by gradually increasing to therapeutic doses starting from smaller doses. This may be related to the fact that lysergic insulin molecules are less likely to form polymorphs and are absorbed more rapidly than regular insulin, and Hiroaki et al. did not show any allergic reaction to the use of glargine insulin in a patient who was allergic to both animal and human insulins, and did not show any allergic reaction after using recombinant human insulin for a period of time.
(5) Desensitization therapy: The starting dose of insulin is 0.00001 U, gradually increase the dose 10 times to 1 U, and then increase the dose to 2, 4, 8, 12, 16 and 20 U. If local allergic reactions occur, the last dose is repeated until no allergic reaction occurs. If a systemic allergic reaction occurs, the final dose is reduced by half. During desensitization therapy, patients with type 2 diabetes can control their blood glucose by diet and oral hypoglycemic drugs; while patients with type 1 diabetes still need insulin therapy, either insulin preparations or control by insulin pump.
(6) Change of insulin injection route: insulin is continuously pumped in small doses using an insulin pump (CSII) and gradually increased to therapeutic doses for desensitization.
(7) Other: immunosuppressants such as cyclophosphamide and methotrexate can be used as an option; some people give type III insulin allergic reactions to be treated by plasma replacement. In case 1, the patient had an allergic reaction with human insulin (Novolin) and continued to use Novolin after insulin desensitization treatment, and no further insulin allergic reaction occurred. In case 2, after the allergic reaction to insulin, the patient switched to glycemic control by using glargine insulin (insulin analog) plus oral hypoglycemic drugs, and the allergic reaction did not occur again. This shows that once an allergic reaction to insulin occurs, we have to choose a treatment plan suitable for the patient according to the specific situation.
Fat atrophy
1. Mechanism of occurrence of fat atrophy.
Fat atrophy at the insulin injection site is mostly seen in type 1 diabetic patients and is caused by the immune reaction to low purity bovine or porcine insulin resulting in lipolysis. It has been reported that human insulin, like animal insulin, can lead to local allergic reaction and inflammatory reaction, which increases the concentration of circulating inflammatory transmitters, insulin-IgG complexes and complement components, resulting in necrosis of adipocytes and thus fat atrophy. Biopsies of adipose atrophy sites caused by various insulin preparations (mostly animal insulins) showed large deposits of immune complexes (IgM and C3 complement) in the peripheral vasculature. In addition, local macrophages were found to release TNF- and IL-6 as well as dedifferentiated adipocytes. It has been suggested that subcutaneous injection of various insulin preparations (including recombinant human insulin) may have triggered autoimmune mechanisms by some interaction with local molecular interactions, which caused the destruction of local adipose tissue and led to its atrophy. This may explain the allergic reaction of the patient in Case 3 after the use of menadione insulin and the subsequent fat atrophy at the injection site.
2. Treatment of fat atrophy at the insulin injection site.
(1) If the condition permits, stop insulin and choose oral hypoglycemic drugs to control blood glucose.
(2) Change the injection site frequently.
(3) If the patient is using animal insulin (mostly porcine insulin at present), due to the relatively high content of impurities, fat atrophy is prone to occur, so it can be replaced with human insulin (such as clinically used Novolin or Utrolin). Human insulin has high purity and few impurities, and the chance of fat atrophy is greatly reduced. If Novolin or Eugenol is used, human insulin analogues (Novolac or Eugenol) can be tried, which may make fat atrophy remit.
(4) It has been reported that CSII can effectively prevent and control subcutaneous fat atrophy.
(5) Some scholars injected insulin with betamethasone locally at the site of fat atrophy and found that subcutaneous fat atrophy can be completely relieved; local injection of dexamethasone can reverse the tissue changes at the site of fat atrophy.
Fat necrosis
1. Clinical manifestations and pathogenesis of fat necrosis.
Fat necrosis caused by insulin injection is generally manifested as single or multiple hard, non-encapsulated, mobile and painless nodules at the injection site. These nodules mostly occur after trauma and are more common in the lower extremities. The nodules have a tendency to recur after excision. Histologic examination reveals intraperitoneal fat cell necrosis, which may be combined with calcification and inflammatory infiltration. Fat necrosis can also be secondary to injury lipofuscinosis due to local ischemia. Diabetic patients presenting with microangiopathy and poor glycemic control are injected with local vascularization and result in fibrohyalinosis. This patient was a previous user of porcine insulin, which can lead to foreign body reactions due to impurity of porcine insulin. However, the foreign body can gradually dissolve over time and eventually leave a sac-like trace, so the nature of the foreign body cannot be determined under light microscopy.
2.Treatment of fat necrosis.
(1) Surgical excision: Larger nodules that appear in patients can be surgically excised.
(2) Change the injection site: change the injection site frequently to reduce repeated local irritation.
(3) Replaced recombinant human insulin: As porcine insulin is impure, it may cause foreign body reaction. This side effect can be avoided after replacing recombinant human insulin or human insulin analogues with higher purity.
Although both insulin allergic reaction and fat atrophy are uncommon, once they occur, they seriously affect the treatment of diabetes, so we must detect them in time and actively prevent them in the clinical process.