Premixed human insulin and its analogues, which are widely used in clinical practice, can mimic the physiological insulin secretion pattern, effectively control blood glucose, reduce the occurrence and development of complications, and improve the quality of life of patients. However, some rare adverse reactions, such as allergic reactions, fat atrophy and fat necrosis, may occur with all existing insulin dosage forms, including premixed human insulin and its analogues. The clinical manifestations and management strategies of rare adverse reactions of premixed human insulin and its analogues are discussed from several cases.
I. Medical history information
Case 1: Patient, female, 64 years old, “type 2 diabetes” history for 15 years, has been taking oral hypoglycemic therapy (specific unknown), poor glycemic control. After being discharged from the hospital, the insulin dosage was adjusted by the community hospital. Six months later, a red rash appeared on both lower extremities, which gradually extended to the trunk and neck, and was accompanied by itching, bleeding and fusing into crusts after scratching. In the community hospital, paracetamol and cimetidine were given as anti-allergic treatment for “skin eczema”, and the symptoms were slightly relieved. However, the above symptoms recurred and continued to worsen, and the rash gradually increased, so he was admitted to our hospital for further treatment. He was diagnosed as “drug rash” by dermatological consultation, stopped using Novalax 30, gave oral Novalax and metformin to control blood sugar, and added glucocorticoid. Blood glucose, glucocorticoid for five days, vitamin C, cimetidine for two weeks. Two weeks later, the patient’s rash subsided. After discharge, the patient was followed up for one year and had no recurrence of rash.
Case 2: The patient, female, 75 years old, had a history of “type 2 diabetes” for 20 years, and was controlled by diet and exercise, while taking Glucophage 30 mg three times a day without monitoring blood glucose. During the course of the disease, she was treated intermittently with insulin intravenously due to high blood glucose and no adverse reaction occurred. One day ago, he was admitted to our emergency clinic with a random blood sugar of 22 mmol/L and urinary ketone bodies (-). After being given 12 U of insulin intravenously, he developed a generalized itchy, windbag-like rash and swollen lips and mouth. During the course of the disease, the patient had coldness and numbness in the lower extremities, and alternating diarrhea and constipation. He had a previous history of hypertension and coronary heart disease. The patient complained that he had developed pruritus and wind masses one year ago when he was on intravenous insulin 8U, which resolved after stopping the drug. There was a history of alcohol allergy. On examination: Bp 160/100 mmHg, BMI 25.3 kg/m2, homogeneous obesity. FBG 13.7 mmol/L, PBG 16 mmol/L, HbA1c 11.7%. After admission, he was switched to subcutaneous injection of Eugenol R and Novolin R 4 U. Both of them showed edema, erythema, generalized skin itching and wind mass at the injection site about 1 h after injection, and the symptoms could be relieved after paracetamol treatment. The symptoms were relieved after paracetamol treatment, and it was considered as “insulin allergy”. Firstly, oral hypoglycemic drugs were changed, but the glycemic control was not good, so insulin desensitization treatment was performed and antihistamine was added. Dilute Novolin R, starting from 0.001 U, and double the dose every 30 min, and extend the observation time accordingly when the dose is higher, until 4 U. The patient had no adverse reaction. Blood glucose monitoring, according to the blood glucose level gradually to 12-8-10U Novolin R subcutaneous injection 30 min before three meals, and then due to high FBG, added to Lidl (glargine insulin) 6U subcutaneous injection at bedtime, no further skin pruritus and rash.
Case 3: The patient, female, 52 years old, with a history of “type 2 diabetes” for 2 years, was treated with Novalax 30 subcutaneously before breakfast and dinner, with good glycemic control. 15 months ago, the patient found a red rash with itching on her forearm or abdominal injection site. The rash persisted when the disinfectant was changed and lasted for 2-3 h and then subsided on its own. Subsequently, skin depressions of various sizes, 1-4 cm in diameter, without erythema or rupture, with unclear borders and no nodules, were found at the forearm and abdominal insulin injection sites, and the skin temperature was normal, and the patient was admitted to the hospital for further consultation. During the course of the disease, the patient had no numbness in the extremities, no limb movement disorder, and the dorsalis pedis artery could be pulsed. Examination: BP 160/90 mmHg, BMI 24.5 kg/m2, positive insulin antibody (IAA) during hospitalization. The insulin was discontinued and the treatment was changed to oral Novocainone. The blood glucose control was basically normal, with FBG around 5.7 mmol/L and PBG around 6.9 mmol/L. One year follow-up, blood glucose control is still okay, and his skin depression area also basically restored.
Case 4: The patient, male, 33 years old, had a history of “type 1 diabetes mellitus” for 20 years. He started treatment with porcine insulin and switched to genetically recombinant human insulin after 5 years. Due to poor glycemic control, the patient had retinopathy and nephropathy as complications. He is now treated with rapid-acting and intermediate-acting insulins for glucose-lowering (exact dose unknown), in addition to oral perindopril, aspirin and amlodipine. Recently, painless nodules were found on both sides of his abdomen at the insulin injection site. He had a history of obesity, hypertension and hyperlipidemia, and no history of trauma. The patient complained that he had been injecting insulin subcutaneously in the abdomen with the correct injection method and frequently changed the injection needles. Physical examination revealed two large, pale blue, relatively fixed nodules on either side of the midline of the abdomen. Pathology of one of the nodules was excised and showed fat necrosis, fibrous hyaline changes, and foreign body reaction. No fibrous envelope was seen on pathology, and the nature of the foreign body could not be determined by light microscopy. To avoid the reappearance of nodules, it was recommended to change the insulin injection site frequently.
II. Discussion
Insulin allergy, fat atrophy and fat necrosis at the injection site are relatively rare complications of insulin therapy. With the purification of insulin and the emergence of recombinant human insulin and human insulin analogues, the incidence of all these complications has decreased.
1. insulin allergy The causes of insulin allergic reactions.
(1) The patient is allergic.
(2) Allergy to disinfectants: such as iodophor, alcohol, etc.
(3) Allergy to the components 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 and thus cause allergic reactions.
(5) Allergy to genetically recombinant human insulin: Genetically recombinant human insulin has exactly the same structure as 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 conformation, resulting in antigenicity in vivo, and on the other hand, allergy to excipients or impurity proteins in the drug.
(6) Allergy to insulin analogues: insulin analogues theoretically lead to their 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, the mechanism may be that they enter the body in monomeric form and remain under the skin for a shorter period of time, thus leading to their weakened antigenicity.
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 people who use insulin for the first time and in people 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.
Treatment of insulin allergic reactions.
(1) Discontinuation of insulin: milder allergic reactions localized to the injection will resolve on their own after discontinuation of insulin.
(2) Changing oral hypoglycemic drugs: insulin is not used in large doses, and if the patient’s condition allows, stopping insulin and changing oral hypoglycemic drugs to control blood sugar can be considered.
(3) Use of anti-allergic 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 50-60 mg/d [9], but most do not advocate using them because of the side effects and the ease of recurrence after stopping the drug.
(4) Change the type of insulin preparation: patients with allergic reactions caused by using animal insulin can be switched to genetically recombinant human insulin or human insulin analogues with higher purity; patients allergic to genetically recombinant human insulin can be switched 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 multimers and are absorbed more rapidly than regular insulin [8,10]. Hiroaki et al. showed no allergic reactions to glargine insulin in a patient who was allergic to both animal and human insulins, and no further allergic reactions occurred after switching to recombinant human insulin after a period of use, the exact mechanism of which is unknown.
(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 a local allergic reaction occurs, 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, type 2 diabetic patients can control their blood glucose by diet and oral hypoglycemic drugs; while type 1 diabetic patients 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 to desensitize.
(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 analogue) 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.
2.Fat atrophy
(1) The mechanism of fat atrophy: fat atrophy at the insulin injection site is mostly seen in patients with type 1 diabetes, which is caused by the immune reaction to low-purity bovine or porcine insulin resulting in fat lysis. 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 administration 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.
②Change the injection site frequently.
③If 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, and can be replaced with human insulin (such as clinically used Novolin or Eugenol). 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.
3.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, painless nodules that can move 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 capsule-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 present in patients can be surgically excised.
(2) Replacement of injection site: The injection site is frequently changed to reduce repeated local irritation.
③Replaced recombinant human insulin: Since 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.