Complications of Insulin Treatment

The most important complication of insulin therapy is hypoglycemia, which is discussed in chapter VIII (Clinical Emergencies in Diabetes. 2: Hy- poglycemia). The other complications are listed below.

Insulin Edema In poorly controlled diabetic patients, insulin therapy can result in a

marked accumulation of fluid, with localized (periorbital, pretibial or presa- cral) or generalized edema. The causes are probably multiple (table 4). A dietary restriction of salt and a temporary use of diuretics can be recommended. Edema will most often subside within 3–5 days.

Table 4. Causes of insulin edema ADH increase (ascribed to hypovolemia resulting from osmotic diuresis)

Cessation of natriuretic effect of hyperglucagonemia Increased plasma volume and transcapillary escape of albumin (with reduced

colloid osmotic pressure) Excessive infusion of isotonic saline Na retention (induced by excess of insulin infused or injected)

Insulin Lipoatrophy It was a common complication prior to the introduction of monocompo-

nent insulins, consisting of a loss of fat at the site of insulin injection or, occasionally, at distant sites. In 25% of lipoatrophic patients, local allergy coexists. Lipoatrophy is frequently observed in young children (50%) or in young women (20%), compared to male adults (5%). Lipoatrophy, moreover, may occur after repeated injections of other substances such as narcotics or GH preparations. Thus, atrophy might be the result of a repeated mechanical trauma, even if insulin impurities can stimulate immune factors or immune complex formation which lead to local release of lipolytic substances. These reactions occur without overt inflammation and were considered also second- ary to insulin degradation or aggregation products. Indeed, in biopsy specimens of lipoatrophic areas, antigen-antibody reactions were not seen. Local reactions to protamine (a constituent of insulin preparations) and to silicone oil (the lubrificant in disposable syringes) may play a role in some patients. Switching to purified or human insulins and rotating the site of injections result in improvement of skin alterations in 97% of lipoatrophic patients. Very few cases were reported with recombinant human insulins, and the reason why it nent insulins, consisting of a loss of fat at the site of insulin injection or, occasionally, at distant sites. In 25% of lipoatrophic patients, local allergy coexists. Lipoatrophy is frequently observed in young children (50%) or in young women (20%), compared to male adults (5%). Lipoatrophy, moreover, may occur after repeated injections of other substances such as narcotics or GH preparations. Thus, atrophy might be the result of a repeated mechanical trauma, even if insulin impurities can stimulate immune factors or immune complex formation which lead to local release of lipolytic substances. These reactions occur without overt inflammation and were considered also second- ary to insulin degradation or aggregation products. Indeed, in biopsy specimens of lipoatrophic areas, antigen-antibody reactions were not seen. Local reactions to protamine (a constituent of insulin preparations) and to silicone oil (the lubrificant in disposable syringes) may play a role in some patients. Switching to purified or human insulins and rotating the site of injections result in improvement of skin alterations in 97% of lipoatrophic patients. Very few cases were reported with recombinant human insulins, and the reason why it

lipogenic effect of insulin). Addition of dexamethasone to the insulin in the syringe (4 lg/U, total daily dose not exceeding 0.75 mg) has also been sug- gested. In a recent case of severe well-circumscribed lipoatrophy, good results

were obtained by treating the area with a fatty acid mixture while the patient was instructed to avoid this area for insulin injection.

Insulin Lipohypertrophy It consists of visible or palpable increase of localized subcutaneous fat

(most prevailingly in the anterior or lateral part of thighs) at the site of insulin injection, sometimes coexisting with lipoatrophy. Repeated and prolonged use of the same site for insulin injection is a main determinant in the development of lipohypertrophy. Often the affected patients report that injection into lipohy- pertrophic areas is less painful, perhaps because the subcutaneous tissue tends to be fibrous. Lipohypertrophy is due to a possible growth factor effect of insulin on cellular elements of subcutaneous tissue, and may alter the absorp- tion rate of insulin, thus possibly affecting metabolic control. Prevalence rates of lipohypertrophy vary between 20–45% in type 1 and 3–6% in type 2 diabetic patients. Independent risk factors which contribute to the presence of lipohypertrophy are female sex, type 1 diabetes, higher BMI and missing rotation of insulin injections. The most severe cases of insulin lipohypertrophy can be treated with liposuction, but prevention is important, primarily by systemat- ized rotation of injection sites within the recommended areas. An important role is played by educational interventions to establish an organized rotation system for insulin injection sites, to self-recognize lipohypertrophy and to normalize the high BMI.

Syndrome of Immunologic Insulin Resistance All patients who receive insulin develop circulating antibodies, whose

production can be influenced by several factors (table 5). Patients never treated with exogenous insulin may have circulating insulin antibodies, probably in- volved in the autoimmune reactions of type 1 diabetes. The high level of insulin antibodies may function as a reservoir from which insulin may be released unpredictably (thus inducing delayed hypoglycemia), or may bind insulin (thus causing hyperglycemia), or may form immune complexes (thus sequestering insulin in the reticuloendothelial system or stimulating procoagulant activity and favoring diabetic complications). In diabetic patients, this syndrome may result in an excessive insulin requirement (100–200 U/day in adults and up to

2.5 U/kg in children). In the most severe cases, steroids even at high doses for 3–4 weeks should be used. It is noteworthy that the immunogenicity of insulin

Table 5. Factors influencing the formation of insulin antibodies Insulin species (human insulin is less immunogenic than animal insulins)

Insulin purity (monocomponent insulins are less immunogenic) Insulin pharmaceutical form (regular insulin is less immunogenic than modified insulins) Pattern of insulin treatment (episodic therapy and CSII may increase insulin immunogenicity) Genetic factors (HLA-A2-B44 and HLA-B44-DR7 predispose to immune complications of

insulin therapy) Residual insulin secretion (when present, it reduces immune response to insulin)

lispro has been found to be similar to that of human insulin in both type 1 and type 2 diabetic patients.

Insulin Allergy It includes different forms: (a) Local allergy comprises immediate or biphasic or delayed reactions and

consists of erythematous and pruritic indurated lesions or more severe reactions in subcutaneous areas injected with insulin preparations. Protamine or zinc have been implicated. These reactions are IgE-dependent and may occur with conven- tional insulin treatment or CSII in subjects with intermittent insulin treatment or with allergy to other drugs (such as penicillin) or with obesity. The affected patients will improve within 30–60 days continuing the use of insulin (probably because of a spontaneous desensitization), whereas in the most severe cases local steroids in low doses or oral antihistaminics may be considered.

(b) Generalized allergy ranges from a simple urticaria to more severe reactions such as anaphylaxis with angioedema, bronchospasm, pharyngeal edema and collapse. These generalized reactions are due to the interaction of insulin (acting as an antigen) with specific IgE bound to mast cells or blood basophils and are very uncommon (=0.05%). No deaths for insulin allergy are reported. Human insulins are efficacious in the majority of allergic patients for the treatment of this systemic allergy, while in the remainder desensitization is successful (about half of patients who cannot be desensitized are overweight). Immunologic insulin resistance may coexist with or following insulin allergy. Insulin allergy is different from stress-induced urticaria, in which the central nervous system is important in the generation of immune response.

Complications of Insulin Treatment