Abnormal Hyperinsulinemia Due To Receiving Exogenous Insulin:Case Report And Literature Review

Objective:We will explore the cases in which the patients with Type 2 diabetes have poor glucose control due to insulin antibody (IAb) receiving exogenous insulin, by analysing clinical characteristics, laboratory examinations and etiological basis of type 2 diabetes and insulin autoimmune syndrome, in order to improve the acknowledge of the therapies.Methods:In this case, three diagnosed cases was reported from the history of disease. we will explore the possible mechanism of this phenomenon in details from clinical manifestations and laboratory examinations. In the meantime, we reviewed the literature about hyperinsulinemic hypoglycemia by searching Pubmed、CNKI、CBM、 the database of Chinese scientific and technical journals since 1991.Results:Diabetes is complex metabolic disorder, characterized by clinical chronic (long-term) hyperglycemia, which is a result of insufficient insulin secretion or insulin resistance or insufficient insulin secretion and insulin resistanceat the same time. It is one of the highest incidence of chronic diseases.The main pathogenesis of type 2 diabetes is insulin resistance, and varying degrees of impaired insulin secretion may come along with or without the symptom.when pancreatic auto-antibodies are generally negative, the therapies can not dependent on insulin therapy because lifestyle plays an important role in regulating insulin level. In the therapeutic progress of diabetes, although the production of IAb has been significantly decreased due to the widespread use of recombinant human insulin and insulin analogue, few reports have indicated that IAb may still appear in type 2 diabetes receiving above insulins through subcutaneous injection, especially in Asian region. Circulating IAb induced by exogenous insulin might modify the pharmacokinetics and the bioavailability of insulin, resulting in insulin resistance, poor glucose control and other clinical features.Previous studies revealed that the IAb is usually classified into two types:low affinity with high capacity and high affinity with low capacity. The former type has often been found in patients diagnosed as insulin autoimmune syndrome (IAS) or some diseases similar to IAS induced by exogenous insulin.Insulin autoimmune syndrome (IAS), also known as autoimmune hypoglycemia (AIH), is a rare condition characterized by the combination of recurrent, severe spontaneous hypoglycemia, high concentration of total immunoreactive insulin(IRI) and the presence of autoantibodies to insulin in patients who have not received insulin injections.Since Hirata et al first described the disease, it is also called Hirata’s disease. These patients suffered from spontaneous immunological hypoglycemia because of their IAb characteristics. High capacity caused massive volumes of insulin binding to the insulin antibody, so a marked increase in insulin resistance is induced, triggering hyperglycemia. Low affinity led to massive volumes of insulin become dissociated, free insulin increased all at once, triggering hypoglycemia. However, different from IAS, both of our patients did not develop frequent hypoglycemia, we suggested that the IAb in our patients may be the latter type. Their high affinity resulted that it was hard for high amount of insulin to dissociate from the insulin-IAb complex, so our patients did not suffer from severe hypoglycemia.The mechanisms underlying IAb production with insulin analogue treatment were not fully understood. Previous studies showed cytokines play important roles in many immune disease. So we assessed the concentrations of various cytokines, related to IAb, in the serum of two patients. Our results found the concentrations of IFN-y decreased and the levels of IL-4, IL-10 increased gradually at follow-up period, which may elucidate the pathophysiologic process of this situation partly. Therefore, to apply this therapy into clinical applications, further more studies will be needed to clarify the relationship and mechanism between exogenous insulin and insulin antibody.Conclusion:Although high level of insulin and IAb resulted from insulin analogue are rare, clinicians should pay attention to this situation. Hence, when type 2 diabetic patients receiving long term insulin analogue with unexplainable poor glucose control, we should consider IAb production. Once IAb formation caused by exogenous insulin is confirmed, the patients should be advised to substitute insulin with oral antidiabetic agents.