Insulin Autoimmune Syndrome (Hirata Disease): A Comprehensive Review Fifty Years After Its First Description

Abstract

Insulin autoimmune syndrome (IAS), also named Hirata's disease, is a rare condition characterized by hypoglycemic episodes due to the presence of high titers of insulin autoantibodies (IAA). IAS is a form of immune-mediated hypoglycemia, which develops when a triggering factor (ie, a medication or a viral infection) acts on an underlying predisposing genetic background. IAS pathogenesis involves the formation of insulin-IAA complexes that induce glycemic alterations with a double-phase mechanism: IAA prevent insulin to bind its receptor in the postprandial phase, possibly resulting in mild hyperglycemia; thereafter, insulin is released from the complexes irrespective of blood glucose concentrations, thus inducing hypoglycemia. The diagnosis of IAS is challenging, requiring a careful workup aimed at excluding other causes of hyperinsulinemic hypoglycemia. The gold standard for the definitive diagnosis is the finding of IAA in a blood sample. Because IAS is frequently a self-remitting disease, its management mostly consists of supportive measures, such as dietary modifications, aimed at preventing the development of hypoglycemia. Pharmacological therapies may occasionally be necessary for patients presenting with severe manifestations of IAS. Available therapies may include drugs that reduce pancreatic insulin secretion (somatostatin analogues and diazoxide, for instance) and immunosuppressive agents (glucocorticoids, azathioprine and rituximab). The purpose of this review is to provide a comprehensive analysis of the disease, by describing the burden of knowledge that has been obtained in the 50 years following its first description, took in 1970, and by highlighting the points that are still unclear in its pathogenesis and management.

Keywords: Hirata; IAS; autoimmunity; hypoglycemia; insulin autoimmune syndrome.

Figure 1

The insulin autoimmune syndrome pathogenesis. Notes: Panel (A) schematic overview of the physiologic insulin secretion and action: following glucose intake, pancreatic beta-cells secrete insulin which enters into the bloodstream, getting to peripheral tissues when it exerts its physiological functions in order to maintain glucose homeostasis. Panel (B) schematic overview of the double-phase mechanism of the insulin autoimmune syndrome. Following glucose intake, pancreatic beta-cells secrete insulin which enters into the blood stream getting included in the insulin-IAA macro-complexes. In the early postprandial phase, inclusion intro macro-complexes prevents insulin to act on its receptors in peripheral tissues, thus inducing hyperglycemia (phase 1). Due to the relatively low affinity for insulin, IAA subsequently release insulin molecules irrespective of plasma glucose concentrations, thus inducing hypoglycemic episodes (phase 2). Below both panels is reported a schematic representation of glucose and insulin concentrations over time: the continuous line represents plasma glucose concentrations, dotted line represents total insulin, pointed line represents free unbound insulin.

Figure 2

Flowchart for the diagnosis of insulin autoimmune syndrome. Abbreviations: PEG, polyethylene glycol; IAA, insulin autoantibodies.