Literature
Clinical Pearls & Morning Reports
Published April 3, 2024
What causes type B insulin resistance syndrome?
Primary insulin-signaling defects are rare genetic or acquired disorders in which insulin signaling is directly impaired upstream, at the level, or downstream of the insulin receptor. Read the NEJM Case Records of the Massachusetts General Hospital here.
Clinical Pearls
Q: Is acanthosis nigricans seen in patients with insulin-signaling defects that occur upstream of the insulin receptor?
A: Primary insulin-signaling defects that occur upstream of the insulin receptor (prereceptor insulin-signaling defects) are caused by insulin antibodies that bind to circulating insulin. Insulin antibodies impair the ability of insulin to interact with its receptor, which leads to postprandial hyperglycemia. Fasting hypoglycemia may also occur owing to the gradual dissociation of insulin from its antibodies. Acanthosis nigricans does not typically develop in patients with insulin antibodies, since bound insulin does not cross-react with the insulin-like growth factor 1 receptor (such cross-reactivity can be associated with acanthosis nigricans, skin tags, and acromegaly-like features).
Q: What causes type B insulin resistance syndrome?
A: Primary insulin-signaling defects that occur at the level of the insulin receptor are caused by mutations in the receptor or by antibodies that target the receptor. Type B insulin resistance syndrome is a rare disorder characterized by the presence of antibodies to the insulin receptor. This disorder most commonly occurs in middle-aged Black women who have other autoimmune features or lymphoproliferative disorders.
Morning Report Questions
Q: How is type B insulin resistance syndrome treated?
A: The goal of treatment for type B insulin resistance syndrome is the complete remission of diabetes resulting from the elimination of the insulin-receptor antibody. Spontaneous remission can occur in some patients, but the time to remission may take many years. When left untreated, type B insulin resistance syndrome is associated with a mortality rate close to 50%. Owing to the rarity of this condition, data from randomized, controlled trials of immunosuppressive or antibody-depletion therapies for the treatment of type B insulin resistance syndrome are lacking. A variety of treatment approaches have been tested in small numbers of patients, including plasmapheresis and plasma exchange, intravenous immune globulin, and immunosuppressive agents (e.g., rituximab, glucocorticoids, azathioprine, cyclophosphamide, and mycophenolate mofetil).
Q: Describe the management of diabetes in patients being treated for type B insulin resistance syndrome.
A: The induction of remission of diabetes in patients with type B insulin resistance syndrome usually takes months; therefore, effective management of diabetes while awaiting remission is a critical component of care. Owing to the extreme nature of type B insulin resistance syndrome, the standard inpatient or outpatient targets for blood glucose control are not feasible. Instead, the goals of diabetes management are to reverse the catabolic state observed in most patients and to allow patients to be safely treated with immunosuppressive therapy, while reducing the risk of both diabetic ketoacidosis and hypoglycemia. The median dose of insulin used in a case study involving 22 patients with type B insulin resistance syndrome was 1775 units per day; doses as high as 18,000 units per day were reported. In such cases, concentrated insulin products, including human regular U-500 insulin, can be used to reduce the injection burden.