To the Editor:
A 40-year-old African American woman presented with type B insulin resistance (TBIR) secondary to systemic lupus erythematosus (SLE). The patient’s SLE manifestations included pancytopenia, discoid and malar rashes, Raynaud phenomenon, arthralgias, hypocomplementemia, positive antinuclear antibody (ANA), anti-Sm and anti-Sm/RNP antibodies, thyroid autoantibodies, and elevated inflammatory markers.
She was recently diagnosed with type 2 diabetes mellitus (glycated hemoglobin [HbA1c] 6.9%), Hashimoto thyroiditis, and SLE. She had a maternal family history of type 2 diabetes mellitus; her mother and sister had thyroid disease.
Three months later, she presented with an unintentional weight loss of 36 kg; polyuria; polydipsia; new and extensive acanthosis nigricans involving the face, neck, axilla, trunk, and mons pubis; elevated blood sugars; and an elevated SLE Disease Activity Index (SLEDAI) of 35. Select laboratory variables are shown in the Table.
Select laboratory tests on admission.
During her hospitalization, she had rapidly worsening nonketotic, hyperglycemia > 400 mg/100 mL, and increasing insulin requirement from 90 to 750 units daily without achieving euglycemia. TBIR, a condition of severe insulin resistance, was suspected, and testing for causative autoantibodies against the insulin receptor was positive (binding index 254; normal = 1).
When attempting to optimize glycemia during hospitalization, she became febrile; infectious evaluation revealed methicillin-susceptible Staphylococcus aureus) bacteremia. Despite appropriate treatment, she continued to have high-grade fevers. Evaluation for malignancy was unremarkable. Her mental status deteriorated, with fluctuations in alertness and catatonia concerning for neuropsychiatric SLE. Laboratory tests showed evolving macrophage activation syndrome (MAS) with increasing transaminases, decreasing platelets, and ferritin > 10,000 μg/L.
She was admitted to the intensive care unit (ICU) and given pulse methylprednisolone for neuropsychiatric SLE and MAS. Laboratory tests and mental status began to improve following pulsed dose corticosteroids, but her blood glucose was increasingly difficult to control. In close consultation with the ICU pharmacist, daily insulin requirements increased from 1000 units to as high as 26,000 units per day (Figure). Canagliflozin, which reduces renal glucose reabsorption, was added to control blood sugar independent of the insulin receptor. Intravenous (IV) immunoglobulin was administered to neutralize insulin receptor autoantibodies.1
Dosing of medications used to manage type B insulin resistance on each hospital day, daily administration of insulin illustrating the massive insulin requirement need particularly after pulse dose corticosteroids, and average blood glucose levels daily. IVIG: intravenous immunoglobulin.
Definitive induction therapy for TBIR with IV cyclophosphamide and rituximab was administered (Figure), in accordance with published TBIR treatment protocols.2,3 The patient’s blood glucose improved, and at the time of discharge she was taking 1000 units of insulin regular subcutaneously at breakfast and 500 units with lunch. Her cytopenias and complements gradually improved; SLEDAI at discharge was 3. At the time of discharge, the patient was still undergoing induction therapy. Unfortunately, she was lost to follow-up.
TBIR is a little-known complication of SLE, characterized by the presence of polyclonal antibodies to the insulin receptor. These antibodies behave as partial agonists at the insulin receptor, leading to receptor agonism and hypoglycemia when present at low titers, and receptor antagonism and hyperglycemia with severe insulin resistance when present at high titers.4-6 A systematic review of TBIR identified just over 100 cases in the medical literature.7 The most common underlying cause of TBIR is SLE, which accounts for approximately 60% of cases, but TBIR can occur secondary to other autoimmune diseases or as a paraneoplastic process.6-8 TBIR exhibits a female predominance, which reflects the female predominance of SLE.
A highly catabolic state is a characteristic clinical manifestation of TBIR, and patients generally have substantial, unintentional, weight loss. They also have the most severe insulin resistance of any diabetes subgroup.2,8,9 Patients may have extensive acanthosis nigricans, including in the periocular and perioral regions, which is a distinct manifestation of TBIR.6 Women of reproductive age with TBIR frequently have hyperandrogenism and polycystic ovaries; these features improve with treatment. Hyperandrogenism was absent in our patient.
Patients with TBIR typically have very high fasting serum insulin levels, elevated HbA1c, elevated adiponectin, low insulin-like growth factor I, negative insulin antibodies, and positive insulin receptor antibodies. Testing for antiinsulin receptor antibodies is not routinely available. Thus, the diagnosis of TBIR is made clinically in the setting of severe insulin resistance, and treatment may need to be initiated before confirmatory antibody testing results are available. Without treatment, mortality is as high as 50%.6
Treatment of TBIR requires a 2-fold approach, including high-dose insulin to reverse the hypercatabolic state, and antibody depletion therapy to eliminate or treat the underlying autoimmune disease.10 Numerous treatments have been tried with varying levels of efficacy in case reports and series. A 2018 study of 22 patients with TBIR found that combination immunodepletion using rituximab, cyclophosphamide, and corticosteroids was effective in achieving remission of TBIR; azathioprine was used for maintenance.2,3 This treatment approach was used as a framework for the treatment of our complex case.
This case of SLE-associated TBIR increases awareness of this disease in the rheumatologic community. A multidisciplinary approach, including rheumatology, endocrinology, and pharmacy, is extremely helpful.
Footnotes
CONTRIBUTIONS
SAO: writing - original draft, visualization, data curation; SW, ML: writing - review and editing; RJB: writing - review and editing, visualization, supervision.
FUNDING
This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Institutes of Health Clinical Center, within the National Institutes of Health (NIH). The contributions of the NIH author(s) are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.
COMPETING INTERESTS
The authors declare no conflicts of interests relevant to this article.
ETHICS AND PATIENT CONSENT
The study was approved by NIH IRB (76-DK-0006). The patient provided written informed consent.
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