With severe insulin resistance and hyperglycemia, but some manifest hypoglycemia following a period of hyperglycemia or hypoglycemiaĪlone. Type B insulin resistance is a rare syndrome caused by autoantibodies to the insulin receptor. When the specific ligand binds to the extracellular domain, the β subunit kinase is activated, and consequently, phosphorylates itself (autophosphorylation) as well as intracellular components (Rees-Jones and Taylor, 1985 White et al., 1985 Bernier et al., 1987). The α subunit of Mr = ~125,000 is extracellular and responsible for ligand binding, whereas the β subunit of Mr = ~90,000 is a transmembrane protein carrying a tyrosine-specific protein kinase in its cytoplasmic domain. The receptors for insulin and IGF-I consist of α and β subunits, linked in a β-α-α-β form by disulfide bonds. Recent progress made in purification and subsequent cloning of both receptors revealed ~60% identity in their overall amino acid sequence (Ullrich et al., 1985 Ebina et ai., 1985 Ullrich et ai., 1986). In the case of insulin and IGF-I, the ligands not only share amino acid sequence homology (Rinderknecht and Humbel, 1978 Blundell et ai., 1978), but also the receptors are structurally and functionally similar (Jacobs et ai., 1983 Rechler and Nissley, 1985 Fujita-Yamaguchi et al., 1986). The receptor specifically binds its ligand, which approaches the cell from the outside, transduces the signal to the inside, and, consequently initiates biological programs specific to the receptor-ligand complex. Peptide hormone/growth factor receptors are membrane glycoproteins. There is a high rate of mortality even in patients who entered remission, and a switch from hyperglycemia to hypoglycemia is an indicator of poor prognosis. Immunotherapy did not have a significant impact on duration of diabetes. About one-third of patients remit spontaneously. Type B insulin resistance is a heterogeneous metabolic syndrome seen predominantly in female African-American patients with a high association with SLE.

Three patients who had presented with hyperglycemia and then developed hypoglycemia died from complications of hypoglycemia. Eight of the 13 deaths occurred in patients who went into remission. Another striking feature was the high rate of mortality: 13 of 24 patients (54%) died at 56 ± 12 years. None of the agents appeared more likely to induce remission. The remaining 6 patients received similar immunotherapy protocols, but did not go into remission despite 21-228 months (mean, 100 mo) of follow-up.

After 6-54 months of diabetes, 6 of these patients remitted within 6 weeks of immunotherapy. Twelve remaining patients received various immunosuppressive regimens (steroids, cyclophosphamide, and cyclosporine). The autoantibody disappeared spontaneously in 7 of 18 patients within 11-48 months (mean, 30 mo). Patients presenting with hyperglycemia received high doses of insulin for therapy (mean dose, 5,100 IU/day). After a prolonged period of hyperglycemia (3-21 mo), spontaneous hypoglycemia ensued in 3 of the patients. Long-term follow-up information is available for 18 of the 21 patients presenting with hyperglycemia. The remaining 21 patients (80%) presented with hyperglycemia and major weight loss (up to 120 lb within 5 mo). Three of 24 patients presented with spontaneous hypoglycemia. Thirteen of 24 patients had proteinuria, most commonly associated with lupus nephritis (n = 7). Systemic lupus erythematosus (SLE) (n = 11) was the most common underlying syndrome. All but 1 patient displayed nonspecific 'autoimmune' features. Acanthosis nigricans (+/-:21/3) and hyperandrogenism in females (7/20 patients) were common. Twenty-one patients (88%) were African American. We evaluated 24 patients (M/F: 4/20 age of presentation: 10-68 yr) with this disease between January 1973 and December 2000. we studied the natural history of the disease caused by autoantibodies to the insulin receptor. Autoantibodies to the cell surface receptors represent an important mechanism of endocrine disease.

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