title: Syndromic insulin resistance: models for the therapeutic basis of the metabolic syndrome and other targets of insulin resistance.
abstract: OBJECTIVE
  To investigate the link between insulin resistance and the metabolic syndrome how to develop treatment approaches.
  
  
  METHODS
  We present 3 cases of extreme syndromic insulin resistance: lipodystrophy, autoantibodies to the insulin receptor, and mutations in the insulin receptor gene, with accompanying discussion of pathophysiology and treatment.
  
  
  RESULTS
  In lipodystrophy, insulin resistance is a direct consequence of leptin deficiency, and thus leptin replacement reverses metabolic syndrome abnormalities, including diabetes and hypertriglyceridemia. The insulin "receptoropathies," including autoantibodies to the insulin receptor and insulin receptor gene mutations, are characterized by extreme insulin resistance and ovarian hyperandrogenism, without dyslipidemia or fatty liver disease. Autoantibodies to the insulin receptor can be treated using an immunosuppressive paradigm adapted from treatment of other autoimmune and neoplastic conditions. Leptin treatment has shown some success in treating hyperglycemia in patients with insulin receptor gene mutations. Treatment for this condition remains inadequate, and novel therapies that bypass insulin receptor signaling, such as enhancers of brown adipose tissue, are needed.
  
  
  CONCLUSIONS
  We present a clinical approach to the treatment of syndromic insulin resistance. The study of rare diseases that replicate the metabolic syndrome, with clear-cut pathophysiology, promotes understanding of novel physiology and development of targeted therapies that may be applicable to the broader population with obesity, insulin resistance, and diabetes.
authors.affiliation: Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. phillipg@intra.niddk.nih.gov
authors.forename: Phillip
authors.initials: P
authors.lastname: Gorden
authors.forename: Elika Safar
authors.initials: ES
authors.lastname: Zadeh
authors.forename: Elaine
authors.initials: E
authors.lastname: Cochran
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Brown
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D024821:Metabolic Syndrome / Q000378:metabolism / Q000503:physiopathology*; D055815:Young Adult