title: Novel mutation in insulin receptor gene identified after muscle biopsy in a Niuean woman with severe insulin resistance.
abstract: BACKGROUND
  Severe, early-onset insulin resistance in the absence of obesity, hepatic steatosis and dyslipidaemia is frequently attributable to a genetic defect affecting the insulin receptor. We describe a patient with severe insulin resistance in whom insulin receptor mutation analysis was mistakenly recorded as normal. Western blot analysis of skeletal muscle showed reduced insulin receptor protein and led to re-evaluation of the insulin receptor and the discovery of a novel mutation.
  
  
  METHODS
  A Niuean women, first evaluated at age 6 years for severe acanthosis nigricans, hirsutism, poor growth and cognitive impairment, had extremely elevated fasting insulin levels of 10740 IU/l (fasting reference range 4-24 IU/l) and a normal glucose concentration (4.9 mmol/l). Diabetes was diagnosed at age 9 years and metformin treatment introduced. By age 14 years, she developed refractory hyperglycaemia despite metformin, rosiglitazone and 240 IU insulin daily. Insulin receptor genetic analysis was documented as normal. At age 23 years, with a blood glucose concentration of 37 mmol/l and an HbA1c concentration of 116 mmol/mol, U500 insulin 2000 IU/day was required for glycaemic control. She developed severe proliferative diabetic retinopathy with neovascular glaucoma leading to blindness. There was no renal dysfunction, dyslipidaemia or hepatic steatosis. A muscle biopsy was performed to evaluate the insulin signalling pathway and showed reduced insulin receptor protein. Sequencing of the insulin receptor showed a homozygous p.Val1010Leu missense mutation.
  
  
  CONCLUSIONS
  This patient illustrates the use of muscle biopsy in the evaluation of a patient with unexplained severe insulin resistance. This approach may usefully be applied to other cases of severe insulin resistance, where genetic testing for known mutations in the insulin signalling pathway has been negative.
authors: Department of Medicine, University of Auckland, Auckland, New Zealand.
authors: R
authors: R
authors: Murphy
authors: Department of Pharmacology, University of New South Wales, Sydney, Australia.
authors: G
authors: G
authors: Smith
authors: University of Cambridge Metabolic Research Laboratories, University of Cambridge, Cambridge, UK.
authors: I
authors: I
authors: Isaac
authors: Department of Neurology, Auckland City Hospital, Auckland, New Zealand.
authors: D
authors: D
authors: Hutchinson
authors: University of Cambridge Metabolic Research Laboratories, University of Cambridge, Cambridge, UK.
authors: R K
authors: RK
authors: Semple
mesh_terms: D000052:Acanthosis Nigricans / Q000150:complications / Q000235:genetics; D019943:Amino Acid Substitution; D015703:Antigens, CD / Q000235:genetics*; D001706:Biopsy; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics; D005260:Female; D006628:Hirsutism / Q000150:complications / Q000235:genetics; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics*; D009132:Muscles / Q000473:pathology*; D020125:Mutation, Missense; D009520:New Zealand / Q000208:ethnology; D011972:Receptor, Insulin / Q000235:genetics*; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D015703:Antigens, CD; C435941:INSR protein, human; D011972:Receptor, Insulin