title: The early effect of sunitinib on insulin clearance in patients with metastatic renal cell carcinoma.
abstract: OBJECTIVE
  In patients with diabetes treated with sunitinib symptomatic hypoglycaemia has been reported. To explore the mechanism of this adverse effect we performed a prospective study to investigate the effect of sunitinib on insulin concentration, insulin clearance and insulin sensitivity.
  
  
  METHODS
  We studied the early effects of sunitinib on insulin sensitivity and insulin clearance with a hyperinsulinaemic euglycaemic clamp (insulin infusion rate 60 mU m−2 min−1; steady-state 90–120 min) in patients with renal cell carcinoma before and 1 week after the start of sunitinib 50 mg day−1. Insulin sensitivity index (SI) was defined as steady-state glucose disposal divided by the steady-state plasma insulin.
  
  
  RESULTS
  Ten patients (one with diabetes, treated with metformin) were included in the study protocol. Steady-state insulin concentrations during the clamp increased after 1 week of sunitinib (from 128.9 ± 9.0 mU l−1 to 170.8 ± 12.8 mU l−1, P < 0.05; 95% CI on difference − 64.3, −19.6). The calculated insulin sensitivity index decreased from 0.22 ± 0.04 before to 0.18 ± 0.02 μmol kg−1 min−1 per mU l−1 insulin (P < 0.05; 95% CI on difference 0.07, 0.08). As the insulin infusion rate was similar for both clamps, the increased steady-state insulin concentration indicates reduced insulin clearance.
  
  
  CONCLUSIONS
  Sunitinib affects insulin clearance which could possibly lead to overexposure to insulin in patients using insulin or insulin-secretion stimulating agents.
authors.affiliation: Department of Pharmacology-Toxicology, Radboudumc, Nijmegen.|Department of Medical Oncology, Radboudumc, Nijmegen.
authors.forename: Anna Maria J
authors.initials: AM
authors.lastname: Thijs
authors.affiliation: Department of Internal Medicine, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Cees J
authors.initials: CJ
authors.lastname: Tack
authors.affiliation: Department of Medical Oncology, Radboudumc, Nijmegen.|The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Winette T A
authors.initials: WT
authors.lastname: van der Graaf
authors.affiliation: Department of Pharmacology-Toxicology, Radboudumc, Nijmegen.
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Rongen
authors.affiliation: Department of Medical Oncology, Radboudumc, Nijmegen.
authors.forename: Carla M L
authors.initials: CM
authors.lastname: van Herpen
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D001786:Blood Glucose / Q000032:analysis; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007003:Hypoglycemia / Q000097:blood / Q000139:chemically induced*; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011446:Prospective Studies; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D000077210:Sunitinib; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D001786:Blood Glucose; D007211:Indoles; D007328:Insulin; D011758:Pyrroles; D000077210:Sunitinib
keywords: diabetes; hypoglycaemia; insulin; renal cell carcinoma; sunitinib; tyrosine kinase inhibitor